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PubMed2005

Effect of GABA(A) receptor stimulation in the subthalamic nucleus on motor deficits induced by nigrostriatal lesions in the rat.

Inhibition of the subthalamic nucleus by lesions or GABAergic agonists improves motor symptoms in monkeys or humans with a loss of nigrostriatal dopaminergic neurons, a characteristic of Parkinson's disease. In rats, nigrostriatal lesions induce deficits in a variety of motor tests that are ameliorated by dopaminergic agonists. However, the validity of these tests to predict the beneficial effects of subthalamic inhibition is not known. We have examined the effects of an intrasubthalamic injection of the GABA(A) receptor agonist muscimol (0.1 microg/0.1 microL) in intact rats and in rats with a unilateral nigrostriatal lesion. Muscimol induced a mild ipsiversive rotation in sham-operated (control) rats and blocked contraversive rotations induced by apomorphine in lesioned rats. In addition, in the cylinder test of limb use asymmetry, muscimol decreased the ipsilateral bias after lesion without inducing any significant effect in sham-operated controls. In the forced-step test, however, 0.1 microg (but not 0.01 microg) of muscimol into the subthalamic nucleus induced a behavioral bias by markedly decreasing the number of adjusting steps of the contralateral limb in control rats, similar to the effect of a nigrostriatal lesion. Neither dose improved performance in this test in rats with lesions, and the higher dose exacerbated the deficit. The data support a beneficial role of stimulating subthalamic GABA(A) receptors for akinesia but also reveal negative behavioral effects of this treatment and suggest that the cylinder and forced-step tests measure different aspects of behavioral deficits after dopaminergic lesions.

Animals↗

PubMed1993

[Effects of the stimulation of the subthalamic nucleus in Parkinson disease].

In Parkinson's disease, experimental studies favour a neuronal hyperactivity of the subthalamic nucleus. We carried out a subthalamic nucleus electrical stimulation in a patient aged 51, suffering for 8 years from a severe akineto-rigid form of Parkinson's disease, complicated with an on-off effect. Stereotaxic surgery was done under local anaesthesia on one side. Within the theoretical target, a 130 Hz stimulation induced akinesia alleviation mainly on the contralateral limbs. No abnormal movement was noticed. Then a long-term quadripolar DBS Medtronic electrode was inserted in that area. The study of the effects of chronic stimulation is in progress to determine the best temporal and electrical stimulation variables.

Electric Stimulation Therapy↗

PubMed1993

Evidence that the parafascicular projection to the subthalamic nucleus is glutamatergic.

The parafascicular nucleus projection to the subthalamic neurones has an excitatory synaptic effect. We have examined the possible glutamatergic mediation of this pathway. The initial excitatory response elicited by electrical stimulation of the parafascicular neurones was inhibited by a microinjection of excitatory amino acid receptor antagonists into the subthalamic nucleus. The antagonists were the broad spectrum kynurenic acid, the NMDA selective antagonist d-AP-5 and the AMPA antagonist CNQX. Their effects were dose-dependent and reversible. The results suggest that the excitatory effect of the parafascicular neurones is mediated by AMPA and NMDA receptors.

2-Amino-5-phosphonovalerate↗

PubMed2004

Subthalamic nucleus and internal globus pallidus scale with the rate of change of force production in humans.

