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PubMed2001

Effect of microiontophoretic application of dopamine on subthalamic nucleus neuronal activity in normal rats and in rats with unilateral lesion of the nigrostriatal pathway.

The subthalamic nucleus (STN) receives dopamine inputs from the substantia nigra but their implication in the pathophysiology of parkinsonism is still debated. Extracellular microrecordings were used to study the effect of microiontophoretic injection of dopamine and the D1 receptor agonist SKF 38393 on the activity of STN neurons in normal and 6-hydroxydopamine-lesioned rats under urethane anaesthesia. Dopamine and SKF induced an increase in the firing rate of the majority of STN neurons in both normal and 6-OHDA rats. In rats with 6-OHDA lesions, the percentage of firing rate increase did not differ from that of controls. When GABA, glutamate and dopamine were all applied to the same individual STN neurons, GABA induced an inhibitory effect and glutamate and dopamine caused an excitatory effect in both groups. This excitatory response was suppressed by the application of GABA. Systemic administration of apomorphine provoked a decrease in the firing rate of STN neurons in rats with 6-OHDA lesions. These results show that dopamine exerts an excitatory influence on STN neurons, suggesting that the inhibitory effect induced by the systemic injection of apomorphine is due to the GABAergic inputs from the globus pallidus as predicted by the current model of basal ganglia organization. In addition, we show that dopamine, GABA and glutamate can act on the same STN neuron and that GABA can reverse the excitatory effect of dopamine and glutamate, suggesting the predominant influence of GABAergic inputs to the subthalamic nucleus.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2006

Stimulation of subthalamic nucleus inhibits emotional activation of fusiform gyrus.

In patients with Parkinson's disease, deep brain stimulation of the subthalamic nucleus is known to impair their ability to correctly identify facial expressions of negative emotions. This difficulty exists only when the stimulator is active. The reason for the impairment is unknown. To test the hypothesis that the stimulation itself is responsible, we used positron emission tomography to compare functional activations of brain regions in nine patients with Parkinson's disease treated with surgically implanted electrodes into both subthalamic nuclei, and 22 healthy volunteers. Both groups viewed images with neutral or emotional content from Aarhus University's standard Empathy Picture System () with 360 images of people in pleasant, unpleasant or neutral real-life situations, presenting either the situations or close-ups of the facial expressions of the people involved. Both groups, the patients with stimulation OFF and the healthy volunteers, had raised regional blood flow rates (rCBF) in the right fusiform gyrus when they viewed emotionally expressive faces compared to neutral faces. With stimulation turned on, this response was significantly inhibited in the patients because of a raised rCBF at baseline during the neutral faces. Stimulation of the STN did not alter fusiform reaction to emotionally pregnant scenes; nor did healthy volunteers and patients react differently to these stimuli regardless of stimulation status. Also, STN stimulation raised the emotional activation of the anterior cingulate and lowered the activity of the putamen. The findings suggest that the stimulation of the subthalamic nucleus interferes with the integration of specific neocortical networks involved in the recognition of facial expressions.

Adult↗
PubMed2005

Stimulation of the subthalamic nucleus for the treatment of Parkinson's disease: postoperative management, programming, and rehabilitation.

High-frequency stimulation of the subthalamic nucleus is a neurosurgical procedure for the alleviation of motor symptoms of Parkinson's disease and debilitating medication-induced dyskinesias. Stimulation is achieved with electrodes implanted stereotactically in the subthalamic nucleus by a neurosurgeon specializing in stereotactic surgery and a team composed of an anesthesiologist, a neurophysiologist, certified nurses and nurse practitioners and, at some centers, a neurologist. The teamwork continues in the recovery room and the intensive care unit, where the patient may experience transient adverse behavioral effects. Two weeks after surgery, the neurostimulator is activated and programmed. The medications also are adjusted to complement stimulation to maximize the therapeutic effects and minimize the stimulation-induced side effects. For those patients who are deconditioned or have major speech, gait, or balance problems, rehabilitation therapy is employed.

Anesthesiology↗
PubMed2006

Relationship of stimulation site location within the subthalamic nucleus region to clinical effects on parkinsonian symptoms.

