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PubMed2006

Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes.

Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Deep Brain Stimulation↗

PubMed1991

Acute monoaminergic depletion in the rat potentiates the excitatory effect of the subthalamic nucleus in the substantia nigra pars reticulata but not in the pallidal complex.

Recent neurochemical evidence suggests that chemical or electrical stimulation of the subthalamic nucleus (STH) increases dopamine release in the substantia nigra (SN) with a subsequent decrease in the striatum. In a previous paper, we reported that bicuculline-induced activation of the STH increases neuronal activity in the substantia nigra pars reticulata (SNpr) and in the pallidal complex. In order to investigate the role played by the dopaminergic system in the observed activation, the neuronal responses of subthalamic nucleus target structures were studied in amine depleted rats following subthalamic stimulation. Amine depletion was accomplished by pretreating the rats with reserpine (2 mg/kg; S.C.) and with alpha-methyl-para-tyrosine (alpha-mpt; 50 mg/kg; I.P.). Following this treatment, dopamine levels were reduced by 94% in the striatum as measured by HPLC. Amine depletion significantly increased the spontaneous activity of subthalamic cells by 53%. In the SNpr, no significant changes in the spontaneous neuronal activity were observed, but the excitatory responses to bicuculline-induced stimulation of the STH were potentiated as compared to non-treated animals. In the pallidial complex (GP-EP), no potentiation was found. The data suggest that the spontaneous pattern of discharge of the STH is probably under monoaminergic control. They also suggest a reciprocal interaction between dopamine and glutamatergic afferent terminals from the STH within the SNpr, but not in the pallidal complex.

Action Potentials↗

PubMedDate not supplied

[Hemiballismus with logorrhea and thymo-affective disinhibition caused by hematoma of the left subthalamic nucleus].

A 71 year-old hypertensive right-handed man presented a small intracerebral haematoma limited to the left subthalamic nucleus that resulted in right hemiballismus and a neurobehavioral disinhibition syndrome. The latter associated logorrhoea and euphoria, but there was no frontal signs nor mental confusion. The patient kept full insight into his mental change, that contrasted with his prior personality. Hemiballismus and the manic-like state resolved within 2 months. This case and some others from the literature illustrated that a focal lesion in the basal ganglia could result in manic-like affective change, and that a relation did exist between hyperkinetic syndrome and euphoria. Our case contrasted with most of the published cases of neurobevioral changes following basal ganglia discrete lesions, expressing as hypokinesia, apathy and loss of motivation. With reference to the functional circuits linking the frontal cortex and the basal ganglia, as described by Alexander, this syndrome of combined disinhibition of motricity, speech and affect could involve either the lateral orbito-frontal or the anterior cingulate loops, more especially the indirect pathways travelling through the subthalamic nucleus, lesion of which is known to disinhibit thalamo-cortical activity.

Aged↗

PubMed1992

[Unilateral abolition of parkinsonian rigidity after subthalamic nucleus hemorrhage].

A 63-year-old man with parkinsonism suddenly developed a right hemiballism, and the CT showed a hematoma of the left subthalamic nucleus. After the ballistic movement had disappeared, muscular rigidity improved on the right. This case suggests that excessive output from the subthalamic nucleus to the internal segment of globus pallidus plays a critical role in the pathophysiology of parkinsonian rigidity.

Cerebral Hemorrhage↗

PubMed2006

Subthalamic nucleus neurones in slices from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice show irregular, dopamine-reversible firing pattern changes, but without synchronous activity.

The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABA(A) receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity.

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

PubMed2003

Language recovery following subthalamic nucleus stimulation in Parkinson's disease.