The basal ganglia, motor cortex, and cerebellum have been implicated as a circuit that codes for movement velocity. Since movement velocity covaries with the magnitude of force exerted and previous studies have shown that similar regions scale in activation for velocity and force, the scaling of neuronal activity with movement velocity could be due to the force exerted. The present study implemented a parametric functional magnetic resonance imaging (fMRI) design to determine which brain regions directly scale with the rate of change of force production, independent of the magnitude of force exerted. Nine healthy adults produced force with their right middle finger and thumb at 25% of their maximal voluntary contraction across four conditions: (1) fast pulse, (2) fast hold, (3) medium hold, and (4) slow hold. There were three primary findings: (i) the activation volume in multiple regions increased with the duration of the force contraction, (ii) only the activation volume in the bilateral internal globus pallidus and left subthalamic nucleus parametrically scaled with the rate of change of force production, and (iii) there was an inverse relation between the activation volume in the subthalamic nucleus and internal globus pallidus with the rate of change of force production. The current findings are the first to have used neuroimaging techniques in humans to segregate the functional anatomy of the internal globus pallidus from external globus pallidus, distinguish functional activation in the globus pallidus from the putamen, and demonstrate task-dependent scaling in the subthalamic nucleus and internal globus pallidus. We conclude that fast, ballistic force production is preprogrammed, requiring a small metabolic demand from the basal ganglia. In contrast, movements that require the internal regulation of the rate of change of force are associated with increased metabolic demand from the subthalamic nucleus and internal segment of the globus pallidus.

Adult↗

PubMed2005

The subthalamic nucleus exerts opposite control on cocaine and 'natural' rewards.

A challenge in treating drug addicts is preventing their pathological motivation for the drug without impairing their general affective state toward natural reinforcers. Here we have shown that discrete lesions of the subthalamic nucleus greatly decreased the motivation of rats for cocaine while increasing it for food reward. The subthalamic nucleus, a key structure controlling basal ganglia outputs, is therefore able to oppositely modulate the effect of 'natural' rewards and drugs of abuse on behavior. Modulating the activity of the subthalamic nucleus might prove to be a new target for the treatment of cocaine addiction.

Animals↗

PubMed1999

Effects of dopamine depletion of the dorsal striatum and further interaction with subthalamic nucleus lesions in an attentional task in the rat.

The present study investigated the effects of 6-hydroxydopamine lesions of the dorsal striatum on a five choice serial reaction time task which assesses visual sustained and divided attention. Striatal dopamine loss by itself produced no deficits in accuracy on the standard form of the task, but lengthened response latencies and increased omissions and perseverative behaviour. Reducing the temporal predictability of the visual event led to impaired accuracy, contrasting with previously published effects of ventral striatal dopamine depletion. To further investigate the interactions between dopaminergic and glutamatergic systems within the basal ganglia, we have tested the effects of 6-hydroxydopamine lesions in animals bearing subthalamic nucleus lesions. Previous evidence [C. Baunez and T. W. Robbins, (1997) Eur. J. Neurosci. 9, 2086-2099] has revealed multiple deficits after bilateral lesions of the subthalamic nucleus. The present study replicated these effects. In combination with subthalamic nucleus lesions, striatal dopamine loss antagonised the increase in premature responding but did not counteract any of the other impairments. These results show the involvement of the dopaminergic nigrostriatal pathway in motor attention and arousal. Furthermore, they underline the independence of subthalamic nucleus lesion-induced effects from dopaminergic systems.

Animals↗

PubMed1989

Feline subthalamic nucleus neurons contain glutamate-like but not GABA-like or glycine-like immunoreactivity.

The identity of the neurotransmitter of subthalamic nucleus neurons has not been definitively established. GABA, glycine, and glutamate have all been hypothesized to be the neurotransmitter of these neurons. Immunohistochemistry with 3 well characterized antisera against glutamate, GABA, and glycine were used to study feline subthalamic nucleus neurons. These neurons were found to contain intense glutamate-like but not GABA- or glycine-like immunoreactivity. The surrounding neuropil contained glutamate-like and GABA-like but not glycine-like immunoreactivity. These results support the hypothesis that subthalamic nucleus neurons are glutamatergic.

Animals↗

PubMed1999

Localization of calcium-binding proteins and GABA transporter (GAT-1) messenger RNA in the human subthalamic nucleus.

