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PubMed1993

The subthalamic nucleus: a possible target for stereotaxic surgery in Parkinson's disease.

Hyperactivity in the subthalamic nucleus (STN) projections to the globus pallidus medialis (GPM) has been established as a crucial feature of parkinsonism in animal models of Parkinson's disease (PD). Recent experiments blocking the STN glutamatergic output to GPM or lesioning the STN support this concept by showing a dramatic reversal of parkinsonism. We review the role of stereotaxic surgery in the past and the possible future application of subthalamotomy for PD.

Animals↗

PubMed1986

Excitatory effect of iontophoretically applied dopamine on identified neurons of the rat subthalamic nucleus.

The effects of iontophoretic applications of dopamine were studied on neurons of the subthalamic nucleus (STN) identified by their histological location, their response to contralateral vibrissae stimulation and, for 33% of them, by their antidromic activation from the globus pallidus. A potent and consistent excitatory effect of dopamine was found for all the STN neurons tested. Depression of spontaneous activity or mixed responses were never recorded in the STN. The excitatory response was antagonized by iontophoretic application of flupenthixol.

Animals↗

PubMed1997

Excitation of rat subthalamic nucleus neurones in vitro by activation of a group I metabotropic glutamate receptor.

The subthalamic nucleus (SThN) provides a glutamate mediated excitatory drive to several other component nuclei of the basal ganglia, thereby significantly influencing locomotion and control of voluntary movement. We have characterised functionally the metabotropic glutamate (mGlu) receptors in the SThN using extracellular single unit recording from rat midbrain slices. SThN neurones fired action potentials spontaneously at a rate of 10 Hz which was increased by the group I/II mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3 R-ACPD; 1-30 microM) and the group I selective agonist (S, R)-dihydroxyphenylglycine (DHPG; 1-30 microM). However, both the group II selective agonist (1S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; 1 microM) and the group III selective agonist (S)-2-amino-4-phosphonobutanoic acid (L-AP4; 10 microM) were without effect, indicating that the excitation was mediated by a group I mGlu receptor. The excitation caused by DHPG (3 microM) was reversed by co-application of the mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG; 500 microM). Thus a group I mGlu receptor mediates excitation of SThN neurones, and suggests a use for group I mGlu receptor ligands for treatment of both hypo- and hyperkinetic disorders of basal ganglia origin, such as Parkinson's disease and Huntington's disease.

Adenine Nucleotides↗

PubMed1999

Subthalamic nucleus stimulation for gait disturbance in Parkinson's disease.

OBJECTIVE: A preliminary study of subthalamic nucleus (STN) stimulation was performed to determine its applicability for the treatment of gait and postural disturbances in Parkinson's disease. METHODS: Five Parkinson's disease patients with freezing gait and postural instability were selected for this study. Their ages ranged from 60 to 73 years (mean+/-standard deviation, 65.6+/-4.8 years). Semi-microelectrode recording was used to identify the STN and to place a chronic electrical stimulation electrode within the right STN in all patients. The Unified Parkinson's Disease Rating Scale and the modified Hoehn and Yahr Staging Scale were used to assess patients in on- and off-drug conditions before surgery and 3 months after surgery. RESULTS: The scores on the Hoehn and Yahr Staging Scale and the total Unified Parkinson's Disease Rating Scale for akinesia (P < 0.05), gait (P < 0.05), and gait and posture (P < 0.01) in off-drug on-stimulation conditions significantly improved over the preoperative and postoperative off-drug off-stimulation conditions (analysis of variance [ANOVA], P < 0.01). Improvement over the preoperative scores was 24% on the Hoehn and Yahr Staging Scale, 43.6% on the total Unified Parkinson's Disease Rating Scale, 33.4% for akinesia, 36.6% for gait, and 38.7% for gait and posture. However, stimulation in the on-drug phase did not show a significant difference compared with pre- and postoperative conditions (ANOVA, P > 0.05). Comparisons between preoperative on-drug and postoperative off-drug on-stimulation conditions revealed that there were no significant differences in the scores, except for gait (ANOVA, P < 0.05). The scores on subscales for falling, freezing, walking, and gait in off-drug on-stimulation conditions were significantly improved over the scores for preoperative and postoperative off-stimulation (ANOVA, P < 0.05), but the score for postural stability remained unchanged. CONCLUSION: Our findings showed that STN stimulation effectively alleviates freezing gait and improves walking to its status during the preoperative on-drug phase and can be applied for treatment of Parkinson's disease patients with these symptoms.

Aged↗

PubMed2004

Subthalamic nucleus stimulation and dysarthria in Parkinson's disease: a PET study.

