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PubMed2004

Chronic inhibition of the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a popular treatment option for patients suffering from severe Parkinson's disease (PD). Yet the long-term outcome of subthalamic DBS is unknown. A total of 27 patients suffering from severe PD underwent bilateral stereotactic implantation of high-frequency stimulators in the STN. Before surgery and at least annually after surgery they were examined with the Unified Parkinson's Disease Rating Scale (UPDRS). This study presents the results of a mean 30 months (range 23 to 55) follow-up of these patients. We found stable and significant off medication improvement of motor function by DBS (between 40% and 44% in the UPDRS part III). While on medication there was no significant change in the motor function by DBS. UPDRS part III worsened gradually during the follow-up period, suggesting disease progression. Thirty months postsurgery the UPDRS part II (ADL) was still improved by 17%. There was a lasting decrease in fluctuations by more than 50%, and dyskinesias were reduced by about 70%. Freezing was reduced significantly from 2.2 in the UPDRS part II to 1.2 at the endpoint. The daily levodopa-equivalent dose was reduced by 39% at 12 months and by 30% at 30 months after STN stimulator implantation. Subthalamic DBS improves sustainable motor function in patients with severe Parkinson's disease and leads to a lasting reduction of medication. Limitations of this procedure were found for disturbances of speech and swallowing.

Adult↗

PubMed1987

Efferent projections of the subthalamic nucleus in the rat: light and electron microscopic analysis with the PHA-L method.

Efferent projections of rat subthalamic nucleus were studied by use of the axonal transport of phaseolus vulgaris-leucoagglutinin (PHA-L), and the results were analyzed with light and electron microscopes. PHA-L injections in the subthalamic nucleus (STH) resulted in heavy labeling of fiber plexus with en passant boutons and terminals in the pallidal complex, i.e., the entopeduncular nucleus (EP), the globus pallidus (GP) and the ventral pallidum (VP), and the substantia nigra pars reticulata (SNR). Labeling in GP was characterized by two distinct bands of labeled terminals oriented dorsoventrally, whereas labeling in SNR was patchy. STH efferents to the pallidum and SNR displayed a mediolateral topographic organization. With regard to dorsoventral organization, projections to GP were inverted, but those to SNR were not. There were moderate projections to the neostriatum and sparse projections to the frontal cortex, substantia innominata, substantia nigra pars compacta (SNC), pedunculopontine tegmental nucleus, ventral part of the central gray matter including the dorsal raphe nucleus, and the mesencephalic and pontine reticular formation. PHA-L injections in the zona incerta and the lateral hypothalamic area resulted in fiber and terminal labelings in many structures, including the basal forebrain, EP, SNC, and other brainstem areas that overlap with some of the terminal sites of STH projections. Ultrastructural observations of PHA-L labeled processes in GP and SNR revealed that STH terminals in both structures contained small pleomorphic vesicles and formed asymmetrical contacts. These contacts were mainly on dendritic shafts, but some were on somata. It also was observed that the myelinated axons of STH neurons lost their myelin after reaching their target areas and the synaptic boutons arose from relatively thin unmyelinated axons.

Animals↗

PubMed2004

Long-term stimulation of the subthalamic nucleus in hemiparkinsonian rats: neuroprotection of dopaminergic neurons.

