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PubMed2003

Neurochemical mechanisms induced by high frequency stimulation of the subthalamic nucleus: increase of extracellular striatal glutamate and GABA in normal and hemiparkinsonian rats.

High frequency stimulation (HFS) (130 Hz) of the subthalamic nucleus (STN) provides beneficial effects in patients suffering from severe parkinsonism, but the mechanisms underlying these clinical results remain to be clarified. To date, very little is known concerning the effects of STN-HFS on neurochemical transmission in the different basal ganglia nuclei and in particular the striatum. This study examines the effects of STN-HFS in intact and hemiparkinsonian rats on extracellular striatal glutamate (Glu) and GABA levels by means of intracerebral microdialysis. Unilateral STN-HFS was found to induce a significant bilateral increase of striatal Glu and GABA both in intact and in dopamine-lesioned animals. In intact rats, these increases were reversed by local administration of the D1 antagonist SCH 23390, but were potentiated by the D2 antagonist sulpiride. Potentiation was also observed after local administration of both D1 and D2 antagonists whose amplitude was similar to that measured in hemiparkinsonian rats. These data furnish the first evidence that STN-HFS influences striatal amino-acid transmission and that this influence is modulated by dopamine. They provide evidence that the effects of STN-HFS are not only restricted to the direct STN targets, but also involve adaptive changes within other structures of the basal ganglia circuitry.

Animals↗

PubMed2000

A Kv3-like persistent, outwardly rectifying, Cs+-permeable, K+ current in rat subthalamic nucleus neurones.

A persistent outward K+ current (IPO), activated by depolarization from resting potential, has been identified and characterized in rat subthalamic nucleus (SThN) neurones using whole-cell voltage-clamp recording in brain slices. IPO both rapidly activated (tau = 8 ms at +5 mV) and deactivated (tau = 2 ms at -68 mV), while showing little inactivation. Tail current reversal potentials varied with extracellular K+ concentration in a Nernstian manner. Intracellular Cs+ did not alter either IPO amplitude or the voltage dependence of activation, but blocked transient (A-like) outward currents activated by depolarization. When extracellular K+ was replaced with Cs+, IPO tail current reversal potentials were dependent upon the extracellular Cs+ concentration, indicating an ability to conduct Cs+, as well as K+. IPO was blocked by Ba2+ (1 mM), 4-aminopyridine (1 mM) and tetraethylammonium (TEA; 20 mM), with an IC50 for TEA of 0.39 mM. The IPO conductance appeared maximal (38 nS) at around +27 mV, half-maximal at -13 mV, with the threshold for activation at around -38 mV. TEA (1 mM) blocked the action potential after-hyperpolarization and permitted accommodation of action potential firing at frequencies greater than around 200 Hz. We conclude that IPO, which shares many characteristics of currents attributable to Kv3.1 K+ channels, enables high-frequency spike trains in SThN neurones.

4-Aminopyridine↗

PubMed2005

Movement-related changes in oscillatory activity in the human subthalamic nucleus: ipsilateral vs. contralateral movements.

A voluntary movement is accompanied by a series of changes in neuronal oscillatory activity in the subthalamic nucleus (STN). These changes can be recorded through electrodes implanted for deep brain stimulation to treat Parkinson's disease in the time interval between the surgery and the internalization of the connections to the batteries. Both baseline activity and movement-related changes are different in the 'on' and 'off' medication motor states. In the 'off' state a low frequency activity in the alpha-beta range (8-25 Hz) that dominates the spectrum is interrupted during the movement, while in the 'on' state baseline frequencies are higher and a peri-movement gamma increase (70-80 Hz) is usually observed. Similar changes have been described with electrocorticographic recordings over the primary motor cortex but the gamma increase was only present during contralateral movements. We compared ipsi- and contralateral movement-related changes in STN activity, using a time-frequency analysis of the recordings obtained simultaneously in both STN and the scalp (electroencephalography) during right and left hand movements. The movement-related changes observed in the STN in the 'on' and the 'off' states were similar to those described previously in terms of predominant frequency bands, but we found bilateral changes in the STN during movements of either hand. A contralateral earlier start of the beta STN changes was mostly observed when the moving hand corresponded to the less-affected side, irrespective of hand dominance. These results suggest that movement-related activity in the STN has, by and large, a bilateral representation and probably reflects cortical input.

Aged↗

PubMed2004

Turning behaviour induced by stimulation of the 5-HT receptors in the subthalamic nucleus.