In Parkinson's disease, functional imaging studies during limb motor tasks reveal cerebral activation abnormalities that can be reversed by subthalamic nucleus (STN) stimulation. The effect of STN stimulation on parkinsonian dysarthria has not, however, been investigated using PET. The aim of the present study was to evaluate the effect of STN stimulation on regional cerebral blood flow (rCBF) during speech production and silent articulation in patients with Parkinson's disease. Ten Parkinson's disease patients surgically implanted bilaterally in the STN and with significant improvement of their dysarthria induced by STN stimulation were included. Ten healthy control subjects also participated in this study. Control subjects performed six sessions of [15O]H2O-PET scanning corresponding to three duplicated conditions externally cued by an auditory signal. The conditions were: (i) rest; (ii) production of a short, simple sentence; and (iii) silent articulation of the same sentence. Parkinson's disease patients carried out the six PET sessions twice, i.e., in the ON and OFF STN stimulation states. PET data analysis was performed using statistical parametric mapping (SPM99). In control subjects, speech production (SP) compared with rest was associated with increased rCBF bilaterally in the primary motor cortex (M1) corresponding to the orofacial somatotopy, the supplementary motor area (SMA), the associative auditory cortex and the cerebellar hemispheres. Silent articulation (SA) compared with rest induced a bilateral rCBF increase restricted to the orofacial M1 and cerebellar hemispheres. In Parkinson's disease patients in the OFF stimulation condition, during both SP and SA there was a lack of activation in the right orofacial M1 and in the cerebellum, abnormal increased rCBF in the right superior premotor cortex, and overactivation of the SMA. There was also an abnormal, increased rCBF in the dorsolateral prefrontal cortex (DLPFC) only during SP and increased rCBF in the left insula only during SA. In Parkinson's disease patients ON stimulation, for both SP and SA the activation pattern appeared similar to that in control subjects. In conclusion, our results suggest that parkinsonian dysarthria is associated with altered recruitment of the main motor cerebral regions (orofacial M1, cerebellum), and increased involvement of the premotor and prefrontal cortices (DLPFC, SMA, superior premotor cortex). These abnormal activations are different from those reported during hand motor tasks. They could be a compensatory mechanism, but might also arise directly as part of the pathophysiology of Parkinson's disease. STN stimulation tends to reverse these abnormal activations, which is consistent with the observed improvement of Parkinson's disease dysarthria.

Brain↗

PubMed2005

The effect of subthalamic nucleus stimulation on kinaesthesia in Parkinson's disease.

BACKGROUND: Parkinson's disease is accompanied by deficits in passive motion and limb position sense. OBJECTIVE: To investigate whether deep brain stimulation of the subthalamic nucleus (STN-DBS) reverses these proprioceptive deficits. METHODS AND RESULTS: A passive movement task was applied to nine patients with Parkinson's disease and bilateral chronic STN-DBS and to seven controls. Thresholds for 75% correct responses were 0.9 degrees for controls, 2.5 degrees for Parkinson's disease patients when stimulation was OFF, and 2.0 degrees when stimulation was ON. CONCLUSIONS: STN-DBS improves kinaesthesic deficits in Parkinson's disease, but does not lead to a full recovery of proprioceptive function.

Adult↗

PubMed2002

Deep brain stimulation of the subthalamic nucleus versus levodopa challenge in Parkinson's disease: measuring the on- and off-conditions with FDG-PET.

In order to compare the effects of high-frequency stimulation of the subthalamic nucleus (STN-DBS) and a levodopa-challenge on cerebral metabolic activity, we conducted PET scans with [(18)F]2-fluoro-2-deoxyglucose (FDG) in the drug- and stimulation- on- and off-condition in a single patient suffering from advanced PD. Our data revealed evidence for improved thalamocortical processing released from inhibition by overactive basal ganglia output nuclei in both on-conditions. While levodopa also led to a reduction of lentiform hyperactivity, effective STN stimulation seemed to interfere with distinct cerebellar and limbic circuits.

Aged↗

PubMed2004

Improvement in quality of life in patients with advanced Parkinson's disease following bilateral deep-brain stimulation in subthalamic nucleus.