Neuropsychological consequences of stimulation of the subthalamic nucleus for treatment of drug-resistant Parkinson's disease (PD) have been studied previously. However, no detailed investigations of linguistic function modifications have been carried out. We studied four consecutive patients with PD who underwent chronic bilateral stimulation of the subthalamic nuclei. Neuropsychological and linguistic evaluations were performed before and 2 weeks after surgery. Linguistic abilities were studied also 1 year after surgery with stimulators both off and on. Intraphrasal hesitation pauses, phonemic paraphasias and morpho-syntactic errors were significantly reduced and lexical retrieval improved with stimulation of the subthalamic nuclei. Implicit linguistic phenomena, mainly occurring within basal ganglia circuitry, benefited by recovery of functional equilibrium within basal nuclei and between overall basal ganglia circuitry and cerebral cortex.

Aged↗

PubMed1980

Efferent connections of the subthalamic region in the rat. I. The subthalamic nucleus of Luys.

The efferent connections of the subthalamic nucleus of Luys (STN) in the rat were investigated with the aid of the anterograde autoradiographic and the retrograde horseradish peroxidase (HRP) tracer techniques. A small microelectrophoretic injection of tritiated proline and leucine centered in the STN (case RST-4) was found to label fibers directed mainly at 3 ipsilateral structures: the substantia nigra (chiefly the ventral portion of its pars reticulata), the entopeduncular nucleus and the globus pallidus (including the ventral pallidum). In addition to this major labeling pattern, much sparser labeling was seen in striatal, thalamic, hypothalamic, pretectal, tectal and reticular territories. In another series of experiments, microelectrophoretic HRP injections confined to the substantia nigra or the globus pallidus consistently resulted in retrograde labeling of neurons in the ipsilateral STN. On the other hand, HRP injections of the ventromedial portion of the midbrain tegmentum (including the red nucleus), the superior colliculus, the pretectal area or a midbrain region at the lateral border of the central gray substance resulted in retrograde labeling of cells in the zona incerta, but no labeled cells appeared in these cases in the ventrally adjacent STN. These HRP results, together with autoradiographic data obtained in control cases, suggest that the minor projections to territories other than the substantia nigra and the pallidal complex originate in the zona incerta or the cerebral cortex rather than in STN.

Animals↗

PubMed1987

Early postnatal development of monkey subthalamic nucleus: a light and electron microscopic study.

The subthalamic nuclei of 9 rhesus monkeys, ranging in age from newborn to 17 weeks, were examined at the light and/or electron microscopic levels, using computer assisted quantitative methods. The volume of the structure does not change significantly over the period of study. The mean cross-sectional area of neuronal somata, however, decreases by 33%, and most markedly during the first month. This is paralleled by a similar change in the mean area of cell nuclei but the perikaryon/nucleus ratio increases steadily after the first week. There is an overall decline in total cell numbers from newborn to 17 weeks. Ultrastructural features include dendritic growth cones in the neonatal monkey, and signs of axonal degeneration during the entire period. In addition to conventional axosomatic and axodendritic synapses, there are also synaptic junctions between vesicle-containing profiles which are seen only after the first month. The distributions of plaque diameters were reconstructed by the Coupland stereologic method from linear measurements of synaptic profiles and used to calculate synaptic densities and estimate the total number of synapses. This number is stable during the first postnatal month, declines markedly in the second month, and to a lesser degree thereafter, reaching a value of 55% of that at birth by 16 weeks. Findings indicate the occurrence of substantial changes within the subthalamic nucleus during the first 4 postnatal months, the most prominent of which is a marked synapse elimination.

Aging↗

PubMed2006

Direct visualization of the human subthalamic nucleus with 3T MR imaging.