OBJECT: The goal of this study was to evaluate the neuroprotective effects conferred by long-term electrical stimulation of the subthalamic nucleus (STN) against degeneration of dopaminergic neurons by assessing motor functional and immunohistological findings in hemiparkinsonian rats. METHODS: In 13 of 25 rats, a concentric microelectrode was stereotactically implanted into the right STN under the guidance of extracellular microelectrode recording. After this had been done the animals were given an injection of 6-hydroxydopamine (6-OHDA) into the right striatum. Seven of the rats received continuous stimulation (frequency 130 Hz, intensity 80-100 microA) for 2 weeks (Group A); the other six did not receive any stimulation during this period (Group B). Twelve rats did not receive electrode implantation and underwent 6-OHDA injection only; these animals served as a control group (Group C). After 2 weeks, motor function in the rats was evaluated by conducting an amphetamine-induced rotation test. Finally, tyrosine hydroxylase-immunoreactive neurons in the pars compacta of the substantia nigra (SNc) were counted to evaluate the extent of degeneration of dopaminergic neurons. Ipsilateral rotation was significantly decreased in Group A, regardless of the effects of stimulation delivered during the test (p < 0.05). Rats in Group B demonstrated typical circling as did those in Group C, except that on stimulation Group B rats immediately stopped circling or changed direction. Tyrosine hydroxylase-immunoreactive neurons in the SNc were significantly preserved in the animals in Group A, whereas neurons in animals in Groups B and C were moderately depleted (p < 0.01). CONCLUSIONS: Acutely, STN stimulation improved rotation symmetry in rats with moderate SNc degeneration. When STN stimulation had been applied for the preceding 2 weeks, motor function was better and SNc neural degeneration was significantly milder. Subthalamic nucleus stimulation thus appears to protect dopaminergic neurons in this hemiparkinsonian model, in addition to improving motor function in these animals.

Adrenergic Agents↗

PubMed2004

Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance.

Although the basal ganglia play an important role in self-generated movement, their involvement in externally paced voluntary movement is less clear. We recorded local field potentials (LFPs) from the region of the subthalamic nuclei of eight patients with Parkinson's disease during the performance of a warned reaction time task in which an imperative cue instructed the subject to move or not to move. In 'go' trials, LFP activity in the beta frequency band ( approximately 20 Hz) decreased prior to movement, with an onset latency that strongly correlated with mean reaction time across patients. This was followed by a late post-movement increase in beta power. In contrast, in 'nogo' trials the beta power drop following imperative signals was prematurely terminated compared with go trials and reversed into an early beta power increase. These differences were manifest as power increases when go trials were subtracted from nogo trials. In six patients these relative beta power increases in nogo-go difference trials were of shorter latency than the respective reaction time. The findings suggest that, firstly, the subthalamic nucleus is involved in the preparation of externally paced voluntary movements in humans and, secondly, the degree of synchronization of subthalamic nucleus activity in the beta band may be an important determinant of whether motor programming and movement initiation is favoured or suppressed.

Aged↗

PubMedDate not supplied

Ionotropic glutamate receptor expression and dopaminergic modulation in the developing subthalamic nucleus of the rat: an immunohistochemical and electrophysiological analysis.

Using standard immunohistochemical procedures, we investigated the changes in the expression of ionotropic glutamate receptor (GluR) subunits, GluRl, GluR5/6/7, and NMDAR1, in the subthalamic nucleus of developing rats. The general sequence of development for each subunit was the same. At early postnatal ages, there was dense neuropil staining and cellular clustering which progressed to decreased neuropil staining and an even distribution of conspicuous cells in the later postnatal ages and in the adult. GluR5/6/7 displayed the earliest maturation, while GluR1 exhibited the slowest maturation. These morphological changes suggest a different time course for the functionality of GluR subtypes in the developing subthalamic nucleus. Correlative electrophysiological studies demonstrated functional GluRs as early as 16 days of age. All neurons tested displayed robust responses to kainate and N-methyl-D-aspartate, and these responses were modulated by dopamine.

Action Potentials↗

PubMed1985

Subcortical changes in the regional uptake of [3H]-2-deoxyglucose in the brain of the monkey during experimental choreiform dyskinesia elicited by injection of a gamma-aminobutyric acid antagonist into the subthalamic nucleus.