The distribution of messenger RNA encoding the human GAT-1 (a high-affinity GABA transporter) was investigated in the subthalamic nucleus of 10 neurologically normal human post mortem cases. Further, the distribution of messenger RNA and protein encoding the three neuronally expressed calcium-binding proteins (calbindin D28k, parvalbumin and calretinin) was similarly investigated using in situ hybridization and immunohistochemical techniques. Cellular sites of calbindin D28k, parvalbumin, calretinin and GAT-1 messenger RNA expression were localized using human-specific oligonucleotide probes radiolabelled with [35S]dATP. Sites of protein localization were visualized using specific anti-calbindin D28k, anti-parvalbumin and anti-calretinin antisera. Examination of emulsion-coated tissue sections processed for in situ hybridization revealed an intense signal for GAT-1 messenger RNA within the human subthalamic nucleus, indeed the majority of Methylene Blue-counterstained cells were enriched in this transcript. Further, a marked heterogeneity was noted with regard to the expression of the messenger RNA's encoding the three calcium-binding proteins; this elliptical nucleus was highly enriched in parvalbumin messenger RNA-positive neurons and calretinin mRNA-positive cells but not calbindin messenger RNA-positive cells. Indeed, only an occasional calbindin messenger RNA-positive cell was detected within the mediolateral extent of the nucleus. In marked contrast, numerous parvalbumin messenger RNA-positive cells and calretinin messenger RNA-positive cells were detected and they were topographically distributed; parvalbumin messenger RNA-positive cells were highly enriched in the dorsal subthalamic nucleus extending mediolaterally; calretinin messenger RNA-positive cells were more enriched ventrally although some degree of overlap was apparent. Computer-assisted analysis of the average cross-sectional somatic area of parvalbumin, calretinin and GAT-1 messenger RNA-positive neurons revealed them all to be in the range of 300 microm2. The unique patterns of calcium-binding protein gene expression were similarly reflected at the protein level; an abundance of parvalbumin- and calretinin-immunopositive neurons were observed whereas only occasional intensely-labelled calbindin-immunopositive fibres were seen, no calbindin-immunopositive cells were detected. Single and double labelling studies show that parvalbumin-immunopositive neurons were mainly localized in the dorsal region of the nucleus, and calretinin-immunopositive neurons were mainly localized in the ventral region although there was overlap with double-labelled neurons located in the middle and dorsal regions. The significance of these findings, in particular the expression of GAT-1, a high-affinity GABA uptake protein, for basal ganglia signalling is discussed.

Basal Ganglia↗

PubMed2003

High-frequency stimulation of the subthalamic nucleus enhances striatal dopamine release and metabolism in rats.

High-frequency stimulation of the subthalamic nucleus is believed to exert its main effects via the basal ganglia output structures. Previously, we have shown a concomitant increase in striatal dopamine (DA) metabolites in normal and 6-hydroxydopamine-lesioned rats. The present study was designed to determine whether this increase in striatal DA metabolites reflects enhanced intraneuronal DA turnover or, alternatively, is due to increased DA release with subsequent rapid and efficient reuptake and/or metabolism. Thus, high-frequency stimulation of the subthalamic nucleus was performed in normal rats after inhibition of DA reuptake, metabolism or DA depletion. Extracellular levels of striatal DA and its metabolites were assessed using microdialysis. Our data suggest that subthalamic high-frequency stimulation increases striatal DA release and activates independent striatal DA metabolism. Since such changes could be triggered by modification of either the activity or the gene expression of the rate-limiting enzyme tyrosine hydroxylase, an activity assay and RT-PCR of striatal and nigral samples were performed. Subthalamic stimulation increased striatal tyrosine hydroxylase activity without affecting gene expression. We, therefore, conclude that the application of subthalamic high-frequency stimulation could partially compensate for the DA deficit by inducing increased striatal DA release and metabolism.

Animals↗

PubMed1999

Increased [125I]sulpiride binding in the subthalamic nucleus of rats with nigrostriatal lesions.