OBJECTIVE: To determine the relationship of the stimulation site in the subthalamic region to the clinical effects on parkinsonian symptoms, the monopolar stimulation of 4 electrode contacts and the resulting effects on parkinsonian symptoms were evaluated. METHODS: Seventeen consecutive patients (3 males and 14 females) were enrolled in the study. The patients were evaluated while in a nonmedicated state, and 10-20 min after switching on the pulse generator the effects of stimulation were assessed using separate-subset Unified Parkinson's Disease Rating Scale scores. RESULTS: The relationship between the site stimulated and the percent improvement was analyzed using polynomial regression. Rigidity (p = 0.0004, R2 = 0.15), akinesia (p = 0.02, R2 = 0.07) and total score (p = 0.009, R2 = 0.089) well fit to second-order polynomial regression and showed the greatest improvement after stimulation at 0-1 mm below the horizontal anterior-posterior commissure (AC-PC) plane. Tremor (p = 0.24, R2 = 0.18) and gait (p = 0.36, R2 = 0.001) had a weak relation to the site stimulated, but stimulation at the sites 0-1 mm below the AC-PC plane also produced greater improvement than stimulation at more ventral or dorsal sites. The percent improvement of the posture (p = 0.92, R2 = 0.002) had no relation to the site stimulated. The dorsal border of the subthalamic nucleus was located 0.6 +/- 1.2 mm (n = 27) below the AC-PC plane and the most effective electrode contact 1.2 +/- 1.3 mm (n = 27) below it. CONCLUSIONS: Stimulation around the dorsal border of the subthalamic nucleus, close to the AC-PC plane, produces greater improvement of parkinsonian symptoms than stimulation at more ventral or dorsal sites.

Aged↗
PubMed1988

Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity.

Immunohistochemical studies undertaken with a highly specific antiserum raised against gamma-aminobutyric acid (GABA)-glutaraldehyde-lysyl-protein conjugate showed that cell bodies of the subthalamic nucleus in the squirrel monkey (Saimiri sciureus) were closely surrounded by several GABA-positive terminals but were not themselves immunoreactive. In contrast, after incubation with a monoclonal antibody directed against carbodiimide-fixed glutamate, virtually all cell bodies of the subthalamic nucleus displayed an intense immunoreactivity. They were surrounded by various neuronal processes that also stained for glutamate. These results suggest that the neurons of the subthalamic nucleus in primates utilize the excitatory neurotransmitter glutamate instead of the inhibitory neurotransmitter GABA.

Animals↗
PubMed2006

Subthalamic nucleus stimulation: improvements in outcome with reprogramming.

BACKGROUND: Deep brain stimulation (DBS) is currently the most effective surgical treatment for advanced Parkinson disease (PD). Even when the electrode is well positioned in the target, the optimization of clinical results depends on careful programming of electrical parameters and changes in antiparkinsonian drug dosages. OBJECTIVE: To determine whether stable outcomes from subthalamic nucleus DBS for PD can be improved by revising stimulation parameters and drug dosages through "hands-on" involvement of a neurologist expert in both movement disorders and DBS programming. METHODS: In 44 consecutive patients with PD with long-term stable response to subthalamic nucleus DBS (mean +/- SD, 3.5 +/- 1.7 years), we compared scores from the Unified Parkinson's Disease Rating Scale parts II through IV obtained immediately before and following a formal reprogramming of their stimulation. The reprogramming was performed by a neurologist expert in both PD and DBS and accompanied by further medication adjustments. The patients were subsequently followed up for as long as 14 months. RESULTS: In 24 patients (54.6%), the scores on the Unified Parkinson's Disease Rating Scale parts II and III significantly improved by 15.0% and 25.9%, respectively. Anti-PD drugs were significantly reduced (by 25.9%). No improvement was observed in 16 patients (36.4%), and the conditions of 4 patients (9.1%) worsened. CONCLUSIONS: Further improvement of parkinsonian signs can be achieved in the majority of patients even after long-term stable stimulation. Improved patient outcomes from subthalamic nucleus DBS are obtained when postoperative care is personally managed by a neurologist expert in movement disorders and DBS who is directly responsible for stimulation programming and simultaneous drug adjustments based on observed clinical responses to changing stimulation parameters.

Antiparkinson Agents↗
PubMed2002

The oscillatory activity in the Parkinsonian subthalamic nucleus investigated using the macro-electrodes for deep brain stimulation.

