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PubMed1979

A direct role of dopamine in the rat subthalamic nucleus and an adjacent intrapeduncular area.

The subthalamic nucleus, a clinically important component of the extrapyramidal motor system, and a lateral area extending into the peduncle contain catecholamine terminals and dopamine receptors coupled to adenylate cyclase. In addition, dopamine agonists administered in vivo enhance glucose utilization in the region. Thus, neuronal function in this region is directly affected by dopamine and dopaminergic drugs.

Adenylyl Cyclases↗

PubMed2001

Regulation of limbic information outflow by the subthalamic nucleus: excitatory amino acid projections to the ventral pallidum.

The subthalamic nucleus (STN), a component of the basal ganglia motor system, sends an excitatory amino acid (EAA)-containing projection to the ventral pallidum (VP), a major limbic system output region. The VP contains both NMDA and AMPA subtypes of EAA receptors. To characterize the physiology of the subthalamic pathway to the VP, and to determine the influence of EAA receptor subtypes, in vivo intracellular recordings, and in vivo extracellular recordings combined with microiontophoresis, were made from VP neurons in anesthetized rats. Of the intracellularly recorded neurons, 86% responded to STN stimulation, and these displayed EPSPs with an onset of 8.7 msec, consistent with a monosynaptic input. The EPSPs evoked in spontaneously firing neurons were nearly twice the amplitude of those in nonfiring cells (13.1 vs 6.8 mV, respectively). As neurons were depolarized by current injection, the latency for spiking decreased from 24.2 to 14.2 msec, although EPSP latency was unaffected. Eighty-seven percent of the extracellularly recorded VP neurons responded to STN stimulation with a rapid and robust enhancement of spiking; the response onset, like the EPSP onset, equaled 8.7 msec. Firing rate was enhanced by NMDA in 94% of the STN-excited cells, and AMPA increased firing in 94% as well. The NMDA-selective antagonist AP-5 attenuated 67% of the STN-evoked excitatory responses, and the AMPA-selective antagonist CNQX attenuated 52%. Both antagonists attenuated 33% of responses, and 78% were attenuated by at least one. This evidence suggests that a great majority of VP neurons are directly influenced by STN activation and that both NMDA and non-NMDA receptors are involved. Moreover, the VP response to STN stimulation appears to be strongly dependent on the depolarization state of the neuron.

Action Potentials↗

PubMed1991

The magnocellular and parvocellular divisions of the monkey subthalamic nucleus as revealed by cluster analysis of neuronal sizes.

Cluster analysis of neuronal somal sizes in the subthalamic nucleus of rhesus monkeys from newborn to adult age allows the segregation of two territories with predominance of small and large cells, respectively. The topographic distribution of the 'parvocellular' and 'magnocellular' segments is similar when samples are obtained from coronal, horizontal and sagittal series of sections. The parvocellular component occupies the rostral pole, the entire rostrocaudal extent of the medial tip and dorsomedial border, and probably also the caudal cap. The magnocellular segment is in the central core extending to the ventrolateral border except for the medial tip. These findings and their correlation with the results of other morphologic and physiologic studies allow the following conclusions. (1) The monkey subthalamic nucleus contains at least two differentially distributed cell subpopulations. (2) The magnocellular division is more related to the pallido-subthalamic-pallidal loop involving the lateral pallidal segment. (3) The parvocellular division appears strategically located to control the pallidal output to diencephalic and mesencephalic targets. (4) Cluster analysis can reveal the existence of more than one neuronal population in a particular brain structure where an overall unimodal distribution of cell sizes may suggest the presence of a single type.

Aging↗

PubMed1995

GABAergic projection from the ventral pallidum and globus pallidus to the subthalamic nucleus.

There exists a topographically organized projection from the globus pallidus and ventral pallidum to the subthalamic nucleus and adjacent lateral hypothalamus. The participation of GABA as a neurotransmitter in this projection was evaluated by retrograde labeling of cells in the pallidal area from an iontophoretic deposit of Fluor-Gold in the subthalamus combined with in situ hybridization for mRNA of the GABA synthetic enzyme, glutamate decarboxylase (GAD). A rostrocaudal gradient in the contribution of GABA to the projection was demonstrated with a relatively small percentage of retrogradely labeled cells in the rostral ventral pallidum containing GAD mRNA (7%) compared to the caudal globus pallidus which had over 70% of the Fluoro-Gold containing cells double-labeled for GAD mRNA. Overall the ventral pallidum contribution to the subthalamic nucleus was less GABAergic than the portion arising from the globus pallidus (35% vs. 61%, respectively).