In this article we investigate the changes observed in the scales that quantify the quality of life (PDQ-39) in patients that have already completed 1 and 2 years of bilateral subthalamic stimulation (DBS-STN). Fourteen patients were evaluated 1 year after DBS-STN; the evaluation was repeated on 11 of them, 2 years after surgery. All of them suffered from Parkinson's disease with a 14.3 (+/-5.7) years history of motor complications. Patients were selected according to CAPSIT criteria. All of them were implanted bilateral electrodes in the subthalamic nucleus. The parameters applied were UPDRS II, UPDRS III, PDQ-39, and the scale of quality of life for caregivers (SQLC). Scorings in motor scales (UPDRS III) improved 45% in relation to the first year, and 48% in relation to the second year (P < 0.001). Patient's quality of life (PDQ-39 summary index) improvement was 62% 2 years after surgery (P < 0.001), and caregivers' quality of life improvement was 68% (P = 0.002) by the same time. DBS-STN is a therapy that efficiently improves the quality of life of selected patients with Parkinson's disease. This improvement is still present 2 years after surgery and has a positive impact on caregivers quality of life.

Aged↗

PubMedDate not supplied

Unsupervised Spike Sorting of extracellular electrophysiological recording in subthalamic nucleus of Parkinsonian patients.

The present study demonstrates the application of the Unsupervised Spike Sorting algorithm (USS) to separation of multi-unit recordings and investigation of neuronal activity patterns in the subthalamic nucleus (STN). This nucleus is the main target for deep brain stimulation (DBS) in Parkinsonian patients. The USS comprises a fast unsupervised learning procedure and allows sorting of multiple single units, if any, out of a bioelectric signal. The algorithm was tested on a simulated signal with different levels of noise and with application of Time and Spatial Adaptation (TSA) algorithm for denoising. The results of the test showed a good quality of spike separation and allow its application to investigation of neuronal activity patterns in a medical application. One hundred twenty-four single channel multi-unit records from STN of 6 Parkinsonian patients were separated with USS into 492 single unit trains. Auto- and crosscorrellograms for each unit were analyzed in order to reveal oscillatory, bursting and synchronized activity patterns. We analyzed separately two brain hemispheres. For each hemisphere the percentage of units of each activity pattern were calculated. The results were compared for the first and the second operated hemispheres of each patient and in total.

Action Potentials↗

PubMed2004

Glutamic acid decarboxylase 67 mRNA regulation in two globus pallidus neuron populations by dopamine and the subthalamic nucleus.

The globus pallidus (GP) consists of two neuron populations, distinguished according to their immunoreactivity for parvalbumin (PV). The PV-immunoreactive (PV+) neurons project preferentially to "downstream" targets such as the subthalamic and entopeduncular nuclei, whereas neurons lacking PV (PV- neurons) project preferentially to the striatum, suggesting a role for PV- cells in feedback to striatal neurons. Although dopamine D2 antagonist administration induces immediate early gene expression preferentially in PV- GP neurons, little is known about long-term regulation of PV- versus PV+ GP neurons. Nigral 6-hydroxydopamine (6-OHDA) lesions or repeated D2-class antagonist injections have been shown to increase pallidal expression of glutamate decarboxylase (GAD(67) isoform) mRNA. This increase in GAD(67) is believed to be secondary to activation of excitatory subthalamopallidal projections. The current study examined the effects of subthalamic nucleus (STN) lesion on 6-OHDA- or repeated D2 antagonist-induced changes in GP GAD(67) mRNA expression in PV+ and PV- neurons. Five or 21 d after nigral 6-OHDA injections or after 3, 7, or 21 d of D2 antagonist administration, GAD(67) mRNA increased in both the PV- and PV+ GP neurons, but the magnitude of the increase was significantly greater in PV- neurons. By contrast, STN lesion resulted in declines in GAD(67) mRNA in both cell populations, with the decreases in PV+ neurons exceeding those in PV- neurons. Furthermore, STN lesion completely blocked 6-OHDA- or D2 antagonist-induced GAD(67) mRNA increases in PV+ cells but only partly offset the GAD(67) mRNA increase in PV- pallidal neurons. Thus, the PV+ and PV- neurons are influenced in qualitatively similar ways by dopamine and the STN, but these cell types exhibit contrasting degrees of regulation by the dopaminergic and STN perturbations. This pattern of results has implications for pallidal control of striatal versus downstream basal ganglia nuclei.

Animals↗

PubMed2005

The relationship between oscillatory activity and motor reaction time in the parkinsonian subthalamic nucleus.

Averaging techniques have demonstrated that movement preparatory cues and movement itself are associated with marked reductions in the oscillatory synchrony of local neuronal populations in the area of the human parkinsonian subthalamic nucleus (STN), as indexed by 8-30 Hz local field potential (LFP) activity. In order to examine the detailed nature and strength of the relationship between reductions in oscillatory activity and movement we examined single-trial LFP activity recorded from the STN area of parkinsonian subjects engaged in a choice reaction task. In this task an initial warning cue was either fully predictive or non-predictive of the hand required to make a later motor response. This motor response was elicited by a second go cue to which data were aligned. We observed a significant linear relationship between the onset time of oscillation reduction after go cues and subsequent motor response time across single trials within subjects. Consistent with this observation we also found a positive correlation of power with response time following go cues. In addition, we observed shorter durations of suppression in fully predictive trials where selection of the response could precede go cue presentation. The results are consistent with the hypothesis that reductions in 8-30 Hz population synchrony in the STN area are related to the processing required for motor preparation, particularly response selection.