OBJECTIVES: To investigate the oscillatory activity in the Parkinsonian subthalamic nucleus using the macro-electrodes for deep brain stimulation. METHODS: During bilateral deep brain stimulating electrode implantation, spontaneous and evoked field potentials were recorded from the subthalamic nucleus (STN) in two patients with Parkinson's disease (PD) during spontaneous resting tremor, passive manipulation of the wrist, and following electrical stimulation of the contralateral STN. RESULTS: Frequency analysis of the STN field potentials recorded during spontaneous resting tremor showed significant coherence with electromyographic activity in the contralateral arm, suggesting a close involvement of the STN in the generation of resting tremor in PD. The STN responded to passive movement of the contralateral wrist, but not to ipsilateral movement. High frequency (100 Hz) electrical stimulation of the STN induced tremor (4 Hz) in both forearms, and also oscillation of the contralateral STN (4 Hz). In contrast, low frequency (5 Hz) stimulation induced contralateral arrhythmic involuntary movement (3 Hz), but without altering the contralateral STN activity. CONCLUSIONS: We propose that the functional connection between the STN and arm muscles is mainly contralateral, but cross talk may occur between bilateral STN via a frequency-dependent pathway.

Animals↗
PubMed1990

Reversal of experimental parkinsonism by lesions of the subthalamic nucleus.

Although it is known that Parkinson's disease results from a loss of dopaminergic neurons in the substantia nigra, the resulting alterations in activity in the basal ganglia responsible for parkinsonian motor deficits are still poorly characterized. Recently, increased activity in the subthalamic nucleus has been implicated in the motor abnormalities. To test this hypothesis, the effects of lesions of the subthalamic nucleus were evaluated in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The lesions reduced all of the major motor disturbances in the contralateral limbs, including akinesia, rigidity, and tremor. This result supports the postulated role of excessive activity in the subthalamic nucleus in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Overwhelmingly asynchronous firing of rat subthalamic nucleus neurones in brain slices provides little evidence for intrinsic interconnectivity.

In Parkinson's disease the neurones of the subthalamic nucleus show increased synchrony and oscillatory burst discharge, thought to reflect a breakdown of parallel processing in basal ganglia circuitry. To understand better the mechanisms underlying this transition, we sought to mimic this change in firing pattern within sagittal slices of rat midbrain. The firing patterns of up to four simultaneously extracellularly recorded subthalamic nucleus (STN) neurones were analysed using burst and oscillation detection programs, and correlated activity between pairs of neurones assessed. In control conditions all but 11 of 488 (2%) neurones fired in a predominantly tonic pattern (with mean oscillation frequency >3 Hz), with no significantly cross-correlated activity in any of 393 pairs of neurones. The glutamate antagonists DL-2-amino-phosphonopentanoic acid (APV), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-methyl-2-(phenylethynyl)pyridine (MPEP) did not change the firing rate or pattern of these cells, providing no evidence for a role of glutamatergic collaterals within the STN under these conditions. The GABA(A) receptor antagonist bicuculline and GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl]phenylmethyl phosphinic acid (CGP 55845) were also without effect on firing rate or pattern in these cells, suggesting that there was no active input from other GABAergic basal ganglia nuclei in this slice. The dopamine receptor antagonist haloperidol caused no significant change to firing rate or pattern of firing in these cells, suggesting that there was no active dopaminergic input in this slice. Excitations of STN neurones by muscarine, (+)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), N-methyl-D-aspartic acid (NMDA) or dopamine were all unaccompanied by a change in firing pattern or any significant correlated activity between STN neurone pairs. Burst firing could be induced in STN neurones with either the potassium channel blocker tetraethylammonium (TEA; 10 mM; in 100/138 [72%] of cells) or with a combination of NMDA and the calcium-activated potassium channel blocker apamin (in 101/216 [47%] of cells). Burst firing in TEA was unchanged by CNOX and APV, MPEP, CGP55845, haloperidol, dopamine, and ACPD, although muscarine produced a significant increase in oscillation frequency. Burst firing in NMDA and apamin was unchanged by CNQX and APV, dopamine, muscarine and ACPD, although bicuculline caused a significant increase in oscillation frequency. Such burst firing was not accompanied by synchrony in any condition, either alone, or during application of excitatory agents or glutamate or GABA antagonists. As the bursting seen here was unaccompanied by the synchronous activity that has often been observed (pathologically) in vivo, it probably reflects solely intrinsic STN neuronal properties, rather than network activity. No functional role was found for glutamatergic collaterals within the STN, either when cells are firing tonically or burst firing. The circuitry needed to produce synchrony in the STN is most likely not intrinsic to the STN itself, but requires connections with other basal ganglia nuclei, and/or the cortex, which are not present in this preparation.

Action Potentials↗
PubMedDate not supplied

[Effects of simultaneous transplant of foetal mesencephalic cells in the striatum and the subthalamic nucleus of hemiparkinsonian rats].