Animals↗

PubMed2000

An investigation of the effects of subthalamic nucleus stimulation on acoustic measures of voice.

Seven patients with Parkinson's disease were implanted with deep brain stimulators to provide chronic electrical stimulation to the subthalamic nucleus bilaterally. Acoustic recordings and neurologic assessments were undertaken before surgery in the medication-off and medication-on conditions and after surgery with and without electrical stimulation in the medication-off and medication-on conditions. The data showed significant improvements in limb motor performance in response to medication before surgery and when the subthalamic nucleus was stimulated after surgery. Six months after surgery, there were small but statistically significant increases in sound pressure level and fundamental frequency variability in response to stimulation in the medication-on condition. No other statistically significant speech changes were measured. These findings are consistent with several other studies that have reported disparity between limb and speech improvements after neurosurgical intervention for Parkinson's disease.

Adult↗

PubMed2004

Subthalamic nucleus stimulation in advanced Parkinson's disease: blinded assessments at one year follow up.

OBJECTIVE: To measure the effect of deep brain stimulation (DBS) of the subthalamic nucleus in patients with advanced Parkinson's disease. DESIGN: Open label follow up using blinded ratings of videotaped neurological examinations. PATIENTS: 30 patients with advanced Parkinson's disease (19 male, 11 female; mean age 58.8 years; mean disease duration 12.8 years), complicated by intractable wearing off motor fluctuations and dopaminergic dyskinesias. MAIN OUTCOME MEASURES: Unified Parkinson's disease rating scale (UPDRS), part III (motor), score at one year, from blinded reviews of videotaped neurological examinations. Secondary outcomes included the other UPDRS subscales, Hoehn and Yahr scale, activities of daily living (ADL) scale, mini-mental state examination (MMSE), estimates of motor fluctuations and dyskinesia severity, drug intake, and patient satisfaction questionnaire. RESULTS: Subthalamic nucleus stimulation was associated with a 29.5% reduction in motor scores at one year (p<0.0001). The only important predictors of improvement in UPDRS part III motor scores were the baseline response to dopaminergic drugs (p = 0.015) and the presence of tremor (p = 0.027). Hoehn and Yahr scores and ADL scores in the "on" and "off" states did not change, nor did the mean MMSE score. Weight gain occurred in the year after surgery, from (mean) 75.8 kg to 78.5 kg (p = 0.028). Duration of daily wearing off episodes was reduced by 69%. Dyskinesia severity was reduced by 60%. Drug requirements (in levodopa equivalents) declined by 30%. CONCLUSIONS: The 30% improvement in UPDRS motor scores was a more modest result than previously reported. DBS did not improve functional capacity independent of drug use. Its chief benefits were reduction in wearing off duration and dyskinesia severity.

Activities of Daily Living↗

PubMed2005

Can chronic subthalamic nucleus stimulation induce de novo tremor in Parkinson's disease?

Subthalamic nucleus stimulation dramatically improves parkinsonian symptoms, notably the tremor. The occurrence of a tremor in the first 6 months after the surgical procedure in patients without tremor preoperatively is much less common. We report on the cases of 3 patients who developed such modification of their parkinsonian symptomatology. Physiopathological hypotheses are discussed.

Aged↗

PubMed1993

On the expression of Fos-like protein in the subthalamic nucleus and basal ganglia output systems following kainic acid injections into the rodent striatum.

By immunohistochemistry, Fos-like protein induced in response to intrastriatal kainic acid injections was explored in the basal ganglia and the ventrolateral thalamic nucleus of the rat. In the globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata, subthalamic nucleus and ventrolateral thalamic nucleus, Fos was expressed in neuronal cell nuclei showing the maximal number at 4 h and disappeared within 48 h. The substantia nigra pars compacta neurons lacked prominent Fos induction, suggesting that a different mechanism may operate for changes of dopamine systems. Concurrent Fos expression noted in selected regions suggests the link of relay and output stations of the basal ganglia with the ventrolateral thalamus at the early stage of striatal cell degeneration.

Animals↗

PubMed2006

The subthalamic nucleus: From response selection to execution.