BACKGROUND AND PURPOSE: Electrical stimulation of the subthalamic nucleus (STN) is an accepted treatment for advanced Parkinson disease (PD). Although procedural details are well established, targeting STN remains problematic because of its variable location and relatively small size (20-30 mm(3)). A combination of anatomic imaging with a stereotactic frame, atlas coordinates, and intraoperative neurophysiology is currently considered the most reliable approach for STN targeting. CT imaging is dependent on atlas coordinates, because the STN is not visualized. The STN is also difficult to visualize directly by using MR imaging at 1.5 T. METHODS: We performed preoperative stereotactic MR imaging at 3T to visualize the STN in 13 patients undergoing deep-brain stimulation for PD. With the patient positioned within a standard Leksell type G stereotactic frame localizer, rapidly acquired scout images are used to prescribe volumes of contiguous high-resolution T2-weighted fast spin-echo images in the axial, sagittal, and coronal planes through the midbrain and basal ganglia. The STN is identified in all 3 planes by cross-referencing in a 3-plane viewer. These coordinates are used for surgical targeting. RESULTS: At 3T, the STN was visualized as a small, hypointense, almond-shaped structure in 3 planes located immediately lateral to the anterior edge of the red nucleus, medial to the internal capsule, about 5 mm inferior, 1-2 mm posterior, and 9-12 mm lateral to the midcommissural point. Intraoperative microelectrode recordings confirmed these coordinates in all cases from the first microelectrode pass, thereby eliminating prolonged intraoperative electrophysiological STN searching and tissue disruption that may occur from multiple passes. CONCLUSION: 3T MR imaging appears to be an excellent tool for reliable and accurate direct visualization of the human STN, necessary for precise surgical targeting.

Adult↗

PubMed1999

Placement of deep brain stimulators into the subthalamic nucleus.

We present our technique for deep brain stimulation (DBS) of the subthalamic nucleus (STN) and include information which may be helpful in general DBS. With the patient in a stereotactic head frame, the anterior and posterior commissures are identified on SPGR-sequence magnetic resonance imaging (MRI). STN coordinates are based on a stereotactic brain atlas at 12 mm lateral, 2 mm posterior and 5 mm caudal to the midcommissural point. Surgical navigation software allows for planning of the trajectory. Electromyography is used to quantitatively measure tremor responses to macrostimulation. Permanent lead placement is confirmed with intraoperative fluoroscopy and postoperative MRI.

Brain Mapping↗

PubMed2005

High frequency stimulation of the subthalamic nucleus is efficacious in Parkin disease.

High frequency stimulation (HFS) of the subthalamic nucleus (STN) is an efficacious symptomatic treatment for Parkinson's disease. We have analysed the genetic status of a series of consecutive parkinsonian patients implanted for STN HFS and compared the outcome of five carrying mutations in the parkin gene with that of the non-parkin group. All patients obtained sustained control of PD symptoms and achieved functional improvement; in the parkin group the UPDRS motor score improved by 56.4%, the levodopa equivalent daily dosage was reduced by 75.5%. Postoperative medications were reduced more in parkin than in non-parkin patients. We confirm that the current inclusion criteria for STN HFS do not exclude patients carrying mutations in the parkin gene; their clinical outcome is comparable to that of the non-parkin group.

Adult↗

PubMed2000

Subthalamic nucleus microinjections of 5-HT2 receptor antagonists suppress stereotypy in rats.

The subthalamic nucleus (STN) is an important mediator of basal ganglia output. We studied the effects of STN microinjections of the serotonin-2 (5-HT2) antagonists clozapine, mesulergine and M100,907 on apomorphine-induced stereotypic activity in the rat. Each compound profoundly decreased the expression of stereotypic behavior, with particularly strong effects to reduce gnawing behavior. Because M100,907 does not have appreciable affinity for dopamine D1 and D2 receptors, and since all three agents are 5-HT2 antagonists, the current data suggest that basal ganglia output related to orofacial movements can be significantly modified by 5-HT2 receptors. The results suggest that antipsychotics with serotonergic properties may have direct actions on the STN that influence their potential to produce orofacial and other motor side effects.

Animals↗

PubMed2005

The functional role of the subthalamic nucleus in cognitive and limbic circuits.

