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PubMed2005

Freezing of gait after bilateral subthalamic nucleus stimulation for Parkinson's disease.

OBJECTIVE: To determine the long-term effect of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on freezing of gait in Parkinson's disease patients. PATIENTS AND METHODS: Sixty-seven patients were followed 12 months after bilateral STN DBS and 32 patients were followed 24 months post-surgery. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) with medications on and off at baseline and again in both conditions with stimulation on at follow-up. Specific attention was paid to the freezing item of the ADL section. RESULTS: Freezing scores in the medication off state improved significantly with stimulation at 1 and 2 years. In the medication on state there were no significant improvements in freezing. CONCLUSION: Off period freezing of gait is significantly improved with STN DBS up to 24 months; however, on period freezing is not affected by STN DBS.

Adult↗

PubMed2001

The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics.

Single-cell recording of the subthalamic nucleus (STN) was undertaken in 14 patients with Parkinson's disease submitted to surgery. Three hundred and fifty neurones were recorded and assessed for their response to passive and active movements. Thirty-two per cent were activated by passive and active movement of the limbs, oromandibular region and abdominal wall. All neurones with sensorimotor responses were in the dorsolateral region of the STN. Arm-related neurones were lateral (> or =14 mm plane) to leg-related neurones, which were found more medially (< or =12 mm). Representation of the oromandibular musculature was in the middle of the sensorimotor region (approximately 13 mm plane) and ventral to the arm and leg. Two hundred neurones were adequately isolated for 'off-line' analysis. The mean frequency of discharge was 33 +/- 17 Hz (13-117 Hz). Three types of neuronal discharges were distinguished: irregular (60.5%), tonic (24%) and oscillatory (15.5 %). They were statistically differentiated on the basis of their mean firing frequency and the coefficient of variation of the interspike interval. Neurones responding to movement were of the irregular or tonic type, and were found in the dorsolateral region of the STN. Neurones with oscillatory and low frequency activity did not respond to movement and were in the ventral one-third of the nucleus. Thirty-eight tremor-related neurones were recorded. The majority (84%) of these were sensitive to movement and were located in the dorsolateral region of the STN. Cross power analysis (n = 16) between the rhythmic neuronal activity and tremor in the limbs showed a peak frequency of 5 Hz (4-8 Hz). Neuronal activity of the substantia nigra pars reticulata was recorded 0.5-3 mm below the STN. Eighty neurones were recorded 'on-line' and 27 were isolated for 'off-line' analysis. A tonic pattern of discharge characterized by a mean firing rate of 71 +/- 28 Hz (35-122 Hz) with a mean coefficient of variation of the interspike interval of 0.85 +/- 0.29 ms was found. In only three neurones (11%) was there a response to sensorimotor stimulation. The findings of this study indicate that the somatotopic arrangement and electrophysiological features of the STN in Parkinson's disease patients are similar to those found in monkeys.

Action Potentials↗

PubMed2003

Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) has become an effective treatment option in advanced Parkinson's disease (PD). Recent animal studies showed an increase of neuronal firing in dopaminergic neurons under effective STN-DBS. Increased striatal dopamine levels may also contribute to the stimulation's mechanism of action in humans. We investigated the striatal dopamine release in 6 patients with advanced PD under effective bilateral STN-DBS with positron emission tomography (PET) of the reversible dopamine-D2/3-receptor ligand [(11)C]raclopride (RACLO). Although STN-DBS proved to be a highly effective treatment in these subjects, we found no significant difference of the striatal RACLO binding between the STN-DBS-on and -off condition. The changes of radioligand binding did not correlate with the patients' improvement in clinical rating scales or with the stimulation amplitudes. Therefore, our PET data in living parkinsonian humans do not provide evidence for an increased striatal dopamine concentration under effective STN-DBS. We conclude that the modulation of dopaminergic activity does not seem to play a crucial role for the stimulation's mechanisms of action in parkinsonian humans.

Aged↗

PubMed2001

High frequency stimulation of the subthalamic nucleus increases the extracellular contents of striatal dopamine in normal and partially dopaminergic denervated rats.