Hemichorea/hemiballismus was induced in monkeys by localized injections of a gamma-aminobutyric acid antagonist into the contralateral subthalamic nucleus. During active dyskinesia, [3H]-2-deoxyglucose was administered and, subsequently, regional cerebral metabolic activity was examined by autoradiographic exposure of brain sections. The results indicate that during dyskinesia there was an overall decrease in local cerebral glucose utilization in a number of structures on the side of the brain contralateral to the abnormal movements (ipsilateral to the drug injection). These structures included the injected subthalamic nucleus, both medial and lateral segments of the globus pallidus, the substantia nigra, and the ventral anterior and ventral lateral nuclei of the thalamus. On the basis of evidence that changes in the energy requirement of neurons are due mainly to changes in synaptic activity, the autoradiographic findings are interpreted as indicating that during experimental hemichorea/hemiballismus there was an overall decrease in synaptic activity of subthalamopallidal, subthalamonigral and pallidothalamic pathways on the side of the brain contralateral to the dyskinesia. This interpretation is discussed in relation to current theories of the pathophysiology of choreiform dyskinesias.

Animals↗

PubMed2003

Group II metabotropic glutamate receptor modulation of excitatory transmission in rat subthalamic nucleus.

Patch pipettes were used to record currents in whole-cell configuration to study the effects of group II metabotropic glutamate receptor (mGluR) stimulation on synaptic transmission in slices of rat subthalamic nucleus. Evoked glutamatergic excitatory postsynaptic currents (EPSCs) were reversibly reduced by the selective group II mGluR agonist (2'S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) in a concentration-dependent manner, with an IC50 of 0.19 +/- 0.05 microM. DCG IV (1 microM) had no effect on inhibitory postsynaptic currents mediated by GABA. DCG IV-induced inhibition of EPSCs was reversed by the selective group II mGluR antagonist LY 341495 (100 nM) and mimicked by another selective group II agonist (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I). Inhibition of EPSC amplitude by DCG IV and L-CCG-I was associated with an increase in the paired-pulse ratio of EPSCs. The protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (2 microM) reduced the inhibitory effect of DCG IV on EPSCs. However, the response to DCG IV was not affected by the protein kinase A (PKA) activator forskolin (20 microM), by the adenylyl cyclase inhibitor MDL 12230A (20 microM), or by the phosphodiesterase inhibitor Ro 20-1724 (50 microM). DCG IV-induced inhibition of EPSCs was reduced by the non-selective protein kinase inhibitors H-7 (100 microM), H-8 (50 microM) and HA-1004 (100 microM). These results suggest that group II mGluR stimulation acts presynaptically to inhibit glutamate release by a PKC-dependent mechanism in the subthalamic nucleus.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1975

[Individual anatomic variability of the subthalamic nucleus in frontal sections].

The paper presents the results of studying individual variability of the shape, size and disposition of the subthalamic nucleus. Under investigation were 100 preparations. The structure was studied in serial frontal sections of the diencephalon and midbrain taken 1 mm apart. A considerable variability of the disposition of the subthalamic nucleus was revealed relative to intracerebral reference--points used in stereotaxic operations. The limits are outlined within which stereotaxical lesions should be avoided.

Aged↗

PubMed2002

Predictors of effective bilateral subthalamic nucleus stimulation for PD.

To identify factors predictive of effective bilateral subthalamic nucleus (STN) stimulation for PD with severe motor complications, pre- and postoperative Unified PD Rating Scale (UPDRS) scores were analyzed in a series of 54 patients who received bilateral STN stimulation. Younger age and levodopa responsiveness predict a favorable response to bilateral STN stimulation. For individual PD symptoms, those that improve with a suprathreshold dose levodopa challenge are likely to improve with stimulation.

Adult↗

PubMed2001

Intermuscular coherence in Parkinson's disease: effects of subthalamic nucleus stimulation.

