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PubMed2003

Synaptic plasticity in rat subthalamic nucleus induced by high-frequency stimulation.

The technique of deep brain stimulation (DBS) has become a preferred surgical choice for the treatment of advanced Parkinson's disease. The subthalamic nucleus (STN) is presently the most promising target for such DBS. In this study, whole-cell patch-clamp recordings were made from 46 STN neurons in rat brain slices to examine the effect of high-frequency stimulation (HFS) of the STN on glutamatergic synaptic transmission in STN neurons. HFS, consisting of trains of stimuli at a frequency of 100 Hz for 1 min, produced three types of synaptic plasticity in 17 STN neurons. First, HFS of the STN induced short-term potentiation (STP) of evoked postsynaptic current (EPSC) amplitude in four neurons. STP was associated with a reduction in the EPSC paired-pulse ratio, suggesting a presynaptic site of action. Second, HFS of the STN generated long-term potentiation (LTP) of EPSC amplitude in eight neurons. Although the EPSC paired-pulse ratio was reduced transiently in the first 2 min following HFS, ratios measured 6-20 min after HFS were unchanged from control. This suggests that LTP is maintained by a postsynaptic mechanism. Third, HFS produced long-term depression (LTD) of EPSC amplitude in five STN neurons. LTD was associated with a significant increase in EPSC paired-pulse ratios, indicating a presynaptic site of action. These results suggest that HFS can produce long-term changes in the efficacy of synaptic transmission in the STN. HFS-induced synaptic plasticity might be one mechanism underlying the effectiveness of DBS in the STN as a treatment of advanced Parkinson's disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2006

Deep brain stimulation of the subthalamic nucleus affects resting EEG and visual evoked potentials in Parkinson's disease.

OBJECTIVE: We studied changes of the EEG spectral power induced by deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson's disease (PD). Also analyzed were changes of visual evoked potentials (VEP) with DBS on and off. METHODS: Eleven patients with advanced PD treated with bilateral DBS STN were examined after an overnight withdrawal of L-DOPA and 2 h after switching off the neurostimulators. All underwent clinical examination followed by resting EEG and VEP recordings, a procedure repeated after DBS STN was switched on. RESULTS: With DBS switched on, the dominant EEG frequency increased from 9.44+/-1.3 to 9.71+/-1.3 Hz (P<0.01) while its relative spectral power dropped by 11% on average (P<0.05). Switching on the neurostimulators caused a decrease in the N70/P100 amplitude of the VEP (P<0.01), which inversely correlated with the intensity of DBS (black-and-white pattern: P<0.01; color pattern: P<0.05). CONCLUSIONS: Despite artifacts generated by neurostimulators, the VEP and resting EEG were suitable for the detection of effects related to DBS STN. The acceleration of dominant frequency in the alpha band may be evidence of DBS STN influence on speeding up of intracortical oscillations. The spectral power decrease, seen mainly in the fronto-central region, might reflect a desynchronization in the premotor and motor circuits, though no movement was executed. Similarly, desynchronization of the cortical activity recorded posteriorly may by responsible for the VEP amplitude decrease implying DBS STN-related influence even on the visual system. SIGNIFICANCE: Changes in idling EEG activity observed diffusely over scalp together with involvement of the VEP suggest that the effects of DBS STN reach far beyond the motor system influencing the basic mechanisms of rhythmic cortical oscillations.

Aged↗

PubMed1993

Appearance of EMG activity and motor asymmetry after unilateral lesions of the dopaminergic innervation to the subthalamic nucleus in the rat.

The effects of unilateral injections of 6-hydroxydopamine into the subthalamic nucleus on muscular rigidity and on motor behavior were examined. Muscular rigidity was judged by the appearance of electromyographical activity in the gastrocnemius-soleus muscle and motor behavior by the turning induced by DL-methamphetamine. The unilateral injection of 6-hydroxydopamine produced the appearance of electromyographical activity ipsilateral to the injected side and ipsilateral turning in response to systemic administration of DL-methamphetamine. These results suggest that the dopaminergic innervation exerts a tonic inhibitory action on the spontaneous activity of the subthalamic neurons. The loss of this action would cause muscular rigidity and motor asymmetry.