The subthalamic nucleus (STN) has come under focus in Parkinson disease (PD) because of recent advances in the understanding of the functional organization of the basal ganglia in normal and pathological conditions. Manipulations of the STN have been described to compensate for some imbalance in motor output of the basal ganglia in animal models of PD and have been proposed as a potential therapeutic target in humans. Indeed, high frequency stimulation (HFS) (130 Hz) of the STN has beneficial effects in severe parkinsonian patients but the precise mechanisms underlying these clinical results remain to be elucidated. To date, very little is known concerning the effect of HFS-STN on striatal dopaminergic transmission. Since it has been reported that dopaminergic medication may be reduced in PD patients under HFS-STN, our goal was to study the effect of HFS-STN on striatal dopamine (DA) transmission by using intracerebral microdialysis in normal and partially DA denervated rats. Our results show that HFS STN induces a significant increase of extracellular DA in the striatum of normal and partially DA lesioned rats while striatal extracellular levels of DOPAC were not affected. We conclude that HFS-STN acts directly and/or indirectly on striatal DA levels in control or partially DA lesioned rats.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Bilateral effects of unilateral subthalamic nucleus deep brain stimulation in advanced Parkinson's disease.

To investigate the bilateral effects of unilateral subthalamic nucleus deep brain stimulation (STN-DBS), we prospectively studied 9 consecutive advanced Parkinson's disease (PD) patients (2 men and 7 women) who underwent unilateral STN-DBS. Patients were evaluated preoperatively and at 3 and 6 months postoperatively with and without dopaminergic medications ('on' and 'off' medication, respectively). Postoperatively, patients were assessed with and without stimulation. We found that, when compared with baseline, the 'off' medication scores of the Unified Parkinson's Disease Rating Scale motor part (UPDRS III) and activities of daily living (UPDRS II) were improved by 37% (p = 0.028) and 50% (p = 0.046) at 6 months after surgery, respectively. Stimulation while 'off' medication improved the total UPDRS score by 42% (p = 0.028) at 6 months. At 6 months after surgery, the subscore of UPDRS III of body parts contralateral to the DBS implantation had improved by 48% (p = 0.028), and the ipsilateral subscore of UPDRS III and the axial subscore of UPDRS III had improved by 20% (p = 0.027) and 39% (p = 0.028), respectively. Daily dosage of levodopa was reduced by 15% at 6 months. No patient exhibited permanent side effects. These findings indicate that unilateral STN-DBS may be a reasonable surgical procedure for selected PD patients who have markedly asymmetric parkinsonism.

Activities of Daily Living↗

PubMed2002

Deep brain stimulation of the subthalamic nucleus in PD: an analysis of the exclusion causes.

OBJECTIVE: Deep Brain Stimulation (DBS) of the Subthalamic Nucleus (STN) represents a proper choice for the treatment of advanced Parkinson's disease (PD). A correct selection of the patients as candidates for the surgery is essential for a good outcome. In this study, we analyzed the exclusion causes of a series of PD patients hospitalized for the selection protocol. METHODS: Ninety-eight PD patients as potential candidates for the STN DBS were studied. All patients were hospitalized and underwent a clinical evaluation of the PD stage, a levodopa challenge, a MR of the brain and a neuropsychological assessment. RESULTS: The percentage of subjects considered not suitable for the surgery was 29.6%. A single cause of exclusion was present in 65.5% of not suitable patients, while multiple causes were present in 34.5%. The most frequent cause of exclusion was the finding of neuropsychological or psychic disorders (48.3%); in 37.9% of the patients, the motor disability was not severe enough to justify the surgery, while in 31%, we found relevant abnormalities at the brain MR. Three patients (10.3%) were poorly motivated for the surgery, while in three others (10.3%), we found a significant illness other than PD. CONCLUSIONS: The finding that about 30% of the PD patients potentially suitable for STN DBS presents some exclusion causes underlines the importance of a careful selection of the candidates for this surgery.

Age Factors↗

PubMed2004

Location of the active contact within the subthalamic nucleus (STN) in the treatment of idiopathic Parkinson's disease.