Subthalamic nucleus (STN) hyperactivity follows lesions of mesencephalic dopaminergic neurons in animal models of Parkinson's disease. The mechanism leading to sustained STN hyperactivity in parkinsonism is not well understood, but it seems not to depend on the integrity of striato-pallido-subthalamic connections (the so called indirect pathway). Sustained STN hyperactivity could result from the loss of the direct dopaminergic innervation of the STN. Here we report increased [125I]sulpiride binding in the STN of rats with 6-hydroxydopamine (6-OHDA) lesions of mesencephalic dopaminergic neurons. Furthermore, we found that chronic oral treatment with levodopa reverted the lesion-induced increase in [125I]sulpiride binding. Our results demonstrate that most STN D2-class dopamine receptors are postsynaptic to afferent dopaminergic fibers. Furthermore, they suggest that alterations of local STN dopaminergic mechanisms could play a role in the pathophysiology of parkinsonism and mediate the therapeutic/adverse effects of chronic levodopa administration.

Administration, Oral↗

PubMed2001

Localisation of the subthalamic nucleus using Radionics Image Fusion and Stereoplan combined with field potential recording. A technical note.

Subthalamic nucleus stimulation is an effective therapy for alleviating parkinsonian tremor, rigidity and bradykinesia. Although microelectrode recording is said to be essential for accurate targeting, this often prolongs the operation and the multiple recording tracts required may increase the incidence of complications, particularly haemorrhage. We describe a technique for implantation of deep brain electrodes in the subthalamic nucleus using MRI/CT fusion for anatomical localisation followed by bipolar recording of focal field potentials via the implanted stimulating electrode for neurophysiological confirmation of the stimulation site. The technique is effective, safe and requires much less time, and can be used as an alternative method to microelectrode recording.

Electric Stimulation Therapy↗

PubMed2003

Sonic hedgehog is a neuromodulator in the adult subthalamic nucleus.

It is well established that members of the hedgehog family are involved in tissue patterning during development. We herein show that sonic hedgehog signaling molecules are differentially regulated by dopamine depletion in the basal ganglia of adult animals and specifically that sonic hedgehog levels are reduced in an animal model of Parkinson's disease. In addition, we show that sonic hedgehog protein inhibits electrical activity in the subthalamic nucleus, a key element of basal ganglia, within minutes of application. As the subthalamic nucleus is overactive in parkinsonism, we suggest that enhancement of sonic hedgehog signaling in the subthalamic nucleus may be of therapeutic value in Parkinson's disease.

Animals↗

PubMed2002

Effects of subthalamic nucleus (STN) stimulation on motor cortex excitability.

BACKGROUND: Deep brain stimulation of the internal global pallidus (GPi) and the subthalamic nucleus (STN) has become a treatment alternative in advanced PD. Although the effects of GPi stimulation have been examined recently, little is known about STN stimulation effects on motor cortex excitability. METHODS: The effects of STN stimulation were studied in eight patients with advanced PD using paired-pulse transcranial magnetic stimulation (TMS) in comparison with healthy control subjects. Motor evoked potentials following paired-pulse TMS (interstimulus interval 3 ms to test for corticocortical inhibition vs 13 ms for facilitation) have been recorded from the extensor carpi radialis and its functional antagonist, the flexor carpi radialis muscle. Silent period (SP) was also determined. Patients were examined under four conditions: medication "off"/stimulator "off" vs medication "on"/stimulator "off" vs medication "off"/stimulator "on" vs medication "on"/stimulator "on." RESULTS: Although the mean values for intracortical inhibition (ICI) were not significantly different, data variation was smaller and levels of significance higher with the STN stimulator switched "on," suggesting that ICI was more consistent. SP during stimulator "on"/medication "on" was longer than during stimulator "off"/medication "off." Motor performance as indicated by a finger-tapping test and Unified PD Rating Scale III was significantly better with dopaminergic medication and further improved with stimulator "on." CONCLUSIONS: Results suggest an effect of subthalamic nucleus stimulation on intracortical inhibitory mechanisms. This hypothesis could at least partially explain a more consistent depression of motor evoked potentials following inhibiting paired-pulse transcranial magnetic stimulation, a longer silent period (under stimulator "on"/medication "on"), and a reduction of akinesia and rigidity leading to a better motor performance in subthalamic nucleus-stimulated patients.