The involvement of the subthalamic nucleus in physiological and pathological motor behaviour has now largely been established. Clinical observations in patients suffering from Parkinson disease treated with Deep Brain Stimulation of the STN show that these patients can suffer from postoperative changes in non-motor behaviour mainly involving alterations in cognitive functions. The involvement of the STN in cognition has initially been demonstrated by non-human studies investigating the effects of STN lesions and stimulations on cognitive parameters. In the present review, we discuss the findings of these preclinical studies on cognitive parameters and outline the anatomical and functional place of the STN in the basal ganglia cognitive circuit.

Animals↗

PubMed2000

Improvement of memory guided saccades in parkinsonian patients by high frequency subthalamic nucleus stimulation.

Recent studies in the monkey suggest that the subthalamic nucleus (STN) is involved in control of eye movement, yet its functional significance in humans is unknown. Saccadic eye movements were studied in eight parkinsonian patients treated by bilateral electrical stimulation of the STN. STN stimulation improved the accuracy of memory guided saccades but not of reflexive visually guided saccades and had no effect on the antisaccade task. This study shows that, by contrast with levodopa, STN stimulation improves memory guided saccade deficits, and illustrates for the first time in humans the role of the STN in the control of purposive saccades.

Electric Stimulation Therapy↗

PubMed2005

Comparison of three methods of targeting the subthalamic nucleus for chronic stimulation in Parkinson's disease.

OBJECTIVE: The success of subthalamic nucleus (STN) surgery for Parkinson's disease depends on accuracy in target determination. The objective of this study was to determine which of the following techniques was most accurate and precise in identifying the location for stimulation in STN deep brain stimulation surgery that is most clinically effective: direct targeting, indirect targeting using the positions of the anterior and posterior commissures, or a technique using the red nucleus (RN) as an internal fiducial marker. METHODS: We reviewed 14 patients with Parkinson's disease treated with bilateral STN deep brain stimulation (28 STN targets). Electrode implantation was based on direct and indirect targeting using two-dimensional magnetic resonance imaging with refinement using microelectrode recording. Optimal settings, including the contacts used, were determined during the clinical follow-up. The position of the best contact was defined with postoperative magnetic resonance imaging. This location was compared with the modified direct, indirect, and RN-based targets. The mean distances between the targets and the final position of the optimal contact were calculated. The accuracy and variance of each target were analyzed. RESULTS: The mean position of the best contact was x = 12.12 (standard deviation [SD], 1.45 mm), y = -2.41 (SD, 1.63 mm), and z = -2.39 (SD, 1.49 mm) relative to the midcommissural point. The mean distance between the optimal contact position and the planned target was 3.19 mm (SD, 1.19 mm) using the RN-based method, 3.42 mm (SD, 1.34 mm) using indirect targeting, and 4.66 mm (SD, 1.33 mm) using a modified direct target. The mean distance between the optimal contact and the RN-based target was significantly smaller than the mean distance between the optimal contact and the direct target (post hoc with Tamhane's correction, P < 0.001) but not between the optimal contact and the indirect target. The RN-based target had the smallest variance (F test, P < 0.001), indicating greater precision. CONCLUSION: The use of the RN as an internal fiducial marker for targeting the optimal region of STN stimulation was reliable and closely approximates the position of the electrode contact that provides the optimal clinical results.

Deep Brain Stimulation↗

PubMed2004

Neuropsychological functioning following bilateral subthalamic nucleus stimulation in Parkinson's disease.

The cognitive effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) have been examined. However, there are no reported studies that evaluate, by incorporating a disease control group, whether neuropsychological performance in surgical patients changes beyond the variability of the assessment measures. To examine this issue, 17 PD patients were tested before and after bilateral STN stimulator implantation, both on and off stimulation. Eleven matched PD controls were administered the same repeatable neuropsychological test battery twice. Relative to changes seen in the controls, the surgery for electrode placement mildly adversely affected attention and language functions. STN stimulation, per se, had little effect on cognition. The STN DBS procedure as a whole resulted in a mild decline in delayed verbal recall and language functions. There were no surgery, stimulation, or procedure effects on depression scale scores. In contrast to these group findings, one DBS patient demonstrated significant cognitive decline following surgery.

Aged↗

PubMed2002

Subthalamic nucleus stimulation in Parkinson's disease: clinical evaluation of 18 patients.

