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PubMed1979

Pharmacological properties of acetylcholine-induced excitation of subthalamic nucleus neurones.

1. In 15 rats anaesthetized with ketamine, microiontophoretically applied acetylcholine (ACh) excited all 58 cells studied in the subthalamic nucleus (STN). 2. The ACh-evoked excitation was slow in onset and outlasted the ACh application. There was no sign of desensitization when the ACh application was prolonged or repeated. The excitation was prolonged by a concomitant application of physostigmine. 3. Acetyl-beta-methyl choline and oxotremorine were effective cholinomimetics. Nicotine had no effect. 4. The ACh excitation was antagonized by stropine and scopolamine but not by mecamylamine. 5. It was condluded that STN ACh receptors are muscarinic in character. 6. Since large microiontophoretic applications of Mg2+ did not suppress ACh-evoked excitation, it is suggested that ACh acts postsynaptically. 7. The excitatory response of STN cells to striatal or pallidal stimulation was unaffected by atropine administered either microiontophoretically to single cells or intravenously (3 mg/kg) to the whole animal.

Acetylcholine↗

PubMed1999

Subthalamic nucleus neurons switch from single-spike activity to burst-firing mode.

The modification of the discharge pattern of subthalamic nucleus (STN) neurons from single-spike activity to mixed burst-firing mode is one of the characteristics of parkinsonism in rat and primates. However, the mechanism of this process is not yet understood. Intrinsic firing patterns of STN neurons were examined in rat brain slices with intracellular and patch-clamp techniques. Almost half of the STN neurons that spontaneously discharged in the single-spike mode had the intrinsic property of switching to pure or mixed burst-firing mode when the membrane was hyperpolarized from -41.3 +/- 1.0 mV (range, -35 to -50 mV; n = 15) to -51.0 +/- 1.0 mV (range, -42 to -60 mV; n = 20). This switch was greatly facilitated by activation of metabotropic glutamate receptors with 1S,3R-ACPD. Recurrent membrane oscillations underlying burst-firing mode were endogenous and Ca2+-dependent because they were largely reduced by nifedipine (3 microM), Ni2+ (40 microM), and BAPTA-AM (10-50 microM) at any potential tested, whereas TTX (1 microM) had no effect. In contrast, simultaneous application of TEA (1 mM) and apamin (0.2 microM) prolonged burst duration. Moreover, in response to intracellular stimulation at hyperpolarized potentials, a plateau potential with a voltage and ionic basis similar to those of spontaneous bursts was recorded in 82% of the tested STN neurons, all of which displayed a low-threshold Ni2+-sensitive spike. We propose that recurrent membrane oscillations during bursts result from the sequential activation of T/R- and L-type Ca2+ currents, a Ca2+-activated inward current, and Ca2+-activated K+ currents.

Action Potentials↗

PubMed2004

High-frequency stimulation of the subthalamic nucleus for the treatment of Parkinson's disease--a team perspective.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder affecting more than 1.2 million people in the United States. Genetic and environmental toxins are believed to be risk factors in acquiring the disease. PD is characterized by tremors, rigidity, bradykinesia, poor gait, and postural instability. These cardinal symptoms improve with medication such a levo-dopa (L-dopa). However, over time, as the disease progresses, the patient becomes refractory to medication, or medication produces debilitating side effects. When this occurs or when there are worsening of symptoms, neurosurgical treatment is recommended, particularly deep brain stimulating (DBS) electrodes implanted in the subcortical subthalamic nucleus (STN). Over the last 5 years STN DBS has gained acceptance and become the neurosurgical treatment of choice for PD. To achieve maximum beneficial effects with minimum adverse effects from the surgery, the expertise of an integrated team of physicians and nurses is essential. A clear understanding of the different aspects of the procedure, including the risks and benefits of the treatment, assists neuroscience nurses in communicating with the PD patient, and providing the most appropriate, knowledge-based pre- and postoperative care.

Deep Brain Stimulation↗

PubMed2003

Cytochrome oxidase activity in the monkey globus pallidus and subthalamic nucleus after ablation of striatal interneurons expressing substance P receptors.