BACKGROUND: Chronic electrical stimulation of the subthalamic nucleus (STN) has been shown to be safe and effective in the treatment of medically refractory idiopathic Parkinson's disease. The clinically most relevant location of stimulation within the physiologically defined STN has not been confirmed. We reviewed the locations of active electrical contacts in 33 patients who underwent simultaneous bilateral STN deep brain stimulator (DBS) implantation. METHODS: The location of the microelectrode-defined dorsal STN border was compared to the location of the center of the active contact(s) employed in achieving optimal clinical results 6 to 18 months postoperatively. Furthermore, the location of this optimal contact was determined with respect to each individual patient's midcommissural point. Bilateral monopolar stimulation was employed in 30 patients using quadripolar DBS electrodes. RESULTS: After a minimum follow-up period of 6 months, the motor subscores (UPDRS Part III) in the postoperative on-stimulation/off-medication state were 64 +/- 18% (mean +/- SD) improved as compared to the preoperative off-medication state (p < 0.01). Additionally, an improvement of 53 +/- 38% was noted when comparing the postoperative on-stimulation/on-medication state to the preoperative on-medication state (p < 0.01). On average, the center of the optimal contact was 13.3 mm lateral, 0.5 mm posterior, 0.1 mm inferior to the mid-commissural point and was 0.1 +/- 2.1 mm dorsal to the physiologically defined dorsal STN border. CONCLUSIONS: While the achieved clinical results are comparable to those published in the literature, it appears that monopolar electrical stimulation at the anterior dorsolateral border of the STN yields optimal clinical results. Further studies are crucial in determining the precise mechanism of various modes of DBS in an effort to maximize clinical outcome.

Adult↗

PubMed2004

Subthalamic nucleus lesions alter basal and dopamine agonist stimulated electrophysiological output from the rat basal ganglia.

The subthalamic nucleus (STN) is an important link in the "indirect" striatal efferent pathway. To assess its role on basal ganglia output via the substantia nigra pars reticulata (SNr), we monitored the single unit activities of SNr neurons in chloral hydrate-anesthetized rats 5-8 days after bilateral kainic acid lesions (0.75 microg/0.3 microl/side) of the STN. Consistent with loss of an excitatory input, the average basal firing rate of SNr neurons was significantly reduced in STN-lesioned animals. Moreover, the lesions modified the responses of SNr neurons to individual and concurrent stimulation of striatal D1 and D2 receptors. Bilateral striatal infusions of the D1/D2 agonist apomorphine (10 microg/microl/side) into the ventral-lateral striatum (VLS) were previously shown to cause significant increases in SNr cell firing (to 133% of baseline) in normal rats. However, in STN-lesioned rats, identical infusions caused no overall change in SNr activity (mean, 103% of basal rates). Conversely, selective stimulation of striatal D2 receptors by bilateral co-infusion of the D2 agonist quinpirole and the D1 antagonist SCH 23390 that previously caused little change in SNr firing in normal rats significantly inhibited their firing in STN-lesioned rats. Finally, the modest excitatory responses of SNr neurons to selective stimulation of striatal D1 receptors by co-infusions of SKF 82958 with the D2 antagonist YM09151-2 were not altered by lesions of the STN. These results implicate the STN as a mediator of excitatory response of SNr neurons to D2, and mixed D1/D2, dopamine receptor agonists in normal rats, and challenge conventional views on the role of the STN and the "indirect" pathway in regulating dopamine-stimulated output from the SNr.

Action Potentials↗

PubMed1995

Responses of substantia nigra pars reticulata and globus pallidus complex to high frequency stimulation of the subthalamic nucleus in rats: electrophysiological data.

High frequency stimulation of the subthalamic nucleus (STN-HFS) has been shown to reverse parkinsonian motor symptoms in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. We have studied the effect of STN-HFS on the spontaneous activity of the substantia nigra pars reticulata (SNr), entopeduncular nucleus (EP) and globus pallidus (GP) in rats. STN-HFS induced a decrease in activity of 91% of SNr cells, a suppression of activity in 80% of EP cells and an activation of 100% of GP recorded cells. These results show that STN-HFS exerts an inhibitory influence on the basal ganglia output structures similar to that obtained by STN lesion.

Animals↗

PubMed2003

"The little engine that could": voltage-dependent Na(+) channels and the subthalamic nucleus.

The most effective treatment for late-stage Parkinson's disease is to electrically stimulate the subthalamic nucleus (STN) at high frequencies. Why this strategy works is unclear. The work by Do and Bean shows that the Na channels in STN neurons have distinctive features--like resurgence--that regulate their spiking behavior, providing new insights into the mechanism of DBS.

Animals↗

PubMed2003

Anatomic and neurophysiological methods for the targeting and lesioning of the subthalamic nucleus: Cuban experience and review.