It remains unclear how high frequency stimulation of the subthalamic nucleus (STN) improves parkinsonism. We hypothesized that stimulation may affect the organization of the cortical drive to voluntarily activated muscle. Normally this is characterized by oscillations at 15-30 Hz, manifest in coherence between muscles in the same frequency band. We therefore investigated the effects of STN stimulation on electromyographic (EMG) activity in co-contracting distal arm muscles in nine subjects with Parkinson's disease off drugs. Without stimulation, coherence between EMG signals was diminished at 15-30 Hz compared with nine controls. STN stimulation increased coherence in the 15-30 Hz band, so that it approached that in healthy subjects. The results suggest that STN stimulation facilitates the normal cortical drive to muscles.

Analysis of Variance↗

PubMed2006

The role of the supramammillary commissure in MR localization of the subthalamic nucleus.

PURPOSE: We have discovered a method for localization of the subthalamic nucleus (STN) utilizing the supramammillary commissure (SMC) as reference point. It is our purpose to present our experience and compare our methods with others. MATERIALS AND METHODS: Sixteen patients targeted for bilateral DBS for 32 total STN targets were studied by 1 mm MP-RAGE images with coronal T2W images. A modified red nucleus and mustache method was applied. The predicted target points were then confirmed with electronic calipers measuring the differences in methods. RESULTS: Modified red nucleus method using Surgiplan, and EBAL and BAGM electronic brain map atlas matched the target loci of 12 mm, -3 mm, -4 mm on an X-, Y-, and Z-coordinate system with zero at the mid-commissural point. From the coronal view Y is fixed at -3 mm. The mustache method was in error with values of X-axis at 14.25 (+/- 1.41 SD) (p = 0.69), and of Z-axis at -5.0 (+/- 1.60 SD) (p = 0.55). Three-fourths had moderate to marked ventricular enlargement of the III, but only 3 had enlargement of the frontal horns. CONCLUSION: The mustache method erred in the X-axis because the thalamocaudate groove was located lateral to the target point of the STN, and in the Z-axis because of varying thicknesses of the SMC. The top of the SMC is directly lateral from the STN target by 12 mm from the anterior and posterior commissures line. The SMC being a recognizable structure with constant relation to the STN should be the target structure.

Brain Mapping↗

PubMed2003

Brain flow changes before and after deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) markedly improves motor symptoms and reduces medication needs in Parkinson's disease (PD) patients. However, its effect on brain function has remained unclear. We used SPECT and the tracer ECD to measure regional cerebral blood flow before and 6 months after DBS of the STN in 22 PD patients and 13 healthy controls. PD patients were divided into good and poor responders to DBS, if changes in "off" UPDRS motor scores after surgery were >60% or <40%, respectively. Statistical analysis was performed using the SPM99 software. At baseline, all PD patients showed significant perfusion reductions in cortical areas (premotor frontal, parietal, and occipital). After DBS, changes were normalized only in the good responders, while cortical defects in the poor responders were unchanged. No flow decrements were detected in basal ganglia and thalamus in both groups, suggesting that DBS does not have a "lesion-like" effect. We conclude that good surgery outcome is associated with normalization of cortical flow abnormalities in PD.

Case-Control Studies↗

PubMed2000

Bilateral deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is rapidly becoming the preferred surgical choice for the treatment of advanced Parkinson's disease (PD). We report initial results in 15 patients after 12 months and in nine patients evaluated between 30 and 36 months postoperatively. Our experience confirms the robust antiparkinsonian effect of DBS of the STN in advanced PD. The severity of "off" episodes, as assessed by the Unified Parkinson Disease Rating Scale (UPDRS), was drastically reduced by 74% at 12 months, and dyskinesia scores (Dyskinesia Rating Scale) decreased. The levodopa daily dose was reduced by 55% at 12 months. A double-blind assessment to determine the effect of stimulation performed in nine patients at 3 months in the "off" medication condition was very significant (p<0.05). Nine patients have been followed for 3 years with maintained efficacy in the UPDRS "off" score and the dyskinesia score. The experience of other groups using a similar technique is reviewed. The overall assessment indicates a high antiparkinsonian effect of DBS of the STN even in advanced patients. The existence of a learning curve for this procedure should be taken into account when initial results are evaluated.