The aim of the present study was to assess the efficacy and safety of chronic subthalamic nucleus deep-brain stimulation (STN-DBS) in patients with Parkinson's disease (PD). 18 consecutive severely affected PD patients were included (mean age, SD: 56.9+/-6 years; mean disease duration: 13.5+/-4.4 years). All the patients were evaluated clinically before and 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS). Additionally, a 12 months follow-up was available in 14 patients. The target coordinates were determined by ventriculography under stereotactic conditions, followed by electrophysiology and intraoperative stimulation. After surgery, continuous monopolar stimulation was applied bilaterally in 17 patients at 2.9+/-0.4 V through 1 (n = 31) or 2 contacts (n = 3). One patient had bilateral bipolar stimulation. The mean frequency of stimulation was 140+/-16 Hz and pulse width 68+/-13 micros. Off medication, the UPDRS part III score (max = 108) was reduced by 55 % during on stimulation (score before surgery: 44.9+/-13.4 vs at 6 months: 20.2+/-10; p < 0.001). In the on medication state, no difference was noted between the preoperative and the postoperative off stimulation conditions (scores were respectively: 17.9+/-9.2 and 23+/-12.6). The severity of motor fluctuations and dyskinesias assessed by UPDRS IV was reduced by 76 % at 6 months (scores were respectively: 10.3+/-3 and 2.5+/-3; p < 0.001). Off medication, the UPDRS II or ADL score was reduced by 52.8 % during on stimulation (26.9+/-6.5 preop versus 12.7+/-7 at 6 months). The daily dose of antiparkinsonian treatment was diminished by 65.5 % (levodopa equivalent dose -- mg/D -- was 1045 +/- 435 before surgery and 360 +/- 377 at 6 months; p < 0.01). These results remained stable at 12 months for the 14 patients studied. Side effects comprised lower limb phlebitis (n = 2), pulmonary embolism (n = 1), depression (n = 6), dysarthria and freezing (n = 1), sialorrhea and drooling (n = 1), postural imbalance (n = 1), transient paresthesias and dyskinesias. This study confirms the great value of subthalamic nucleus stimulation in the treatment of intractable PD. Some adverse events such as depression may be taken into account in the inclusion criteria and also in the post-operative outcome.

Adult↗

PubMed2003

Influence of the frequency parameter on extracellular glutamate and gamma-aminobutyric acid in substantia nigra and globus pallidus during electrical stimulation of subthalamic nucleus in rats.

High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas gamma-aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency-dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep-brain-stimulation mechanisms.

Animals↗

PubMed2005

Changes induced by levodopa and subthalamic nucleus stimulation on parkinsonian speech.

Levodopa (L-dopa) and subthalamic nucleus (STN) stimulation treatments have been associated with both improvement and exacerbation of dysarthria in Parkinson's disease (PD). We report four cases illustrating variant responses of dysarthria to dopaminergic and STN stimulation therapies. Patients' motor disability and dysarthria were perceptually rated by the Unified Parkinson's Disease Rating Scale (UPDRS) in four conditions according to medication and STN stimulation. Dedicated software packages allowed acquisition and analysis of acoustic recordings. Case 1, who had a severe off period aphonia, experienced improvement of speech induced by both levodopa and STN stimulation. In Case 2, both treatments worsened speech due to the appearance of dyskinesias. Case 3 had a dysarthria exacerbation induced by STN stimulation with parameters above optimal levels, interpreted as current diffusion from the STN to corticobulbar fibers. In Case 4, dysarthria exacerbation occurred with stimulation at an electrode contact located caudally to the target, also arguing for current diffusion as a potential mechanism of speech worsening. The presented cases demonstrated variant effects in relation to L-dopa and STN stimulation on speech. It seems that motor speech subcomponents can be improved like other limb motor aspect, but that complex coordination of all speech anatomical substrates is not responsive to STN stimulation. These hypotheses may be helpful for better understanding and management of STN stimulation effects on motor speech and skeleton-motor subsystems.

Adult↗

PubMed2001

Effect of bilateral subthalamic nucleus stimulation on parkinsonian gait.