Animals↗

PubMed2004

Somatosensory evoked potentials (SEPs) recorded from deep brain stimulation (DBS) electrodes in the thalamus and subthalamic nucleus (STN).

OBJECTIVE: To examine the location of deep brain stimulation (DBS) electrode somatosensory evoked potentials (SEPs) and determine the generators of the median nerve SEPs recorded in thalamus and subthalamic nucleus (STN). METHODS: SEPs were recorded from contacts of DBS electrodes and microelectrodes in thalamus and STN to establish the latencies of N13, N18 and N20 in 24 patients (8 tremor, 4 chronic pain, 12 Parkinson disease) undergoing chronic DBS. RESULTS: A large SEP with a mean latency of 17.9+/-1.7 ms was recorded from thalamic contacts. Phase reversal occurred at the horizontal level of the anterior commissure-posterior commissure line. Smaller potentials with similar latency but no reversal could be recorded from STN electrodes. CONCLUSIONS: We propose that the thalamic SEP is generated by excitatory post-synaptic potentials in sensory relay neurons in nucleus ventrocaudalis. A small potential in STN at a similar latency, may be due to volume conduction from thalamus. Intraoperative and postoperative SEP recordings from DBS electrodes could be used to determine the optimal position of the contacts relative to the sensory pathways and the choice of contacts for chronic stimulation.

Adult↗

PubMed2001

Deep brain stimulation of subthalamic nucleus: behavioural modifications and familiar relations.

The present study investigated behavioural modifications and familiar relations in a group of 15 parkinsonian patients treated with bilateral deep brain stimulation of the subthalamic nucleus. In 70% of the patients, during the first months after surgery we observed a euphoric mood owing to motor signs amelioration, but a series of problems (fear to come back to the pre-operative condition, sense of failure, slowness in changing the old habits) arose when it was necessary to adjust the parameters of stimulation and the pharmacological therapy to obtain a stable clinical picture. The caregivers showed an aggressive behaviour as reaction to the persistent psychological dependence of the patients. This distressed condition could be the cause of the onset of incomprehensions within the couple.

Anxiety↗

PubMed2002

Oscillatory local field potentials recorded from the subthalamic nucleus of the alert rat.

Hitherto, high-frequency local field potential oscillations in the upper gamma frequency band (40-80 Hz) have been recorded only from the region of subthalamic nucleus (STN) in parkinsonian patients treated with levodopa. Here we show that local field potentials recorded from the STN in the healthy alert rat also have a spectral peak in the upper gamma band (mean 53 Hz, range 46-70 Hz). The power of this high-frequency oscillatory activity was increased by 30 +/- 4% (+/-SEM) during motor activity compared to periods of alert immobility. It was also increased by 86 +/- 36% by systemic injection of the D2 dopamine receptor agonist quinpirole. The similarities between the high-frequency activities in the STN of the healthy rat and in the levodopa-treated parkinsonian human argue that this oscillatory activity may be physiological in nature and not a consequence of the parkinsonian state.

Animals↗

PubMed2003

The timing of antiparkinsonian treatment reduction after subthalamic nucleus stimulation.

The objective of this work was to precisely analyse the reduction of the antiparkinsonian treatment in 18 consecutive patients with Parkinson's disease (PD) operated on for bilateral subthalamic nucleus (STN) stimulation, first after 1 month of follow-up, then at 1 year postoperatively. Trihexyphenidyle, selegiline, entacapone, apomorphine and lisuride could be withdrawn shortly after starting STN electrical stimulation. The levodopa mean daily dose was reduced by 57% at 1 month after surgery and remained stable at 1 year. The mean ropinirole and bromocriptine daily dose decrements after surgery corresponded to 54 and 63%, respectively, at 1 month and to 77 and 40% at 1 year. At 12 months postoperatively, one third of the patients no longer received any antiparkinsonian drugs and the others were on monotherapy of either levodopa or dopamine agonists or received a combined treatment of a dopaminergic agonist and levodopa. In conclusion, STN stimulation allows a major reduction and simplification of antiparkinsonian treatment which can usually be achieved during the early postoperative period.