The basal ganglia, which receive a rich serotonergic innervation, have been implicated in hyperkinetic and hypokinetic disorders. Moreover, a decrease in subthalamic nucleus (STN) activity has been associated with motor hyperactivity. To address the role of subthalamic serotonergic innervation in its motor function, turning behaviour was studied in rats with stimulation of the subthalamic serotonin (5-HT) receptors by intracerebral microinjections. The intrasubthalamic administration of 5-HT induced dose-dependent contralateral turning behaviour, with a maximal effect at a dose of 2.5 microg in 0.2 microL. Similar results were observed with microinjections of other 5-HT receptor agonists: quipazine (a 5-HT2B/C/3 agonist), MK-212 (a 5-HT2B/C agonist) and m-chlorophenylbiguanidine (a 5-HT3 agonist), while microinjections of 5-HT into the zona incerta or in the previously lesioned STN were ineffective. The effect of 5-HT was blocked by coadministration of the antagonist mianserin. Stimulation of subthalamic 5-HT receptors in animals bearing a lesion of the nigrostriatal pathway did not modify the motor response, which indicates that the dopamine innervation of the nucleus is not involved in this effect. Kainic acid lesion of the substantia nigra pars reticulata (SNr) suppressed the contralateral rotations elicited by stimulation of 5-HT2B/C/3 subthalamic receptors. This suggests a role of the subthalamic-nigral pathway in the turning activity. Furthermore, the partial blockade of glutamatergic receptors in the SNr by the antagonist DNQX increased the contralateral circling elicited by stimulation of 5-HT receptors in the STN. We concluded that the activation of the 5-HT2B/C and 5-HT3 subthalamic receptors elicited contralateral turning behaviour, probably via the subthalamic-nigral pathway.

Animals↗

PubMed2003

Bilateral subthalamic nucleus deep brain stimulation for advanced PD: correlation of intraoperative MER and postoperative MRI with neuropathological findings.

This postmortem study correlated intraoperative subthalamic nucleus (STN) deep brain stimulation (DBS) placement and postoperative magnetic resonance imaging (MRI) with autopsy findings in a patient who died suddenly 4 days postoperatively from a pulmonary embolism. The study demonstrates that (1) MRI stereotactic localization combined with microelectrode recording (MER) is an accurate way to target STN; (2) multiple MER tracts do not cause significant injury to the brain; and (3) postoperative MRI accurately demonstrates location of the DBS electrodes.

Electric Stimulation Therapy↗

PubMed2003

Bilateral subthalamic nucleus stimulation for the treatment of Parkinson's disease: results of six patients.

In this study, researchers evaluated the effect of bilateral subthalamic nucleus stimulation on various measures of Parkinson's disease. Assessments were completed before and after surgery in a double-blind fashion under the following six conditions: (a) on medication, (b) off medication, (c) on medication/on stimulation, (d) on medication/off stimulation, (e) off medication/on stimulation, and (f) off medication/off stimulation. On average, improvement was noted in all areas including the Unified Parkinson's Disease Rating Scale, Schwab and England Activities of Daily Living Scale, Modified Hoehn and Yahr Staging, and timed tests: In addition, dyskinesia duration and dyskinesia disability were reduced.

Activities of Daily Living↗

PubMed2006

Stereotactic surgery for subthalamic nucleus stimulation under general anesthesia: a retrospective evaluation of Japanese patients with Parkinson's disease.

We compared retrospectively the outcome of bilateral subthalamic nucleus (STN) stimulation in 15 patients with Parkinson's disease who underwent the procedure under general anesthesia (GA) with that achieved in 10 patients under local anesthesia (LA). At 3 months postoperatively, all cardinal parkinsonian motor symptoms, evaluated on Unified Parkinson's Disease Rating Scale were significantly improved compared to preoperative baselines in both groups. The administration of GA did not adversely affect postoperative improvements in motor and daily activity scores, except for off-medication bradykinesia. Our results suggest that GA compares favorably with LA in surgical procedure for bilateral STN stimulation.

Aged↗

PubMed2006

Chronic stimulation of the subthalamic nucleus increases daily on-time without dyskinesia in advanced Parkinson's disease.

We assessed the efficacy of chronic stimulation of the subthalamic nucleus (STN-DBS) in 20 patients with Parkinson's disease (PD) by means of clinical assessments and patient diaries 12 months after surgery. STN-DBS reduced the UPDRS part III off-medication score by 33%, and successively improved complete daily on-time without dyskinesia at 12 months significantly. In conclusion, our study demonstrates the efficacy of chronic STN-DBS on motor features in a selected population of advanced PD patients. In addition to clinical assessments, patients' diaries serve as an essential tool to evaluate the functional motor status after STN-DBS.