To understand functional roles of striatal interneurons in primate basal ganglia circuitry, we ablated interneurons expressing substance P (SP) receptors (SPR) in the putamen with SP-saporin, a SPR selective neurotoxin. The effect of SP-saporin injection into the putamen was evaluated by examining the loss of cholinergic interneurons and NADPHd-positive (nicotinamide adenine dinucleotide phosphate diaphorase positive) interneurons. We then analyzed regional metabolic changes using cytochrome oxidase (CO) histochemistry. CO activity in some regions of the internal and external segments of the globus pallidus (GP) in the lesioned hemisphere was lower than that in the contralateral or surrounding GP regions. CO activity in the subthalamic nucleus, however, showed no significant change. The present findings suggest that striatopallidal projection neurons exert enhanced inhibitory influence on the GP without modulatory control by the striatal SPR-expressing interneurons.

Animals↗

PubMed2001

Radiosurgery performed with the aid of a 3-mm collimator in the subthalamic nucleus and substantia nigra of the vervet monkey.

OBJECT: Radiosurgery for functional neurosurgery performed using a linear accelerator (LINAC) has not been extensively characterized in preclinical studies. In the present study, the properties of a newly designed 3-mm-diameter collimator were evaluated in a dedicated LINAC, which produced lesions in the basal ganglia of vervet monkeys. Lesion formation was determined in vivo in three animals by examining magnetic resonance (MR) images to show the dose-delivery precision of targeting and the geometry and extent of the lesions. Postmortem immunohistochemical studies were conducted to determine the extent of lesion-induced radiobiological effects. METHODS: In three male vervet monkeys, the subthalamic nucleus (STN; one animal) and the pars compacta of the lateral substantia nigra (SN; two animals) were targeted by a Novalis Shaped Beam Surgery System that included a 3-mm collimator and delivered a maximum dose of 150 Gy. Magnetic resonance images obtained 4, 5, and 9 months posttreatment were reviewed, and the animals were killed so that immunohistological characterizations could be made. CONCLUSIONS: The generation of precise radiosurgical lesions by a 3-mm collimator was validated in studies that targeted the basal ganglia of the vervet monkey. The extent of the lesions created in all animals remained restricted in diameter (< 3 mm) throughout the duration of the studies, as assessed by reviewing MR images. Histological studies showed that the lesions were contained within the STN and SN target areas and that there were persistent increases in glial fibrillary acidic protein immunoreactivity. Increases in immunoreactivity for tyrosine hydroxylase, the serotonin transporter, and the GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptor in penumbral regions of the lesion were suggestive of compensatory neuronal adaptations. This radiosurgical approach may be of particular interest for the induction of lesions of the STN and SN in studies of experimental parkinsonism, as well as for the development of potential radiosurgical treatments for Parkinson disease.

Animals↗

PubMed1999

Thalamic, subthalamic nucleus and internal pallidum stimulation in Parkinson's disease.

The limits of drug therapy in severe forms of Parkinson's disease have lead to a renewal of functional neurosurgery of the basal ganglia and the thalamus. Deep brain stimulation (DBS) of these structures was developed with the aims of reducing the morbidity of surgery and of offering an adaptative treatment. DBS was first applied to the thalamus in patients with severe tremor. Tremor of the hemibody is greatly reduced by stimulation of the contralateral electrode in 85% of the cases. There is little change in other symptoms. However, motor fluctuations and dyskinesias are a more frequent problem than severe tremor; in attempt to treat these symptoms, DBS has recently been applied to the subthalamic nucleus (STN) and the internal pallidum (GPi). STN stimulation greatly decreases off motor symptoms and motor fluctuations, which allows a reduction of drug dosage and consequently of dyskinesias. GPi stimulation decreases dyskinesias in most patients, but the effect on off motor symptoms is more variable from one series to another, from very good to nil. The severe morbidity of DBS applied to these 3 targets is low. Comparative studies of the cost and the efficacy of DBS and lesions applied to these different targets are now required.

Electric Stimulation↗

PubMed2004

The effects of electrode material, charge density and stimulation duration on the safety of high-frequency stimulation of the subthalamic nucleus in rats.