Aged↗

PubMed2004

Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation-induced cellular defects in the rat striatum and globus pallidus.

This study examined the effects of prolonged (4 days) high frequency stimulation (HFS) of the subthalamic nucleus (STN), in comparison with those of STN lesion, on the dopamine denervation-mediated cellular changes in the basal ganglia in a Wistar rat model of Parkinson's disease. STN HFS counteracted the dopamine lesion-induced increase in GAD67 mRNA expression in the output structures of the basal ganglia, as shown previously after STN lesion, providing cellular support for the similar antiparkinsonian benefits produced by the two surgical procedures. The dopamine denervation-induced increase in GAD67 mRNA levels in the globus pallidus was partially antagonized after HFS and totally reversed after ibotenate-induced STN lesion. The overexpression of striatal enkephalin mRNA tended to be further increased by HFS but was antagonized by STN lesion. The decrease in striatal substance P mRNA levels was affected neither by STN HFS nor lesion. As STN HFS for two hours was previously found not to interfere with the effects of dopamine lesion in the globus pallidus and striatum, the present data provide strong evidence that the effects of STN surgery in these structures involve long-term adaptive processes and that the rearrangements mediated by HFS and lesion are, at least in part, different.

Animals↗

PubMed2004

Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in advanced Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a highly effective surgical treatment in patients with advanced Parkinson's disease (PD). Because the STN has been shown to represent an important relay station not only in motor basal ganglia circuits, the modification of brain areas also involved in non-motor functioning can be expected by this intervention. To determine the impact of STN-DBS upon the regional cerebral metabolic rate of glucose (rCMRGlc), we performed positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) in eight patients with advanced PD before surgery as well as in the DBS on- and off-conditions 4 months after electrode implantation and in ten age-matched healthy controls. Before surgery, PD patients showed widespread bilateral reductions of cortical rCMRGlc versus controls but a hypermetabolic state in the left rostral cerebellum. In the STN-DBS on-condition, clusters of significantly increased rCMRGlc were found in both lower thalami reaching down to the midbrain area and remote from the stimulation site in the right frontal cortex, temporal cortex, and parietal cortex, whereas rCMRGlc significantly decreased in the left rostral cerebellum. Therefore, STN-DBS was found to suppress cerebellar hypermetabolism and to partly restore physiologic glucose consumption in limbic and associative projection territories of the basal ganglia. These data suggest an activating effect of DBS upon its target structures and confirm a central role of the STN in motor as well as associative, limbic, and cerebellar basal ganglia circuits.

Aged↗

PubMed2003

Bilateral high-frequency stimulation of the subthalamic nucleus in patients with multiple system atrophy--parkinsonism. Report of four cases.

The aim of this study was to investigate the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in patients with a subtype of multiple system atrophy (MSA) in which levodopa-unresponsive MSA parkinsonism (MSA-P) is predominant. After a local anesthetic was administered, electrodes were stereotactically implanted bilaterally into the STN in four patients with MSA-P and predominantly akinetorigid symptoms. Unified Parkinson's Disease Rating Scale (UPDRS) scores were evaluated preoperatively, at 1 month, and at long-term follow up. At 1 month the median decrease in the UPDRS III motor score was 22 on the 56-point scale (decreases of 16, 13, 29, and 15 points compared with baseline for Cases 1, 2, 3, and 4, respectively). This was mainly due to an improvement in rigidity and akinesia. The median decrease in the UPDRS II score was 11 on the 52-point scale (respective decreases of 5, 7, 13, and 9 points). At 2 years (mean follow up 27 months) there was a median decrease in the UPDRS III score of 12 (respective decreases of 18, 13, 21, and 9 points), and in the UPDRS II score of 5 (with respective decreases of 2, 2, 17, and 2), both compared with the stimulation off state. At long-term follow up there was an increase in the individual Schwab and England scores of 10 to 15% in the stimulation on compared with the stimulation off condition. There was a beneficial effect of STN HFS in these four patients on both a short-term and a long-term basis. A larger prospective study is justified.