Aged↗

PubMed2003

Subthalamic nucleus stimulation for Parkinson's disease preferentially improves akinesia of proximal arm movements compared to finger movements.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) reduces akinesia in Parkinson's disease but its impact on fine motor functions was unknown. We assessed the effects of DBS and a levodopa (L-dopa) test on the timing of the precision grip in 18 patients. Improvement on UPDRS-items reflecting hand functions and the shortening of the first phases of the precision grip were more distinct in the L-dopa test than in the pure STN-DBS condition. Other akinesia items and the time for build-up of lifting force were equally improved in both conditions. This suggests that routine STN-DBS might not be equally effective on all aspects of fine motor functions.

Antiparkinson Agents↗

PubMed2005

Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD--a comparison of neuropsychological effects.

OBJECTIVE: To compare the cognitive and behavioural effects of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation. METHODS: After baseline examination 34 patients were randomly assigned to unilateral pallidotomy (4 left-sided, 10 right-sided) or bilateral STN stimulation (n = 20). At baseline and six and twelve months after surgery we administered neuropsychological tests of language, memory, visuospatial function, mental speed and executive functions. Also a depression rating scale, and self and proxy ratings of memory and dysexecutive symptoms were administered. RESULTS: Six months after surgery, the STN group and the pallidotomy group differed significantly in change from baseline in number of errors on two tests of executive functioning. After 12 months the STN group reported less positive affect compared with baseline than the pallidotomy group. One patient in the STN group showed an overall cognitive deterioration due to complications. CONCLUSIONS: Although we need larger groups to draw firm conclusions, our results suggest that bilateral STN stimulation has slightly more negative effects on executive functioning than unilateral pallidotomy.

Deep Brain Stimulation↗

PubMed2003

Usefulness of neurophysiologic techniques in stereotactic subthalamic nucleus stimulation for advanced Parkinson's disease.

OBJECTIVE: The objectives of this study are to determine the impact of neurophysiologic guidance on subthalamic nucleus (STN) targeting and to assess its safety and effectiveness. METHODS: We have compared the initial theoretic anatomic target (TAT) of the STN with the final microrecording guided coordinates in 15 consecutive patients with bilaterally implanted electrodes in the STN. The clinical results and adverse effects are also reported. All comparisons were done through a paired Student's t test and Pearson's correlation test. RESULTS: Neurophysiological guidance changed the target coordinates in 26 of the procedures. The mean correction applied to the TAT in order to place the electrode in its definite location was 0.4 mm (+/-0.8, range 0-3; P=0.03) in the medial-lateral axis, 1.6 mm (+/-1.2, range 0-5; P=0.01) in the anterior-posterior plane and 0.8 mm (+/-0.8, range 0-3; P=0.26) in the vertical axis. The mean number of microrecording tracks employed to localize each STN was 2.8+/-1.8 (range 1-8) tracks. After surgery, the total UPDRS motor score in the off medication condition improved by 65.9%; UPDRS-II scores were reduced by 71.8% and Schwab and England scores improved by 45.3%. No intraoperative hemorrhages occurred in this series. CONCLUSIONS: Neurophysiological guidance is a safe and useful tool in order to improve and confirm target localization. The correction applied in the target resulted in a significant clinical improvement 6 months after surgery.

Aged↗

PubMed2002

Evaluation of healthcare utilization and health status of patients with Parkinson's disease treated with deep brain stimulation of the subthalamic nucleus.