Aged↗

PubMed1998

Targeting the subthalamic nucleus in the treatment of Parkinson's disease.

As more is learnt about the functional implications of basal ganglia connectivity, the role of the subthalamic nucleus as a target site for stereotactic procedures in the amelioration of the symptoms of Parkinson's disease is becoming clearer. A comparison of various neurosurgical procedures in the disease is discussed in relation to current thinking about circuitry. Experimental investigations involving lesioning or stimulation of the subthalamic nucleus in nonhuman primate models and in clinical studies of Parkinson's disease are compared. Neurosurgical procedures that lesion structures bilaterally are more likely to induce side effects than is deep-brain stimulation, which has the added advantage of reversibility and which is more amenable to titration in relation to medication and dosage. A small but growing number of parkinsonian patients have received subthalamic stimulation either unilaterally or bilaterally. Stimulation of the subthalamic nucleus ameliorates tremor, rigidity and hypokinesia, as opposed to thalamic stimulation which is probably best reserved for tremor-dominant patients. Such procedures also do not involve the same complex technical and ethical issues that are associated with foetal mesencephalic grafting. Although subthalamic stimulation shows great promise, it has not been developed to the point where it can be used as more than an experimental treatment. Further experimental research is required before the new strategies can be used on a larger scale.

Animals↗

PubMed2004

Dopamine D4 receptors inhibit depolarization-induced [3H]GABA release in the rat subthalamic nucleus.

We explored the role of dopamine D4 receptors on [3H]GABA release in the subthalamic nucleus. [3H]GABA release was evoked by high K+ in slices of the nucleus. The selective dopamine D4 receptor agonist PD168,077 (N-[[4-(2-cyanophenyl)-1-piperazynil]methyl]-3-methyl-benzamide) inhibited GABA release with greater potency (EC50=3.2 nM) than quinpirole (EC50=200 nM). SKF 21297 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide), a dopamine D1-like receptor agonist, had no effect. L-745,870 (3-[[4-(4-chlorophenyl)piperazin-1-yl]methyl]-1-1H-pyrollo[2,3-b] pyridine), a selective dopamine D4 receptor antagonist, reverted the quinpirole inhibition with greater potency (IC50=8.7 nM) than that of the dopamine D2/D3 receptor antagonist sulpiride and raclopride (IC50=4804 and 788 nM, respectively). Both methylphenidate and methamphetamine, dopamine reuptake blockers, inhibited by 30% high K(+)-evoked GABA release; the inhibition was blocked by L-745,870. These results show that dopamine D4 receptors modulate GABA release in the subthalamic nucleus. The results would explain how agents that increase interstitial dopamine like methylphenidate and amphethamine might control locomotor hyperactivity seen in disorders of dopamine D4 receptors.

Animals↗

PubMed1999

Effects of transient inactivation of the subthalamic nucleus by local muscimol and APV infusions on performance on the five-choice serial reaction time task in rats.

Within the basal ganglia circuitry, recent conceptions of the subthalamic nucleus are that it fulfils integrative functions. We have previously shown that bilateral excitotoxic lesions of the subthalamic nucleus induce behavioural deficits in a five-choice serial reaction time task in the rat, consistent with attentional impairments and suggesting important roles of this basal ganglia structure in mechanisms of behavioural control. In the present study, we tested the effects of (i) blocking its excitatory inputs (originating mainly in the cerebral cortex and the parafascicular nucleus of the thalamus) via the NMDA receptors and (ii) stimulating its GABA receptors to mimick the influence of its inhibitory inputs (mainly from the globus pallidus). Bilateral microinfusions of APV (NMDA receptor antagonist) or muscimol (GABA-A receptor agonist) into the subthalamic nucleus were administered to rats trained in the same five-choice serial reaction time task. Both APV (0.125-0.5 microg) and muscimol (1-3 ng) reduced choice accuracy, slowed correct responses and increased omissions and perseverative responses. Premature responses tended to increase after APV but decrease after muscimol. Increased perseverations at the food magazine occurred only after muscimol infusions. These results reproduce many of the effects of lesions of the STN and are consistent with an integrative role for this structure in pallidal and thalamo-cortical processing.