High-frequency stimulation (HFS) of deep brain structures is a powerful therapeutic tool for the treatment of various movement disorders in patients. However, the pathophysiological mechanisms of this therapeutic approach on basal ganglia network function are still largely unknown. Hitherto, experimental studies have focused on short-term stimulation. Since patients receive HFS for many years, animal studies which reproduce the conditions of long-term stimulation will be necessary to accurately investigate the effects of HFS. However, stimulation parameters of acute HFS cannot be easily transferred to long-term conditions. Accordingly, for this purpose we studied the influence of different charge densities (0, 3, 6.5, 13 and 26 microC/cm2/phase) and duration (4 h or 3 days) of subthalamic nucleus (STN)-HFS using stainless-steel and platinum-iridium (Pt/Ir) electrodes on neuronal tissue damage in rats. Our data demonstrate the advantage of Pt/Ir over stainless-steel electrodes when used in short-term HFS (frequency 130 Hz, pulse width 60 micros) and indicate that HFS using Pt/Ir-electrodes pulsed with 3 microC/cm2/phase over 3 days did not produce any relevant tissue damage in the STN.

Animals↗

PubMed1997

Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease.

High-frequency electrical stimulation of the internal pallidum (GPi) or the subthalamic nucleus (STN) improves clinical symptoms of Parkinson's disease. In 12 parkinsonian patients, 6 with STN and 6 with GPi stimulators, we used H2(15)O positron emission tomography to evaluate whether changes in movement performance were accompanied by change in regional cerebral blood flow (rCBF). Patients were scanned both at rest and while performing a free-choice joystick movement, under conditions of effective and ineffective electrostimulation. During effective STN stimulation, movement-related increases in rCBF were significantly higher in supplementary motor area, cingulate cortex, and dorsolateral prefrontal cortex (DLPFC) than during ineffective stimulation. No significant change was observed in any of these areas during GPi stimulation. The difference between the effect of STN and GPi stimulation on movement-related activity was mainly localized to DLPFC. These results confirm the dominant role of nonprimary motor areas in the control of movement in parkinsonian patients and demonstrate the importance of STN input in the control of these areas.

Electric Stimulation↗

PubMed1985

Subclassification of neurons in the subthalamic nucleus of the lesser bushbaby (Galago senegalensis): a quantitative Golgi study using principal components analysis.

The morphology of neurons in the subthalamic nucleus (STN) of the lesser bushbaby (Galago senegalensis) is described in coronal brain sections processed by Golgi- and Nissl-staining techniques. Quantitative and statistical methods are used to evaluate (1) soma size and shape, (2) dendritic field size, shape, and branch frequency, (3) the number of dendritic and somatic spines per neuron, and (4) neuron location within the STN. Principal components analysis of these variables suggests that three classes of neurons are present. Two of these classes are considered to be projection cells, referred to as elongate-fusiform and radiate neurons, respectively. Elongatefusiform neurons have somata and dendritic fields which are large in diameter, extremely fusiform in shape, and give rise to few appendages. Somata and dendritic fields of radiate neurons are smaller in diameter, more rounded in shape, and support more spines than the elongate-fusiform neurons. The third class of cells in Galago STN is tentatively identified as consisting of interneurons on the basis of small soma and dendritic field size, thin and varicose dendritic morphology, and the presence of multilobulated dendritic appendages.

Animals↗

PubMed1988

Somatosensory inputs to the subthalamic nucleus: a combined retrograde and anterograde horseradish peroxidase study in the rat.

Previous physiological studies have shown that neurons in the subthalamic nucleus (STN) respond to peripheral somatosensory stimulation. In an attempt to identify anatomical pathways that could mediate such responses, the possible existence of direct projections from somatosensory central territories to the STN was investigated in the rat with the aid of retrograde and anterograde horseradish peroxidase tracer techniques. Our main findings indicate the existence of a hitherto undescribed and relatively substantial direct projection from the primary somatosensory cortex to the ipsilateral STN. The projection appears to originate chiefly from neurons in layer Vb of the rostral half of this cortical area and to terminate basically in the dorsolateral district of the STN. Moreover, our data are compatible with the existence of very sparse direct projections from the spinal trigeminal and dorsal column nuclei to the contralateral STN, but the evidence on this point is hardly conclusive.