OBJECTIVE: To develop a method to place a lesion precisely in the subthalamic nucleus (STN) and evaluate its effectiveness. METHODS: A retrospective study of targeting data collected during stereotactic planning to lesion the STN in 31 patients with Parkinson's disease and of results in more than 50 procedures was performed. The targeting method was based on computed tomographic imaging together with semimicroelectrode recording digital processing and electrical stimulation. Two statistical methods were used to correlate initial with final target coordinates and assess the efficacy of the targeting procedure. RESULTS: The anatomic target based on computed tomographic imaging data showed electrical activity in the subthalamus in the first pass in 82% of the procedures. In the remaining 18%, the STN was an average of 1.93 mm away from the nearest trajectory that recorded the STN (range, 1.41-2.24 mm). The average number of trajectories per procedure was 7.2; the location of the first trajectory relative to the center of the nucleus determined by electrical and physiological means (P < 0.01, analysis of variance, Student's t test) was as follows: in the lateral direction, 1.25 +/- 1.15 mm; in the anteroposterior direction, 1.53 +/- 1.31 mm; and in the vertical direction, 0.67 +/- 0.51 mm. The average number of tracts necessary to lesion the STN was two. CONCLUSION: The combination of computed tomographic imaging, semimicroelectrode recording, and microstimulation provides an effective method to identify the STN lesion in parkinsonian patients. The method used for anatomic localization and electrophysiological mapping of the subthalamus was found to be effective in reaching the sensorimotor region of the nucleus. We carried out an accurate determination of the subthalamus location and its volume in the lesioning.

Adult↗

PubMed2003

A quick and universal method for stereotactic visualization of the subthalamic nucleus before and after implantation of deep brain stimulation electrodes.

For deep brain stimulation (DBS) of the subthalamic nucleus (STN), it would be an advantage if the STN could be visualized with fast acquisition of MR images, allowing direct and individual targeting. We present a protocol for T2-weighted, nonvolumetric fast-acquisition MRI, implemented at 8 centers in 6 countries. Acquisition time varied between 3 min 5 s and 7 min 48 s according to the center, and imaging often provided visualization of the STN on axial and coronal scans. Postoperatively, the same imaging protocol permitted visualization of the target area and DBS electrodes with minimum artifacts. This imaging technique may contribute to a decrease in the number of electrode passes at surgery.

Electric Stimulation Therapy↗

PubMed2006

Stimulation of the subthalamic nucleus in Parkinson's disease: cognitive and affective changes are not linked to the motor outcome.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN0 DBS) is a widely performed surgical treatment in PD. However, the relationship between motor results and cognitive/behavioural modifications is unclear. OBJECTIVE: This study investigated the correlation patterns of the motor, cognitive and behavioural consequences of STN DBS with respect to positioning of the active contact. METHODS: Fifty-eight consecutive PD patients having undergone STN DBS were assessed pre-operatively and 12 months after surgery. RESULTS: Motor, cognitive and behavioural results were neither correlated to each other nor linked to the position of the active contact. Three patients with a history of pre-operative, dopaminergic psychosis or post-surgical confusion became demented. Age and a distant history of depression were associated with the occurrence of post-surgical depression. CONCLUSION: Correct screening of patients for STN DBS remains an important issue, since the current implantation procedure is not able to take account of potential functional heterogeneity within the target.

Affect↗

PubMed2003

Do intraoperative microrecordings improve subthalamic nucleus targeting in stereotactic neurosurgery for Parkinson's disease?

AIM: The clinical importance of intraoperative microrecordings for subthalamic nucleus (STN) localization in neurosurgical practice remains a matter of debate in the various groups. METHODS: To investigate their usefulness in localizing the STN, we retrospectively evaluated how intraoperative microelectrode recordings changed the targeting of the STN estimated only on intraoperative stimulation and neuroanatomic targeting procedures. For neuroradiologic targeting of the nucleus we used a TC-MRI fusion algorithm and direct visualization of the STN. Besides standard microrecordings we also analyzed the power spectral density (PSD) pattern of physiological signals along the track and its neuroanatomic and clinical correlations. RESULTS: In our series of 12 patients with Parkinson's disease undergoing surgery for implantation of deep-brain stimulation (DBS) electrodes in the STN we found that in 25% (1/4) of patients, microrecordings determined the choice of the optimal track. In all the tracks analyzed the PSD peak coincided with the point selected for the final electrode implantation on the basis of the standard procedure for intraoperative monitoring based on both microstimulation and recordings. CONCLUSION: Intraoperative microrecordings are of determinant importance for accurate STN localization and are essential for optimal results in neurosurgical practice. PSD analysis is a simple and quick quantitative signal descriptor that will probably provide even more precise, simple and rapid tool for intraoperative neurophysiological localization of the STN.

Electrodes, Implanted↗

PubMed2002

Excitatory effects of dopamine on subthalamic nucleus neurons: in vitro study of rats pretreated with 6-hydroxydopamine and levodopa.