Electric Stimulation Therapy↗

PubMed2004

Eye movement-related responses of neurons in human subthalamic nucleus.

Intraoperative microelectrode single unit recordings are routinely made in the subthalamic nucleus (STN) of awake and alert Parkinson's disease (PD) patients during surgery for implantation of deep brain stimulation (DBS) electrodes. These recordings not only assist in determining the optimal target for electrode implantation, but also offer the unique opportunity to study movement-evoked responses from the basal ganglia. We report on the responses of human STN neurons to eye movements from eight PD patients (five men and three women). Twenty percent (18/89) of tested STN neurons showed responses to eye movements. Patients made pro-saccades, voluntary saccades or smooth pursuit eye movements in four directions: up, down, left, right. The majority of STN neurons (72% or 13/18), that responded to eye movements were found in the ventral half of the nucleus, while 58% (22/38) of STN neurons that had somatic responses were found in the dorsal half of the nucleus. The firing rate for STN oculomotor neurons was 33+/-15 Hz (n = 18), which was not different from that reported previously for STN neurons. Most neurons only responded to eye movements in a single direction, but 17% (3/18) showed responses to more than one direction. The majority of responses (17/18) to eye movements were increases in firing rate although one neuron did show a pause in firing with eye movement onset. The phasic changes in firing rate in response to eye movement usually occurred up to 250 ms following eye movement onset. Neurons were found that showed task-specific responses to cued versus self-paced saccades, responded to both passive limb movement and voluntary eye movement, and appeared to show either visual or attentional responses. These human physiological data, in conjunction with previous anatomical studies, suggest that the STN might have an oculomotor role. Although there is no evidence that STN is responsible for driving eye movements, it may have a role in either sensory feedback, corollary discharge, or in focusing the substantia nigra pars reticulata to allow a saccade to occur through disinhibition of the superior colliculus.

Action Potentials↗

PubMed1999

Changes in handwriting resulting from bilateral high-frequency stimulation of the subthalamic nucleus in Parkinson's disease.

High-frequency stimulation of the subthalamic nucleus (STN) is a promising therapeutic approach in patients with severely disabling Parkinson's disease (PD). Whereas STN stimulation improves the cardinal signs of PD, little is known about the effects of STN stimulation on fine manual skills like handwriting. Therefore, the present study investigated the changes in handwriting during bilateral STN stimulation in 12 patients with advanced PD. Dopaminergic medication was discontinued at least 12 hours before the study. The patients were asked to write a standardized sentence repetitively. Five samples of the patient's script were recorded during effective bilateral STN stimulation and 1 hour after both stimulators had been switched off. The movements of the tip of the pencil were recorded using a digitizing tablet. Handwriting movements were segmented into subsequent up- and down-strokes, and a stroke-based kinematic analysis of handwriting was performed. During high-frequency STN stimulation, handwriting movements became faster and smoother indicating a partial restoration of an "open-loop" automatic performance. In addition, STN stimulation gave rise to a significant increase in the mean vertical stroke length demonstrating a stimulation-related reduction in micrographia. The present data underscores the importance of the STN in "open-loop" performance of highly skilled sequential hand movements.

Aged↗

PubMedDate not supplied

Implication of the subthalamic nucleus in the pathophysiology and pathogenesis of Parkinson's disease.