INTRODUCTION: The main strategy followed in neural transplants as a method of treatment for Parkinson s disease, both experimental and clinical, has been to introduce foetal mesencephalic cells into the target area: the striatum. However, when the dopaminergic cells in the substantia nigra degenerate, not only is the dopaminergic innervation of the striatum affected but also other nuclei: globus pallidus, substantia nigra, substantia nigra pars reticulata and subthalamic nucleus. A series of data from pharmacological and physiological studies offer strong evidence that the dopamine released in these nuclei may play an important role in regulating the output nuclei of the basal ganglia. AIM: To evaluate the effect of transplanting foetal mesencephalic cells on the behaviour of 6 OH DA rats when introduced into the striatum and the subthalamic nucleus. MATERIALS AND METHODS: 6 OH DA was used to induce lesions in the substantia nigra of rats, which were divided into several experimental groups. The rotating activity induced by D amphetamine (5 mg/kg, intraperitoneally) and apomorphine (0.05 mg/kg, subcutaneously) was evaluated before and three months after the transplant in all the experimental groups, except in the control group of healthy rats. The hemiparkinsonian rats received a total of 350,000 foetal ventral mesencephalic cells, which were implanted within small deposits in the striatum (8) and in the subthalamic nucleus (4). RESULTS AND CONCLUSIONS: Rotation induced by both drugs was significantly lower (p= 0.05) in animals that had had dopaminergic cells transplanted into the striatum body. No significant improvement in this behaviour was to be found when transplants were limited to just the subthalamus or, simultaneously, also to the striatum. A significant increase in rotating behaviour induced by apomorphine was observed in the group which received a transplant in just the subthalamus.

Adrenergic Agents↗
PubMed2006

Enhanced preproenkephalin-B-derived opioid transmission in striatum and subthalamic nucleus converges upon globus pallidus internalis in L-3,4-dihydroxyphenylalanine-induced dyskinesia.

BACKGROUND: A role for enhanced opioid peptide transmission has been suggested in the genesis of levodopa-induced dyskinesia. However, basal ganglia nuclei other than the striatum have not been regarded as potential sources, and the opioid precursors have never been quantified simultaneously with the levels of opioid receptors at the peak of dyskinesia severity. METHODS: The levels of messenger RNA (mRNA) encoding the opioid precursors preproenkephalin-A and preproenkephalin-B in the striatum and the subthalamic nucleus and the levels of mu, delta, and kappa opioid receptors were measured within the basal ganglia of four groups of nonhuman primates killed at the peak of effect: normal, parkinsonian, parkinsonian chronically-treated with levodopa without exhibiting dyskinesia, and parkinsonian chronically-treated with levodopa showing overt dyskinesia. RESULTS: Dyskinesia are associated with reduction in opioid receptor binding and specifically of kappa and mu receptor binding in the globus pallidus internalis (GPi), the main output structure of the basal ganglia. This decrease was correlated with enhancement of the expression of preproenkephalin-B mRNA but not that of preproenkephalin-A in the striatum and the subthalamic nucleus. CONCLUSIONS: Abnormal transmission of preproenkephalin-B-derived opioid coming from the striatum and the subthalamic nucleus converges upon GPi at the peak of dose to induce levodopa-induced dyskinesia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Jules Bernard Luys and the subthalamic nucleus.

Jules Bernard Luys, a highly energetic French investigator who made important contributions to anatomopathology, clinical neurology, and psychiatry, discovered the subthalamic nucleus in 1865. Unfortunately, Luys' description of the nucleus that still bears his name, as well as his highly original insights on the role of this important motor structure, are rarely taken into account in the current thinking about the basal ganglia organization. Thus, we thought it of interest to review Luys' contribution to our knowledge of the subthalamic nucleus and also briefly examine the other remarkable achievements of this singular figure of 19th century neurology.

France↗
PubMed1995

Electrophysiological study of the excitatory parafascicular projection to the subthalamic nucleus and evidence for ipsi- and contralateral controls.