Afferent Pathways↗

PubMed1990

Afferent connections of the subthalamic nucleus: a combined retrograde and anterograde horseradish peroxidase study in the rat.

A comprehensive characterization of the afferent connections of the subthalamic nucleus of Luys (STN) is a necessary step in the unraveling of extrapyramidal mechanisms. In the present study, the STN afferents in the rat were systematically investigated with the aid of retrograde and anterograde horseradish peroxidase tracer techniques. The results indicate that, besides a massive input from the dorsal pallidum, the STN receives substantial projections from several districts of the cerebral cortex (the medial division of the prefrontal cortex, the first motor and primary somatosensory areas, and the granular insular territory), the ventral pallidum, the parafascicular nucleus of the thalamus and the pedunculopontine tegmental nucleus, as well as a modest innervation from the dorsal raphe nucleus. In spite of the fact that many additional structures were found to contain retrogradely labeled neurons after tracer injections in the STN, no other projection to the latter nucleus could be effectively established in our anterograde experimental series.

Animals↗

PubMed1999

Chronic subthalamic nucleus stimulation reduces medication requirements in Parkinson's disease.

OBJECTIVE: To reduce antiparkinsonian medication in parkinsonian patients with bilateral high frequency subthalamic nucleus (STN) stimulation. BACKGROUND: Parkinsonian syndromes are characterized by hyperactivity of the STN. Preliminary data indicate that functional inactivation of the STN may reduce the requirement for dopaminergic therapy in PD. METHODS: Bilateral quadripolar leads were implanted stereotactically in the STN of seven patients with advanced PD (mean age, 57.4 years; mean disease duration, 15.4 years). High-frequency stimulation was applied for 24 hours a day. Following implantation, antiparkinsonian medication was reduced to the minimum possible and stimulation was gradually increased. The patients were evaluated in the practically defined "off" and "on" conditions using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Schwab & England scale. The average follow-up was 16.3+/-7.6 months. A battery of neuropsychological tests was applied before and 9 months after the implant. RESULTS: Parkinsonian features improved in all patients--the greatest change seen in rigidity, then tremor, followed by bradykinesia. Compared with the presurgical condition, off-drug UPDRS motor scores improved by 41.9% on the last visit (p = 0.0002), UPDRS activities of daily living (ADL) scores improved by 52.2% (p = 0.0002), and the Schwab & England scale score improved by 213% (p = 0.0002). The levodopa-equivalent daily dose was reduced by 65%. Night sleep improved in all patients due to increased mobility at night, and in five patients insomnia was resolved. All patients gained weight after surgery and their appetite increased. The mean weight gain at the last follow-up was 13% compared with before surgery. During the last visit, the stimulation amplitude was 2.9+/-0.5 V and the total energy delivered per patient averaged 2.7+/-1.4 W x10(-6). The results of patient self-assessment scales indicated a marked improvement in five patients and a moderate improvement in the other two. The neuropsychological data showed no changes. Side effects were mild and tolerable. In all cases, a tradeoff between the optimal voltage and the severity of side effects made it possible to control parkinsonian signs effectively. The most marked side effects directly related to STN stimulation consisted of ballistic or choreic dyskinesias of the neck and the limbs elicited by contralateral STN stimulation above a given threshold voltage, which varied depending on the individual. CONCLUSIONS: Parkinsonian signs can be controlled by bilateral high-frequency STN stimulation. The procedure is well tolerated. On-state dyskinesias were greatly reduced, probably due to the reduction of total antiparkinsonian medication. Bilateral high-frequency STN stimulation compensated for drug reduction and elicited dyskinesias, which differ from those observed following dopaminergic medication. ADL improved significantly, suggesting that some motor tasks performed during everyday chores, and that are not taken into account in the UPDRS motor score, also improved.

Antiparkinson Agents↗

PubMed2000

Effect of subthalamic nucleus stimulation on levodopa-induced dyskinesia in Parkinson's disease.