The subthalamic nucleus (STN) has been shown to play an important role in the control of movement and has been considered as a key structure in the functional organization of the basal ganglia. Several studies postulated that the STN plays a critical role in the pathophysiology of Parkinson's disease and that its inhibition or its lesioning can reverse the cardinal motor symptoms. Nevertheless, the beneficial effect was accompanied by dyskinetic abnormal movements. In order to avoid unpleasant and irreversible side effects we used high-frequency stimulation (HFS) of the STN instead of lesions. We have shown that parkinsonian motor symptoms, akinesia, rigidity, and tremor can be alleviated by HFS of the STN in the nonhuman primate model. Side effects were controllable and appeared only at intensities higher than that inducing the improvement of motor symptoms. In severe parkinsonian patients, bilateral STN-HFS greatly improved parkinsonian motor symptoms. Motor fluctuations were attenuated and patients became independent in most activities of daily living. It appears that STN-HFS mimics the effects of lesions by inhibiting its neuronal activity. In a rat model of parkinsonism, we studied the implication of the STN in the excitotoxicity of nigral dopamine cells. We showed that kainic acid lesioning of the STN can protect nigral dopaminergic cells against 6-hydroxydopamine-induced toxicity. The evidence reviewed in the present article clearly demonstrates that the STN is implicated in the pathophysiology and pathogenesis of Parkinson's disease.

Animals↗

PubMedDate not supplied

[The value of the internal capsule signs in the stimulation of the subthalamic nucleus in Parkinson's disease].

INTRODUCTION: The effectiveness of stimulating the subthalamic nucleus (DBS-STN) in advanced Parkinson's disease (PD) largely depends on the correct placement of the electrodes. Since the sensory-motor region of the STN lies beside the internal capsule (IC), we believe that the motor effectiveness of DBS-STN could be related to the stimulation threshold in which IC signs appear (IC threshold). PATIENTS AND METHODS: An examination of 17 consecutive patients with advanced PD who had been submitted to bilateral DBS-STN (one case was unilateral) was carried out to determine the motor improvement on each side of the body (n = 33) and the energy consumption one year after surgery according to the IC threshold obtained during the programming. RESULTS: A 45% improvement was observed in the UPDRS III in off and there was a 24% reduction in the equivalent dose of levodopa with bilateral DBS-STN. When the electrodes were considered, there was a statistically significant improvement that depended on the IC threshold. Energy consumption differed significantly between electrodes with an IC threshold of 3-7 V (1.5 +/- 1.2 microW) and those with an IC threshold > 7 V (8.3 +/- 9.4 microW). CONCLUSIONS: During the stimulation phase and following the correct location of the STN, which was achieved by neurophysiological recording, the IC threshold has prognostic implications in medium-long term motor effectiveness and in the consumption of the battery in the generator.

Aged↗

PubMed2006

Computational analysis of subthalamic nucleus and lenticular fasciculus activation during therapeutic deep brain stimulation.

The subthalamic nucleus (STN) is the most common target for the treatment of Parkinson's disease (PD) with deep brain stimulation (DBS). DBS of the globus pallidus internus (GPi) is also effective in the treatment of PD. The output fibers of the GPi that form the lenticular fasciculus pass in close proximity to STN DBS electrodes. In turn, both STN projection neurons and GPi fibers of passage represent possible therapeutic targets of DBS in the STN region. We built a comprehensive computational model of STN DBS in parkinsonian macaques to study the effects of stimulation in a controlled environment. The model consisted of three fundamental components: 1) a three-dimensional (3D) anatomical model of the macaque basal ganglia, 2) a finite element model of the DBS electrode and electric field transmitted to the tissue medium, and 3) multicompartment biophysical models of STN projection neurons, GPi fibers of passage, and internal capsule fibers of passage. Populations of neurons were positioned within the 3D anatomical model. Neurons were stimulated with electrode positions and stimulation parameters defined as clinically effective in two parkinsonian monkeys. The model predicted axonal activation of STN neurons and GPi fibers during STN DBS. Model predictions regarding the degree of GPi fiber activation matched well with experimental recordings in both monkeys. Only axonal activation of the STN neurons showed a statistically significant increase in both monkeys when comparing clinically effective and ineffective stimulation. Nonetheless, both neural targets may play important roles in the therapeutic mechanisms of STN DBS.

Animals↗