2-Amino-5-phosphonovalerate↗

PubMed2004

Determining the position and size of the subthalamic nucleus based on magnetic resonance imaging results in patients with advanced Parkinson disease.

OBJECT: The subthalamic nucleus (STN) is a target in surgery for Parkinson disease, but its location according to brain atlases compared with its position on an individual patient's magnetic resonance (MR) images is incompletely understood. In this study both the size and location of the STN based on MR images were compared with those on the Talairach and Tournoux, and Schaltenbrand and Wahren atlases. METHODS: The position of the STN relative to the midcommissural point was evaluated on 18 T2-weighted MR images (2-mm slices). Of 35 evaluable STNs, the most anterior, posterior, medial, and lateral borders were determined from axial images, dorsal and ventral borders from coronal images. These methods were validated using histological measurements in one case in which a postmortem examination was performed. The mean length of the anterior commissure-posterior commissure was 25.8 mm. Subthalamic nucleus borders derived from MR imaging were highly variable: anterior, 4.1 to -3.7 mm relative to the midcommissural point; posterior, 4.2 to 10 mm behind the midcommissural point; medial, 7.9 to 12.1 mm from the midline; lateral, 12.3 to 15.4 mm from the midline; dorsal, 0.2 to 4.2 mm below the intercommissural plane; and ventral, 5.7 to 9.9 mm below the intercommissural plane. The position of the anterior border on MR images was more posterior, and the medial border more lateral, than its position in the brain atlases. The STN was smaller on MR images compared with its size in atlases in the anteroposterior (mean 5.9 mm), mediolateral (3.7 mm), and dorsoventral (5 mm) dimensions. CONCLUSIONS: The size and position of the STN are highly variable, appearing to be smaller and situated more posterior and lateral on MR images than in atlases. Care must be taken in relying on coordinates relative to the commissures for targeting of the STN.

Adult↗

PubMed2002

Intraoperative microrecordings of the subthalamic nucleus in Parkinson's disease.

Microelectrode recordings of single unit neuronal activity were used during stereotactic surgery to define the subthalamic nucleus for chronic deep brain stimulation in the treatment of Parkinson's disease. By using five parallel trajectories, often two to three microelectrodes allow us to recognize subthalamic nucleus (STN) neuronal activity. STN neurons were easily distinguished from cells of the overlying zona incerta and the underlying substantia nigra. During a typical exploratory track, we can observe a very low background noise in the zona incerta and almost complete absence of single cell recording. Penetration of the electrode tip into the STN is characterized by a sudden increase in background activity and single cell activity of spontaneously active neurons. The exit of electrode tip out of the STN corresponds to a decrease in background noise and a loss of single cell activity. Spontaneous neuronal activity increases again when the electrode tips enters the substantia nigra pars reticulata (SNr); however, the activity is less rich than in the STN, indicating a more cell-sparse nucleus. STN neurons are characterized by a mean firing rate of 42.30 +/- 22.00 spikes/sec (mean +/- SD). The STN cells exhibited irregular or bursty discharge pattern. The pattern of single cell activity in the SNr is a more regular tonic activity that can easily be distinguished from the bursting pattern in the STN. The most useful criteria to select a trajectory are (1) the length of an individual trajectory displaying typical STN activity, (2) the bursting pattern of activity, and (3) motor responses typical of the sensorimotor part of the nucleus. In conclusion, microelectrode recording of the subthalamic area improves the accuracy of targeting the STN.

Brain Mapping↗