OBJECTIVE: To assess the effects on motor functioning, health status and direct medical costs of high-frequency stimulation of the subthalamic nucleus (DBS-STN) in patients with idiopathic Parkinson's disease (PD). In addition, the cost-effectiveness of DBS-STN vs. drug treatment was investigated. METHODS: 16 consecutive patients with PD from two centers (Düsseldorf/Cologne; Kiel) treated by DBS-STN were prospectively evaluated. Clinical evaluations were done at baseline and 1, 3, 6, 12 months following surgery by means of the Unified Parkinson's disease Rating Scale (UPDRS). Health status of PD patients was assessed using the Sickness Impact Profile (SIP) at baseline and 6 months following surgery. Relevant economic data were taken from the medical records and costs (1999) were derived from different German medical economic resources. Costs were determined from the perspective of the health care provider. RESULTS: Following DBS-STN UPDRS scores (subscores and sum score) as well as health status improved considerably in PD patients. The overall SIP score and the physical dimension score (p < 0.009) were significantly different (p < 0.01) six month after surgery compared with baseline values. Mean costs of DM 40,020 (US dollars 20,810, EURO 20,410, GB pounds 12,810) per patient were spent during the 12 month observation period for in-patient and out-patient care. These expenses included already the costs for the electronic device for bilateral stimulation. Following DBS-STN medication was considerably reduced. Mean daily drug costs at baseline were DM 46.7+/-21.8 (US dollars 24, EURO 24, GB pounds 15) and DM 18.3+/-17.7 (US dollars 10, EURO 9, GB pounds 6) at 12 months following DBS-STN. Accounting for the decreased drug consumption, total annual costs amounted to DM 31,400 (US dollars 16,330, EURO 16,010, GB pounds 10,050). Further, we estimated the incremental cost effectiveness as DBS-STN had higher costs but was more effective than baseline treatment. The incremental total cost-effectiveness ratio for DBS-STN was DM 1.800 (US dollars 940, EURO 920, GB pounds 580) for one point decrease of the UPDRS. CONCLUSION: DBS-STN is an effective treatment that considerably alleviates the severity of signs and symptoms and improves the health status of patients with PD. Compared with drug treatment, however, the expenditures associated with DBS-STN are increased when only direct medical costs are considered in a one year horizon. However, on a long-term basis costs will decrease considerably because of the reduction of the drug expenditure and improved functioning in all activities of daily living. To adequately evaluate the cost-effectiveness of DBS-STN compared with standard drug regimen for PD it is necessary to include direct, indirect and intangible costs on a long-term basis and under standardized circumstances.

Aged↗

PubMed1992

Role of the subthalamic nucleus in the regulation of nigral dopamine neuron activity.

The influence of subthalamic nucleus (STN) afferents on dopaminergic (DA) neurons of the rat substantia nigra (SN) was investigated. Hemisections of the brain placed between the STN and the SN or located anterior to the STN caused an increase in the firing rate of DA cells without producing significant changes in their firing pattern. In contrast, electrolytic and ibotenic acid lesions of the STN resulted in 93% and 49% reductions, respectively, in the level of burst firing without affecting the firing rate of DA cells recorded in the lateral SN. Furthermore, procedures which interrupted the STN input to the SN produced rapid pacemaker-like firing in 18% of the lateral SN DA neurons recorded. Activation of the STN using single pulses of electrical stimulation caused: 1) a 20-50 msec inhibition of DA cell firing followed by an excitation, which in 35% of DA cells was accompanied by spikes occurring in a burst-like pattern, and 2) a short-latency inhibition lasting 5-25 msec in 75% of non-DA SN zona reticulata (ZR) neurons. On the other hand, stimulation of the STN for 1 minute at 20 Hz resulted in an initial decrease in DA cell burst firing followed by elevated firing rates and increased burst firing by 30-60 minutes after the stimulation. Pharmacological activation of the STN by infusion of bicuculline caused a rapid inhibition of DA cells followed by a two-fold increase in burst firing 6-14 minutes later, whereas SN ZR cells responded with an elevation in firing rate which dissipated in 6-14 minutes. Muscimol-induced STN inhibition produced complimentary biphasic changes in SN neuron firing: 1) an initial increase followed by a decrease in burst firing and firing rate of DA neurons and 2) a rapid inhibition followed by an excitation of ZR cells over a similar time course. Thus, the STN appears to exert a dual action on SN DA cells: 1) initial inhibition possibly mediated through STN excitation of the inhibitory SN ZR projections to DA cells, and 2) a facilitation of burst firing which may be a direct effect of excitatory STN afferents.

Animals↗

PubMed1994

Direct projections from the deep layers of the superior colliculus to the subthalamic nucleus in the rat.

Direct projections from the superior colliculus to the subthalamic nucleus were found in the rat in antero- and retrograde tracing experiments; these projections arose mainly from the deep layers of the superior colliculus at its middle to caudal levels. The present findings suggest that signals from the deep layers of the superior colliculus may modulate the basal ganglia activity during orienting behavior.

Animals↗

PubMed1995

Behavioral and neurochemical consequences of ibotenic acid lesion in the subthalamic nucleus of the common marmoset.