Increased output from the subthalamic nucleus (STN) following chronic dopamine depletion has been linked to the rigidity and tremor seen in Parkinson's disease (PD). We used extracellular microelectrode recordings from rat brain slices to investigate effects of dopamine on STN neurons. In brain slices prepared from rats that received unilateral 6-hydroxydopamine (6-OHDA) treatment, the spontaneous firing rate of STN neurons was reduced by 63%, and the firing pattern was more irregular, compared to STN neurons from normal rats. However, treatment with levodopa (50 mg/kg, i.p., daily) for 4 weeks normalized the firing rate and pattern of STN neurons in the 6-OHDA-treated rats. Dopamine (3-300 microM), added to the superfusate, significantly increased the firing rates of STN neurons in a concentration-dependent fashion, and also produced a more regular firing pattern in 6-OHDA-lesioned tissue. This excitatory effect of dopamine was mimicked by a D2 receptor agonist (quinpirole), and was reduced by the D2 antagonists haloperidol, clozapine and sulpiride. Antagonists of the D1 receptor (SCH-23390) and ionotropic glutamatergic receptors (CNQX and AP5) could not block the effect of dopamine on firing rate. These results suggest that dopamine exerts a direct excitatory influence on STN neurons via the activation of D2-like receptors.

Animals↗

PubMed2004

Unilateral pallidotomy versus bilateral subthalamic nucleus stimulation in PD: a randomized trial.

OBJECTIVE: To compare the efficacy of unilateral pallidotomy and bilateral subthalamic nucleus (STN) stimulation in patients with advanced Parkinson disease (PD) in a randomized, observer-blind, multicenter trial. METHODS: Thirty-four patients with advanced PD were randomly assigned to have unilateral pallidotomy or bilateral STN stimulation. The primary outcome was the change from baseline to 6 months in the motor part of the Unified PD Rating Scale (motor UPDRS) in the off phase. Secondary outcomes were parkinsonian symptoms in the on phase (motor UPDRS), dyskinesias (Clinical Dyskinesia Rating Scale and dyskinesias UPDRS), functional status (activities of daily living UPDRS and Schwab and England scale), PD Quality of Life questionnaire, changes in drug treatment, and adverse effects. RESULTS: The off phase motor UPDRS score improved from 46.5 to 37 points in the group of pallidotomy patients and from 51.5 to 26.5 in the STN stimulation patients (p = 0.002). Of the secondary outcome measures, on phase motor UPDRS and dyskinesias UPDRS improved significantly in favor of the STN stimulation patients. Reduction of antiparkinsonian drugs was greater after STN stimulation than after pallidotomy. One patient in each group had a major adverse effect. CONCLUSIONS: Bilateral STN stimulation is more effective than unilateral pallidotomy in reducing parkinsonian symptoms in patients with advanced PD.

Aged↗

PubMed2003

Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.

Activities of Daily Living↗

PubMed2004

Deep brain stimulation of the subthalamic nucleus improves cognitive flexibility but impairs response inhibition in Parkinson disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN) improves motor symptoms of Parkinson disease. Although several studies have assessed cognitive functions before surgery and after long-term STN stimulation, only a few have assessed patients while stimulation is on and off to more specifically address the short-term cognitive effects of STN deep brain stimulation. OBJECTIVE: To examine the short-term effects of STN stimulation on several tests sensitive to executive function and the long-term effects of STN stimulation on a global cognitive scale. DESIGN: Twenty-three patients with Parkinson disease were tested 6 to 12 months after surgery with STN stimulation switched on and off in a random order while taking their regular medication. The Unified Parkinson's Disease Rating Scale motor score was also rated in the on and off stimulation condition. The neuropsychological battery included digit span, verbal fluency, Stroop color test, and random number generation in a single- and dual-task condition. RESULTS: Short-term stimulation improved the results on the Random Number Generation Task, requiring suppression of habitual responses, but induced more errors in the interference task of the Stroop color test. Digit span, verbal fluency, and dual-task performance results did not change. There was a significant correlation (r = 0.47, P =.02) between improved performance on the Random Number Generation Task and impaired response inhibition in the Stroop interference condition. A preoperative to postoperative comparison showed no changes in global cognitive function with long-term STN deep brain stimulation. CONCLUSIONS: Short-term STN stimulation improves cognitive flexibility (giving up habitual responses) but impairs response inhibition. Long-term STN stimulation does not change global cognitive function.

Cognition↗