Clinical reports show that bilateral subthalamic nucleus (STN) stimulation is effective in improving parkinsonian gait. Quantitative analysis of the efficacy of STN stimulation on gait is of interest and can be carried out using a commercially available stride analyser. Ten parkinsonian patients (5 men, 5 women) with a mean age of 55.8, SD 9.6 years were included in our study. They had a mean duration of Parkinson's disease (PD) of 13.3, SD 4.5 years and a motor examination score (part III of the Unified Parkinson's Disease Rating Scale) (UPDRS) of 43, SD 13 in off-stimulation off-drug condition. All the patients had bilateral chronic STN stimulation which had started from 3 to 36 months before the study. Patients were evaluated in off-drug and on-drug conditions both with and without stimulation. We analysed the principal gait measures: velocity, cadence, stride length, gait cycle, duration of single and double limb support. The clinical parkinsonian signs were evaluated with the part III of the UPDRS. In the off-drug condition, STN stimulation significantly (p < 0.05) improved velocity and stride length. The effect was similar to that of levodopa. When STN stimulation was switched on at the best of the levodopa induced effect, no further improvement was observed. The UPDRS motor score was significantly (p < 0.001) decreased after both stimulation and levodopa. In conclusion, STN stimulation is effective on parkinsonian gait.

Adult↗

PubMed1999

Neurophysiological effects of stimulation through electrodes in the human subthalamic nucleus.

The effects of stimulation through macroelectrodes implanted in the subthalamic nucleus (STN) were studied in 14 patients with parkinsonism. Single stimuli delivered directly to the STN electrodes with an external stimulator modulated voluntary electromyography (EMG) of contralateral muscles in most patients. A short-latency facilitation ('peak') was attributed to the activation of the corticospinal system. A longer latency inhibition ('dip'), often preceded or followed by facilitations, appeared to arise from the activation of large-diameter fibres running parallel to the electrode and to be transmitted through the motor cortex. It is possible that the dip could result from the inhibition of thalamocortical neurons. With high-frequency stimulation ( approximately 100 Hz) the peaks occurred at the stimulus frequency; the dips became confluent and outlasted the duration of the stimulus train. There was no evidence that high-frequency stimulation produced 'blocking'. The studies were repeated in 12 patients a mean of 5.8 months after implantation of the stimulator. The same short-latency effects were obtained. They were present on 7 out of 23 sides at the settings in use and on the majority of sides if the stimulus intensity was slightly increased. There was no clear relationship between these short-latency effects and the patients' overall clinical improvement; the effects may result from the spread of current to large-fibre systems near the STN. In five patients, high-frequency stimulation on one side immediately reduced tremor in the contralateral limbs. This effect arose from the activation of large-diameter fibres and, like the dip, had about the same threshold at each of the contacts. Frequencies as low as 70 Hz were sufficient. We conclude that the control of tremor by STN stimulation is due to the activation of a large-fibre system.

Adult↗

PubMed2002

Presynaptic modulation of synaptic transmission by opioid receptor in rat subthalamic nucleus in vitro.

Presynaptic modulation of synaptic transmission in rat subthalamic nucleus (STN) neurons was investigated using whole-cell patch-clamp recordings in brain slices. Evoked GABAergic inhibitory postsynaptic currents (IPSCs) were reversibly reduced by methionine enkephalin (ME) with an IC(50) value of 1.1 +/- 0.3 microM. The action of ME was mimicked by the mu-selective agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO), and was partially blocked by the mu-selective antagonists naloxonazine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP). Evoked GABA(A) IPSCs were also inhibited by the delta-selective agonist [D-Pen(2,5)]-enkephalin (DPDPE), but not by the kappa-selective agonist (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U-69593) and the orphan receptor agonist orphanin FQ/nociceptin (OFQ). DPDPE-induced inhibition was completely blocked by the delta-selective antagonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864). ME, DAMGO and DPDPE increased the paired-pulse ratio of IPSCs. Evoked excitatory postsynaptic currents (EPSCs) were reversibly reduced by ME with an IC(50) value of 0.35 +/- 0.14 microM. Inhibition by ME was associated with an increase in the paired-pulse ratio of EPSCs. The action of ME was mimicked by DAMGO, and blocked by naloxonazine. DPDPE had little effect on evoked EPSCs. Neither U-69593 nor OFQ had any effect. ME significantly decreased the frequency of spontaneous miniature EPSCs (mEPSCs) without change in their amplitude. The action of ME was mimicked by DAMGO. DPDPE had no effect. The presynaptic voltage-dependent potassium conductance blocker 4-aminopyridine (4-AP, 100 microM) abolished the inhibitory effects of ME on evoked IPSCs and EPSCs. In contrast, 4-AP only partially blocked the actions of baclofen. These results suggest that opioids inhibit inhibitory synaptic transmission in the STN through the activation of presynaptic mu- and delta- receptors. In contrast, inhibition of excitatory synaptic inputs to the STN occurs through the activation of only mu-receptors. Both inhibitions may be mediated by blockade of voltage-dependent potassium conductance.

Animals↗