Article abstract-The authors studied the effect of bilateral subthalamic nucleus stimulation on levodopa-induced dyskinesias in 24 consecutive parkinsonian patients with disabling dyskinesias. The improvement in the three subtypes of levodopa-induced dyskinesias was significant from the third postoperative month and was mainly due to the decrease in the daily dose of levodopa allowed by the stimulation-induced improvement in the motor score.

Adult↗

PubMed1996

Dual somatotopical representations in the primate subthalamic nucleus: evidence for ordered but reversed body-map transformations from the primary motor cortex and the supplementary motor area.

The subthalamic nucleus (STN) is a key structure for somatic motor control via the basal ganglia. In the present study, we demonstrate that the STN of the macaque monkey has dual sets of body part representations. Each of the two separate portions of the STN is characterized with somatotopically arranged direct cortical inputs that are derived from the primary motor cortex (MI) and the supplementary motor area (SMA). The first set of body part representations is transformed from the MI to the lateral STN, whereas the second set is transformed from the SMA to the medial STN. Intracortical microstimulation mapping was carried out to guide paired injections of anterograde tracers into somatotopically corresponding regions of the MI and the SMA. We found that direct inputs from the MI were allocated mostly within the lateral half of the STN, whereas those from the SMA were distributed predominantly within its medial half. Of particular interest was that the arrangement of somatotopical representations from the SMA to the medial STN was reversed against the ordering of those from the MI to the lateral STN; the orofacial, forelimb, and hindlimb parts were represented from medial to lateral within the medial STN, whereas these body parts were represented, in the inverse order, mediolaterally within the lateral STN. Moreover, inputs from homotopical MI and SMA regions were found to converge only partially into the STN. The present findings could account for somatotopically specific involuntary movements manifested in hemiballism that is caused by destruction of the STN.

Animals↗

PubMed2004

PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain.

Pitx2, a homeodomain transcription factor, is essential for normal development of the pituitary gland, craniofacial region, eyes, heart, abdominal viscera, and limbs. Complete loss of Pitx2 in mice (Pitx2(-/-)) results in embryonic lethality by approximately e15 due to cardiac defects, whereas embryos with partial loss of function (Pitx2(neo/-) or Pitx2(neo/neo)) survive until later in development (e17-e19). Pitx2 is expressed in discrete populations of postmitotic neurons in the mouse brain, but its role in mammalian central nervous system (CNS) development is not known. We undertook an analysis of Pitx2-deficient embryos to determine whether loss of Pitx2 affects CNS development. The CNS is normal in hypomorphic e16.5 Pitx2(neo/-) and e18.5 Pitx2(neo/neo) embryos, with no evidence of midline or other defects. Midgestation (e10.5) Pitx2(-/-) embryos have normally formed neural tube structures and cerebral vesicles, whereas older (e14.5) Pitx2(-/-) embryos exhibit loss of gene expression and axonal projections in the subthalamic nucleus (a group of cells in the ventrolateral thalamus) and in the developing superior colliculus of dorsal midbrain. Our results suggest a role for Pitx2 in regulating regionally specific terminal neuronal differentiation in the developing ventrolateral thalamus and midbrain.

Animals↗

PubMed2006

Implantation of electrodes for deep brain stimulation of the subthalamic nucleus in advanced Parkinson's disease with the aid of intraoperative microrecording under general anesthesia.