Activities of Daily Living↗

PubMed2005

Stimulation of the subthalamic nucleus in a patient with Parkinson disease and essential tremor.

BACKGROUND: The preferred surgical target for the treatment of Parkinson disease (PD) is either the internal globus pallidus or the subthalamic nucleus (STN); the target for treatment of essential tremor (ET) is the thalamic subnucleus ventralis intermedius (Vim). Some patients with PD have coexistent ET, and the identification of a single surgical target to treat both parkinsonian motor symptoms and ET would be of practical importance. OBJECTIVE: To describe the use of the STN target in deep brain stimulator (DBS) surgery to treat PD motor symptoms and the action-postural tremor of ET. DESIGN: Case report. PATIENT: A 62-year-old man had a greater than 30-year history of action-postural tremor in both hands, well controlled with beta-blockers for more than 20 years. He developed resting tremor, bradykinesia, and rigidity on his right side that progressed to his left side during the past 10 years. Dopaminergic medication improved his rigidity and bradykinesia, with only mild improvement of his resting tremor and no effect on his action-postural tremor. INTERVENTIONS: Left pallidotomy followed by placement of a left DBS in the Vim and subsequent placement of a right STN DBS. MAIN OUTCOME MEASURES: Control of symptoms of PD and ET. RESULTS: The left pallidotomy controlled the patient's parkinsonian motor symptoms on the right side of his body, but did not affect the action-postural component of his tremor. The symptoms on the left side of the body, including both an action-postural and a resting tremor (as well as the rigidity and bradykinesia), improved after placement of a single right STN DBS. CONCLUSION: Placement of an STN DBS should be considered as the procedure of choice for surgical treatment of patients with a combination of PD and ET.

Deep Brain Stimulation↗

PubMed2005

Comparison of 2-dimensional magnetic resonance imaging and 3-planar reconstruction methods for targeting the subthalamic nucleus in Parkinson disease.

OBJECTIVE: The study aims to compare 2-dimensional (2D) and 3-planar (3P) reconstruction magnetic resonance imaging (MRI) methods of targeting the optimal region of the subthalamic nucleus (STN) for chronic stimulation in patients with Parkinson disease. METHODS: We studied 14 patients with Parkinson disease treated with bilateral STN deep brain stimulation (DBS) (28 STN targets). Electrode implantation was based on direct and indirect targeting based upon the position of the anterior and posterior commissures using 2D MRI, with selection of the final target based on microelectrode recording. Optimal settings, including the contacts used, were determined during the clinical follow-up. The position of the best contact was defined with postoperative MRI. Optimal contact position was compared to targets calculated by the direct method from the preoperative 2D MRI and 3P reconstruction. Optimal contact position was also compared to the indirect targets calculated from the preoperative 2D MRI and 3P reconstruction. The distance between the targets and the position of the best contact were calculated. RESULTS: The mean improvement in OFF-period Unified Parkinson Disease Rating Scale III subscores with STN DBS was 52%. The mean distance between the optimal contact position and the direct target was 4.66 mm (SD = 1.33) using the 2D MRI and 3.49 mm (SD = 1.29) using the 3P reconstruction (t test, P < .001). The mean distance between the optimal contact and the indirect target was 3.42 mm (SD = 1.34) using the 2D MRI and 2.61 mm (SD = 0.97; t test, P = .001) using the 3P reconstruction. The variance of the direct target was less using the 3P reconstruction than using the 2D MRI (F test, P = .002), indicating greater precision. Similarly, the variance of the indirect target using the 3P reconstruction was less than using the 2D MRI (F test, P = .012). CONCLUSION: Indirect and direct targets chosen using 3P reconstruction more closely approximate the position of the clinically optimal contact than targets chosen using 2D MRI.

Deep Brain Stimulation↗

PubMed2002

Cognitive changes following subthalamic nucleus stimulation in two patients with Parkinson disease.