Once it was believed that the subthalamic nucleus (STN) was no more than a relay station serving as a "gate" for ascending basal ganglia-thalamocortical circuits. Nowadays, the STN is considered to be one of the main regulators of motor function related to the basal ganglia. The role of the STN in the regulation of associative and limbic functions related to the basal ganglia has generally received little attention. In the present review, the functional role of the STN in the control of cortico-basal ganglia-thalamocortical associative and limbic circuits is discussed. In the past 20 years the concepts about the functional role of the STN have changed dramatically: from being an inhibitory nucleus to a potent excitatory nucleus, and from being involved in hyperkinesias to hypokinesias. However, it has been demonstrated only recently, mainly by reports on the behavioral (side-) effects of STN deep brain stimulation (DBS), which is a popular surgical technique in the treatment of patients suffering from advanced Parkinson Disease (PD), that the STN is clinically involved in associative and limbic functions. These findings were confirmed by results from animal studies. Experimental studies applying STN DBS or STN lesions to investigate the neuronal mechanisms involved in these procedures found profound effects on cognitive and motivational parameters. The anatomical, electrophysiological and behavioral data presented in this review point towards a potent regulatory function of the STN in the processing of associative and limbic information towards cortical and subcortical regions. In conclusion, it can be stated that the STN has anatomically a central position within the basal ganglia thalamocortical associative and limbic circuits and is functionally a potent regulator of these pathways.

Animals↗

PubMed2005

Subthalamic nucleus lesion reverses motor abnormalities and striatal glutamatergic overactivity in experimental parkinsonism.

Subthalamic nucleus (STN) is a target of choice for the neurosurgical treatment of Parkinson's disease (PD). The therapeutic effect of STN lesion in PD is classically ascribed to the rescue of physiological activity in the output structures of the basal ganglia, and little is known about the possible involvement of the striatum. In the present study, therefore, we electrophysiologically recorded in vitro single striatal neurons of DA-depleted rats unilaterally lesioned by 6-hydroxydopamine, treated or not with therapeutic doses of levodopa (l-DOPA), or with a consecutive ipsilateral STN lesion. We show that the beneficial motor effects produced in parkinsonian rats by STN lesion or l-DOPA therapy were paralleled by the normalization of overactive frequency and amplitude of striatal glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Since neither l-DOPA treatment nor STN lesion affected sEPSCs kinetic properties, the reversal of these abnormalities in striatal excitatory synaptic transmission can be attributable to the normalization of glutamate release.

Animals↗

PubMed2000

Dyskinesias and the subthalamic nucleus.

Severe dyskinesias or ballism can occur following hemorrhagic events in the subthalamic nucleus (STN), and it has recently been established that the STN plays a major role in the pathophysiology of the motor dysfunction of Parkinson's disease (PD) and that STN inhibition improves parkinsonian dysfunction. Deep brain stimulation of the STN in PD patients is therefore currently being evaluated as a therapy. High-frequency stimulation of the STN in PD patients can induce intense dyskinesias that are similar to those induced by levodopa. These may occur with a variable latency and resemble all types of levodopa-induced dyskinesias (LIDs). They can be decreased by reducing the levodopa dosage, which is permitted by the antiparkinsonian effect of stimulating the STN. STN stimulation has been shown to improve all types of LIDs, with the most dramatic effect being that on off-period dystonia. The improvement in LIDs may relate to the decrease in drug dosage, while the off-period dystonia is likely improved by the simultaneous administration of levodopa and STN stimulation. It is thought that the STN is an important node in a network, which can produce dyskinesias when disturbed by a lesion, and is particularly sensitive for the induction of these abnormal movements.

Animals↗

PubMed2002

Imaging of subthalamic nucleus and ventralis intermedius of the thalamus.