OBJECTIVE: Deep brain stimulation (DBS) is widely accepted in the treatment of advanced Parkinson's disease (PD) and other movement disorders. The standard implantation procedure is performed under local anesthesia (LA). Certain groups of patients may not be eligible for surgery under LA because of clinical reasons, such as massive fear, reduced cooperativity, or coughing attacks. Microrecording (MER) has been shown to be helpful in DBS surgery. The purpose of this study was to evaluate the feasibility of MER for DBS surgery under general anesthesia (GA) and to compare the data of intraoperative MER as well as the clinical data with that of the current literature of patients undergoing operation under LA. CLINICAL PRESENTATION: The data of nine patients with advanced PD (mean Hoehn and Yahr status, 4.2) who were operated with subthalamic nucleus (STN) DBS under GA, owing to certain clinical circumstances ruling out DBS under LA, were retrospectively analyzed. All operations were performed under analgosedation with propofol or remifentanil and intraoperative MER. For MER, remifentanil was ceased completely and propofol was lowered as far as possible. INTERVENTION: The STN could be identified intraoperatively in all patients with MER. The typical bursting pattern was identified, whereas a widening of the baseline noise could not be as adequately detected as in patients under LA. The daily off phases of the patients were reduced from 50 to 17%, whereas the Unified Parkinson's Disease Rating Scale III score was reduced from 43 (preoperative, medication off) to 19 (stimulation on, medication off) and 12 (stimulation on, medication on). Two patients showed a transient neuropsychological deterioration after surgery, but both also had preexisting episodes of disorientation. One implantable pulse generator infection was noticed. No further significant clinical complications were observed. CONCLUSION: STN surgery for advanced PD with MER guidance is possible with good clinical results under GA. Intraoperative MER of the STN region can be performed under GA with a special anesthesiological protocol. In this setting, the typical STN bursting pattern can be identified, whereas the typical widening of the background noise baseline while entering the STN region is obviously absent. This technique may enlarge the group of patients eligible for STN surgery. Although the clinical improvements and parameter settings in this study were within the range of the current literature, further randomized controlled studies are necessary to compare the results of STN DBS under GA and LA, respectively.

Aged↗

PubMed1980

Single subthalamic nucleus neurons project to both the globus pallidus and substantia nigra in rat.

The organization of the major efferents of the rat subthalamic nucleus (STN) was investigated using a fluorescent retrograde double-labeling technique. Red fluorescent Evans Blue was injected into the globus pallidus and blue fluorescent DAPI-Primuline was injected into the substantia nigra. After retrograde axonal transport many double-labeled neurons were seen throughout the STN. Occasionaly double-labeled cells were seen in the lateral hypothalamus just medial to the STN and in a thin lateral strip of neurons extending laterally from the STN. Evidence for a mediolateral topography in both the STN-pallidal and STN-nigral pathways was obtained. The STN contains few, if any, local interneurons. Cell counts revealed that at least 94% of, and possibly all, STN neurons send axon collaterals to both the globus pallidus and substantia nigra.

Animals↗

PubMed2006

Long-term effects of bilateral subthalamic nucleus stimulation on health-related quality of life in advanced Parkinson's disease.

We evaluated the long-term effects of subthalamic nucleus (STN) stimulation on health-related quality of life (HRQL) in patients with advanced Parkinson's disease (PD). STN stimulation improves motor function and decreases medication requirements in patients with advanced PD. The impact of STN stimulation on HRQL is less well established, especially beyond 1 year after surgery. We report HRQL outcomes for 18 patients with advanced PD. Patients were evaluated with the Parkinson's Disease Questionnaire-39 (PDQ-39), the Medical Outcome Study Short Form (SF-36), and the EuroQol visual analogue scale (VAS) before surgery, 6 months postoperatively, and at a long-term follow-up visit (mean, 35.9 months; range, 18-57 months after surgery). Preoperative scores on HRQL measures were compared to results obtained at short- and long-term follow-up evaluations. The VAS and all domains of the PDQ-39 except for cognition, communication, and social support showed marked improvements at 6 months after surgery. At the long-term follow-up, there were sustained improvements in the VAS (63% improvement; P = 0.0009) and in several domains of the PDQ-39 [mobility: 20%, P = 0.01; activities of daily living (ADL): 29%, P = 0.005; emotional well-being: 26%, P = 0.02; stigma: 43%, P = 0.003; and bodily discomfort: 35%, P = 0.007]. At the long-term evaluation, only the vitality domain of the SF-36 was significantly improved from baseline (16%; P = 0.01). In this selected group of patients, many of the short-term gains in HRQL persist beyond 18 months after STN implantation. Benefits in nonmotor aspects of HRQL such as bodily discomfort and stigma appear to be among the most durable.

Adult↗