The activity of subthalamic neurons was recorded extracellularly in anaesthetized rats after stimulation, inhibition or lesioning of the parafascicular nucleus. Electrical stimulation of the parafascicular nucleus evoked a complex response with two excitatory phases. The first response was correlated with a monosynaptically-driven excitation via a parafascicular input to the subthalamic nucleus. Since the second phase was observed even when the early excitation was not recorded and was eliminated by lesion of the globus pallidus, we suggest that it is not generated by a mechanism intrinsic to the subthalamic nucleus and is due to a disinhibitory effect originating from the globus pallidus. Microinjection of carbachol into the parafascicular nucleus enhanced by 119% the discharge rate of the neurons in the ipsilateral subthalamic nucleus and that of muscimol decreased the discharge rate by 91%. Opposite changes, a decrease of the discharge rate of 49% after microinjection of carbachol and an increase of 47% after muscimol, occurred in the contralateral subthalamic nucleus. In contrast to the above results, the unilateral excitotoxic lesion of the parafascicular nucleus, performed one week before recording, decreased the discharge rate by 69% of the ipsilateral subthalamic nucleus neurons and by 34% that of the contralateral neurons. We suggest that the parafascicular input to the subthalamic nucleus is an excitatory pathway which can tonically drive the neuronal activity in this structure. The opposite changes recorded in the ipsi- and contralateral subthalamic nucleus during unilateral microinjection of excitatory or inhibitory drugs in the parafascicular nucleus emphasize the importance of this thalamic structure in the bilateral regulation of basal ganglia activity via the subthalamic nucleus.

Animals↗
PubMedDate not supplied

[Surgery of the subthalamic nucleus in Parkinson's disease].

INTRODUCTION AND DEVELOPMENT: The subthalamic nucleus (STN) plays a crucial part in the pathophysiology of Parkinsonism. Its inactivation improves all the main signs and symptoms of Parkinson's disease. Surgery of the STN in patients with the disease is effective and the benefit/risk relationship very favorable. Although the dyskinesias are not a definite limitation, it seems most reasonable to use techniques of deep cerebral stimulation until greater experience has been obtained with subthalamotomy. The long term efficacy is being studied and preliminary data indicate that the clinical benefit obtained is maintained in the long term. CONCLUSIONS: More studies are necessary to determine the mechanism of action of surgery on the STN. The potential neuroprotector effect of subthalamic surgery requires more extensive study.

Humans↗
PubMed2004

Facial expression recognition and subthalamic nucleus stimulation.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor signs in Parkinson's disease. However, clinical studies suggest that DBS of the STN may also affect cognitive and emotional functions. OBJECTIVE: To study the impact of STN stimulation in Parkinson's disease on perception of facial expressions. RESULTS: There was a selective reduction in recognition of angry faces, but not other expressions, during STN stimulation. CONCLUSIONS: The findings may have important implications for social adjustment in these patients.

Adult↗
PubMed2002

Electrophysiological localization of the subthalamic nucleus in parkinsonian patients.

Deep brain stimulation of the subthalamic nucleus (STN) is becoming the procedure of choice to reduce symptoms of Parkinson's disease such as rigidity, akinesia and tremor. We present here a series of electrophysiological recordings performed in 34 patients along a standardized electrode trajectory. Neuronal activity along the trajectory consists of a first heterogeneous population of thalamic cells with a mean frequency of 24.8+/-1.4 Hz followed by a silent zone and a second population of STN neurones with a significantly higher spiking frequency (P<0.001) of 42.3+/-1.8 Hz. This study confirms previous findings and suggests that rapid measurement of neuronal spiking frequency and burst index is sufficient to determine precisely the vertical position of the STN.

Action Potentials↗
PubMed2002

Anatomo-clinical correlation of intraoperative stimulation-induced side-effects during HF-DBS of the subthalamic nucleus.

The efficacy of deep brain stimulation of the subthalamic nucleus (STN) is dependent on the accuracy of targeting. In order to reduce the number of passes and, consequently, the duration of surgery and risk of bleeding, we have set up a new method based on direct magnetic resonance imaging (MRI) localisation of the STN. This procedure allows a short duration of the neurophysiological session (one or two initial tracks). Whenever a supplementary track is needed, the stimulation-induced side effects are analysed to choose from one of the remaining holes in Ben's gun. A good knowledge of anatomical structures surrounding the STN is mandatory to relate side effects to the actual position of the track. In our series of 11 patients (22 sides, 37 tracks), the most common and reproducible side effects were those characterised by motor, sensorial, oculomotor and vegetative signs and symptoms. Moreover, the therapeutic window (distance between the current intensity needed to obtain the best clinical effect and the intensity capable to induce side effects) predicted clinical efficacy in the long-term, and contributed to the choice of which among the examined tracks had to be implanted with the chronic macroelectrode.

Electric Stimulation Therapy↗