The techniques of targeting the subthalamic nucleus (STN) and the ventralis intermedius nucleus (Vim) are similar, only the coordinates are different. Targeting ideally consists of gathering all data about a target and positioning the electrode correctly within that target. The electrode should be positioned within a statistical range of coordinates, where the neuronal firing fits a given pattern and responds to external stimuli, particularly to proprioceptive inputs, in a somatotopically organized manner. Moreover, final placement should provide the best clinical improvement of symptoms under the stimulation parameters expected to be used in the long term. This latter criterion is by far the most important, because intraoperative findings indicate the functional benefit for the patient, which is the ultimate purpose of this surgery. A variety of radiological modalities are available to provide data for electrode placement, but each type has its drawbacks. Ventriculography, although safe when performed accordingly to strict technical procedure, is the most precise method but provides more indirect targeting and is more invasive than magnetic resonance imaging (MRI). MRI is the best method for visualizing the STN and, to some extent, for discerning the Vim, but it is plagued with unpredictable and nonreproducible deformations that induce a systematic distortion. These shortcomings no doubt will be corrected in the near future, and the technologies will better assist us in the proper placement of electrodes, which will provide the patient with the highest possible benefit.

Cerebral Ventriculography↗

PubMed2001

The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma.

The subthalamic nucleus (STN) currently is considered to play a key role in the pathophysiological origin of the parkinsonian state and is therefore the main target for surgical treatment of Parkinson's disease. The authors review the incidence of hemichorea/ballism (HCB) as a complication of thalamotomy, pallidotomy or campotomy procedures before the introduction of levodopa therapy, including the few reported cases accompanied by a neuropathological study. The literature shows that only a small number of parkinsonian patients with HCB had a lesion of the STN. Preliminary data in Parkinson's disease patients submitted to a subthalamotomy with current functional stereotaxy also indicate that HCB is a very rare complication. To explain this observation, we suggest that the parkinsonian state is characterized by an increased threshold for the induction of dyskinesia following STN lesioning. This arises as a consequence of reduced activity in the 'direct' GABA projection to the globus pallidus medialis (GPm) which accompanies dopamine depletion. Lesioning of the STN reduces excitation of the GPm, and theoretically this should induce dyskinesias. However, an STN lesion also, simultaneously, further reduces the hypoactivity in the globus pallidus lateralis (GPl) that is a feature of Parkinson's disease, and hence may compensate for GPm hypoactivity, thus self-stabilizing basal ganglia output activity and reducing the risk of HCB. We conclude that lesioning of the STN in Parkinson's disease is a feasible approach in some circumstances.

Adult↗

PubMed2006

Intra-operative recordings of local field potentials can help localize the subthalamic nucleus in Parkinson's disease surgery.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) can be a highly effective treatment for Parkinson's disease (PD). However, therapeutic efficacy is limited by difficulties in consistently and correctly targeting this nucleus. Increasing evidence suggests that there is abnormal synchronization of beta frequency band activity (approximately 20 Hz) in the STN of PD patients, as reflected in the oscillatory nature of the local field potential (LFP). We hypothesized that an increase in the power of the LFP beta activity may provide intra-operative confirmation of STN targeting in patients undergoing STN implantation for the treatment of advanced PD. Accordingly, we recorded LFPs from the four contacts of DBS electrodes as the latter were advanced in 2 mm steps from a point 4-6 mm above the intended surgical target point in the STN, to a point 4 mm below this. Contacts were configured to give three bipolar recordings of LFPs. These were analyzed on 16 sides in 9 patients. The power in the 13-35 Hz band recorded at the lowest contact pair underwent a steep but focal increase during electrode descent. The depth of the peak beta activity showed excellent agreement with the level of the intra-operative clinical stun effect (k coefficient = 0.792). The depth of peak beta activity also showed 100% specificity and 100% sensitivity for placement within STN in comparison to pre- and Post-operative stereotactic MRI. Functional physiological localization of STN by the on-line spectral analysis of LFPs is quick to perform and may provide information directly relevant to the position of the electrode contact actually used for DBS.

Adult↗