Aged↗

PubMedDate not supplied

[Bilateral deep brain stimulation of subthalamic nucleus STN in the surgical treatment of Parkinson's disease].

Dopamine deficiency in the nigrostriatal system leads to a series of changes in the basal ganglia, resulting in an increased neuronal activity of the subthalamic nucleus (STN). Reduction of the STN glutaminergic excitatory effect on the main output structures of the basal ganglia (globus pallidum pars interna GPi and substantia nigra pars reticulata SNr) is accompanied by a marked alleviation of parkinsonian motor sings in the MPTP monkey model of parkinsonism. Also a high-frequency stimulation of STN in the MPTP monkey model of parkinsonism produced the same clinical effect as did lesioning. Due to these observations bilateral deep subthalamic stimulation was introduced in the treatment of PD patients with severe akinetic-rigid form of this disease. Four patients with akinetic-rigid PD form of PD were included in the study. The electrodes for deep brain stimulation were implanted in two separate surgical interventions in every case. The second implantation was performed not earlier than at least 3 months after the first procedure. Evaluations using the UPDRS were conducted before surgery in "on" and "off" conditions and at 3, 6 and 12 months after the bilateral implantation. Bilateral DBS STN seems to be the best stereotactic target in controlling motor symptoms in the "off" condition in the treatment of PD patients with severe symptoms. The technique enables a dramatic reduction in the daily dose of L-dopa.

Aged↗

PubMed2001

Effect of bilateral stimulation of the subthalamic nucleus on parkinsonian voice.

The purpose of this study was to assess several acoustic features of the voices of 26 parkinsonian patients under two conditions, with and without bilateral chronic stimulation of the subthalamic nucleus (STN) to estimate the effectiveness of this procedure on parkinsonian speech. When compared to unstimulated patients, stimulated patients showed longer duration of sustained vowels, shorter duration of sentences, nonsense words, and pauses, more variable fundamental frequency (f0) in sentences, and more stable f0 during sustained vowels. Relative intensity was unchanged in both conditions. Further acoustic analyses are warranted to clarify the role of STN stimulation on parkinsonian speech.

Dysarthria↗

PubMed2002

Dopamine receptors in the subthalamic nucleus are involved in the regulation of muscle tone in the rat.

The effects of injecting an irreversible dopamine receptor antagonist, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) bilaterally into the subthalamic nucleus (STN) on changes in muscle tone and behaviour were investigated. Increased muscle tone (i.e. rigidity) was assessed quantitatively as increases in tonic electromyographic (EMG) activity in the hindlimb muscles of conscious, unrestrained rats. Significant, sustained increases in EMG activity were observed for 3-5 h post-injection in the tibialis and gastrocnemius muscles following injection of EEDQ into the STN. This effect was associated with 73% dopamine D1 and 66% dopamine D2 receptor occupancy in the STN, while dopamine receptors in surrounding regions were minimally occupied. These results provide new evidence that dopamine receptors located in the STN play an important role in the regulation of normal muscle tone.

Animals↗

PubMed2005

Functional interconnectivity between the globus pallidus and the subthalamic nucleus in the mouse brain slice.