Five marmosets were unilaterally lesioned within the subthalamic nucleus (STN) by injection of 10 micrograms ibotenic acid. Seven marmosets served as saline injected controls. The lesioned marmosets showed an increased locomotor activity, occasional tongue protrusions, posture asymmetry, and abnormal movements of the contralateral legs and arms. The animals were sacrificed 21 days after the ibotenic acid injection and markers of gamma-aminobutyric acid (GABA), dopamine (DA), and acetylcholine were studied in a variety brain regions. There was a bilateral increase in the activity of glutamic acid decarboxylase (GAD) in the caudate, putamen, globus pallidus, superior colliculus, and the ventral anterior/ventral lateral (VA/VL) thalamus, whereas GABA concentrations were only increased ipsilaterally in the ventral posterior medial/centromedial/parafasciculus (VPM/CM/Pf) complex of the thalamus. Tyrosine hydroxylase (TH) activity was bilaterally increased in the medial segment of globus pallidus and nucleus accumbens. However, there were also changes restricted to the side contralateral to the lesion. TH activity and DA concentrations were increased contralateral to the lesion in the putamen. Choline acetyltransferase (CAT) activity was bilaterally increased in the medial segment of globus pallidus and hypothalamus. The ibotenic acid induced STN-lesion in the marmoset, thus, seemed to cause a widespread bilateral activation of neurons within the basal ganglia.

Acetylcholine↗

PubMed1997

Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats.

Lesioning the subthalamic nucleus (STN) has been suggested as possible therapy for the treatment of parkinsonism. Previous experiments investigating this hypothesis in rats confirmed that excitotoxic STN lesions alleviate the motor impairment induced by striatal dopamine depletion, which reproduced the degeneration observed in parkinsonism, but elicited presumed non-motor deficits such as premature responding, suggesting that the STN could be involved in other aspects of response control. The aim of the present study was to extend this analysis to choice paradigms. We thus investigated the behavioural effects of bilateral excitotoxic lesions of the STN in rats performing a five-choice test of divided and sustained visual attention, modelled on the human continuous performance task. This task required the animals to detect a brief visual stimulus presented in one of five possible locations and respond by a nose-poke in this illuminated hole within a fixed delay, for food reinforcement. Bilateral lesions of the STN severely impaired several aspects of performance, including discriminative accuracy, but also increased premature, anticipatory responding as well as perseverative panel pushes and nose-poke responses. While increasing the stimulus duration and reducing the waiting period for the stimulus partially alleviated the accuracy deficit and the premature responding deficit respectively, other deficits, such as perseverative panel pushes and nose-poke responses, were sustained under these conditions. Systemic injection of the mixed dopaminergic D1/D2 receptor antagonist, alpha-flupenthixol (0.03-0.18 mg/kg), reduced premature responses and perseverative panel pushing without affecting the perseverative nose-poke responses, suggesting that some of the deficits were independent of striatal dopaminergic transmission. These results suggest that STN lesions have multiple, dissociable effects on attentional performance, including discriminative deficits, impulsivity and perseverative behaviour. They are consistent in part with a hypothesized role of the STN in recent models of basal ganglia function in action selection and inhibition. The results also show that other aspects of behaviour should be monitored when examining the capacity of STN lesions to reverse the parkinsonian deficit induced by striatal dopamine depletion.

Analysis of Variance↗

PubMed1980

Vesicle containing dendrites in the subthalamic nucleus of the cat.

During the ultrastructural investigation of the cat's subthalamic nucleus (STN), profiles exhibiting features attributed to dendrites and simultaneously containing synaptic vesicles, were encountered. Most of them take part in synaptic triads, usually as an intermediate component. On the basis of their electron microscopical appearance, and synaptic relationships, they might be discriminated, as a distinct ultrastructural entity. Although not conspicuous in number, they might have their own contribution to the synaptic events taking place in the STN.

Animals↗

PubMed2004

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease 1993-2003: where are we 10 years on?

Since its advent in 1993, high frequency stimulation (HFS) of the subthalamic nucleus (STN) has rapidly developed into the most commonly practiced surgical procedure for the treatment of Parkinson's Disease (PD). Although its exact mechanism of action, be it through an inhibitory depolarization block, desynchronization of neuronal circuits or other means, is not clear, the efficacy and safety of the technique are now well established. HFS of the STN improves the motor function by at least 60%, drastically reduces the levodopa requirement and significantly improves the quality of life in PD. This review updates the recent concepts on the pathophysiology of PD and analyses the basic science principles underlying the clinical practice of the STN HFS. The evolution of the surgical technique and long-term patients' outcome are further discussed.

Antiparkinson Agents↗