In accordance with its central role in basal ganglia circuitry, changes in the rate of action potential firing and pattern of activity in the globus pallidus (GP)-subthalamic nucleus (STN) network are apparent in movement disorders. In this study we have developed a mouse brain slice preparation that maintains the functional connectivity between the GP and STN in order to assess its role in shaping and modulating bursting activity promoted by pharmacological manipulations. Fibre-tract tracing studies indicated that a parasagittal slice cut 20 deg to the midline best preserved connectivity between the GP and the STN. IPSCs and EPSCs elicited by electrical stimulation confirmed connectivity from GP to STN in 44/59 slices and from STN to GP in 22/33 slices, respectively. In control slices, 74/76 (97%) of STN cells fired tonically at a rate of 10.3 +/- 1.3 Hz. This rate and pattern of single spiking activity was unaffected by bath application of the GABA(A) antagonist picrotoxin (50 microM, n = 9) or the glutamate receptor antagonist (6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) 10 microM, n = 8). Bursting activity in STN neurones could be induced pharmacologically by application of NMDA alone (20 microm, 3/18 cells, 17%) but was more robust if NMDA was applied in conjunction with apamin (20-100 nM, 34/77 cells, 44%). Once again, neither picrotoxin (50 microM, n = 5) nor CNQX (10 microM, n = 5) had any effect on the frequency or pattern of the STN neurone activity while paired STN and GP recordings of tonic and bursting activity show no evidence of coherent activity. Thus, in a mouse brain slice preparation where functional GP-STN connectivity is preserved, no regenerative synaptically mediated activity indicative of a dynamic network is evident, either in the resting state or when neuronal bursting in both the GP and STN is generated by application of NMDA/apamin. This difference from the brain in Parkinson's disease may be attributed either to insufficient preservation of cortico-striato-pallidal or cortico-subthalamic circuitry, and/or an essential requirement for adaptive changes resulting from dopamine depletion for the expression of network activity within this tissue complex.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2003

D5 (not D1) dopamine receptors potentiate burst-firing in neurons of the subthalamic nucleus by modulating an L-type calcium conductance.

Dopamine is a crucial factor in basal ganglia functioning. In current models of basal ganglia, dopamine is postulated to act on striatal neurons. However, it may also act on the subthalamic nucleus (STN), a key nucleus in the basal ganglia circuit. The data presented here were obtained in brain slices using whole-cell patch clamp. They reveal that D5 dopamine receptors strengthen electrical activity in the subset of subthalamic neurons endowed with burst-firing capacity, resulting in longer discharges of spontaneous or evoked bursts. To distinguish between D1 and D5 subtypes, the action of agonists in the D1/D5 receptor family was first investigated on rat subthalamic neurons. Single-cell reverse transcription-PCR profiling showed that burst-competent neurons only expressed D5 receptors. Accordingly, receptors localized in postsynaptic membranes within the STN were labeled by a D5-specific antibody. Second, agonists in the D1/D5 family were tested in mouse brain slices. It was found that these agonists were active in D1 receptor knock-out mice in a similar way to wild-type mice or rats. This proved that D5 rather than D1 receptors were involved. Pharmacological tools (dihydropyridines, omega-conotoxins, and calciseptine) were used to identify the target of D5 receptors as an L-type channel. This was reached via G-protein and protein kinase A. The action of dopamine on D5 receptors therefore shapes neuronal activity. It contributes to normal information processing in basal ganglia outside striatum. This finding may be useful in drug therapy for various disorders involving changes in STN activity, such as Parkinson's disease and related disorders.

Animals↗

PubMed2004

Fear recognition is impaired by subthalamic nucleus stimulation in Parkinson's disease.

Behavioural disturbances such as disorders of mood, apathy or indifference are often observed in Parkinson's disease (PD) patients with chronic high frequency deep brain stimulation of subthalamic nucleus (STN DBS). Neuropsychological modifications causing these adverse events induced by STN DBS remain unknown, even if limbic disturbances are hypothesised. The limbic system supports neural circuits processing emotional information. The aim of this work is to evaluate changes of emotional recognition in PD patients induced by STN DBS. Thirty PD patients were assessed using a computerised paradigm of recognition of emotional facial expressions [Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press], 15 before STN DBS and 15 after. The two patients groups were compared to a group of 15 healthy control subjects. One series of 55 pictures of emotional facial expressions was presented to each patient. Patients had to classify the pictures according to seven basic emotions (happiness, sadness, fear, surprise, disgust, anger and no emotion). The intact ability to percept faces was firstly assured using the Benton Recognition Test. Recognition of fear expressions was significantly and selectively reduced in the post-operative group in comparison to both pre-operative and control groups. Our results demonstrate for the first time a selective reduction of recognition of facial expressions of fear by STN DBS. This impairment could be the first neuropsychological marker of a more general limbic dysfunction, thought to be responsible for the behavioural disorders reported after STN DBS.

Aged↗

PubMed2003

Subthalamic nucleus tumor causing hyperphagia--case report.

A 42-year-old woman with locally advanced breast cancer developed headache just after completing adjuvant chemotherapy. Magnetic resonance imaging revealed a mass located in the left subthalamic nucleus (STN) and involving the posterior part of the thalamus and the hypothalamus. The patient refused a radiologically guided biopsy and gamma knife treatment was not financially possible. Palliative whole brain radiotherapy with hormonal therapy was administered. The patient gained 19 kg body weight during 4 months follow up because of hyperphagia. This solitary tumor, either a breast cancer metastasis or a primary tumor, involving the STN is extremely unusual.

Adult↗