The limits of a drug therapy in severe forms of Parkinson disease have led to refining neurosurgery on the basal ganglia. Deep brain stimulation of the subthalamic nucleus has been recognized as one of the most promising techniques to decrease "off" motor symptoms and motor fluctuations, allowing a reduction of drug therapy and limiting side effects of the drugs. There is still open debate on the possible consequences of chronic subthalamic stimulation in other ways, apart from motor symptoms, of general cognitive performance. We examined and followed two patients with Parkinson disease for 9 mo. after surgery for deep stimulation, studying their cognitive performances. There is a general amelioration of cognitive performances, in particular as far as linguistic capabilities is concerned. We discuss the possible significance of these results, reminding strenuously that only two patients were involved, so the potential for generalization is seriously limited.

Aged↗

PubMed2002

Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients.

Expectations about future events are known to trigger neural mechanisms that affect both perception and action. Here we report that different and opposite expectations of bad and good motor performance modulate the therapeutic effects of subthalamic nucleus stimulation in Parkinsonian patients who had undergone chronic implantation of electrodes for deep brain stimulation. By analyzing the effects of subthalamic stimulation on the velocity of movement of the right hand, we found hand movement to be faster when the patients expected a good motor performance. The expectation of good performance was induced through a placebo-like procedure, thus indicating that placebo-induced expectations have influence on the treatment outcome. All these effects occurred within minutes, suggesting that expectations induce neural changes very quickly.

Aged↗

PubMed2004

Effects of subthalamic nucleus stimulation and L-dopa in trunk kinematics of patients with Parkinson's disease.

In the advanced phase of Parkinson's disease (PD), high frequency electrical stimulation (HFS) of the subthalamic nucleus (STN) can represent a good therapeutic option, whose effects on walking have been recently quantified by kinematic and dynamic gait analysis. The goal of the present study was to compare, in a group of PD patients, the effects of STN stimulation and of L-dopa on trunk kinematics during walking. The additive effect of these two treatments was investigated as well. Ten idiopathic PD patients implanted bilaterally with a STN stimulation system and ten age-matched controls were studied using a three dimensional motion analyser. Four conditions were considered: with (s+) and without (s-) STN stimulation and with (m+) and without (m-) L-dopa administration. The results showed that both stimulation alone and L-dopa alone significantly increased the stride length and the gait speed, with an additional effect if applied simultaneously. Cadence was more influenced by L-dopa. The range of lateral bending and torsion of the trunk, which were reduced in s-/m-, increased similarly in s-/m+ and in s+/m- conditions. The exaggerated forward inclination of the trunk reduced towards control values in all therapeutic conditions. There was a tendency for L-dopa to increase trunk movements in the frontal plane, similar to events seen in quiet stance. Due to the presence of additive and synergistic effects, we concluded that the mechanisms of action of the two treatments are likely to be different.

Aged↗

PubMed2004

Efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's disease 4 years after surgery: double blind and open label evaluation.

OBJECTIVE: To evaluate the long term (4 years) efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinson's disease. METHODS: We performed a double blind crossover evaluation of the efficacy of DBS of the STN in the "off" medication condition in 10 patients with Parkinson's disease. Assessments included the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor) and two timed tests (arm tapping and walking). Open evaluation of the effect of stimulation in the off and on drug states preoperatively and at 1 and 4 years postoperatively was also conducted. The latter assessment included the UPDRS parts II (activities of daily living) and III (dyskinesia scale and global assessment) as judged by the patient and examiner. The mean amount of levodopa daily dose at base line, 1 year, and 4 years after surgery was compared. RESULTS: A significant (p<0.04) effect of stimulation was observed in the overall group regarding both the UPDRS motor and the timed tests. Open evaluation also showed a significant benefit of STN DBS with respect to preoperative assessment in both the motor and activities of daily living scales, dyskinesia scale, and in global assessment. Levodopa daily dose was reduced by 48% and 50% at 1 and 4 years, respectively. There was no difference between the 1 and 4 years evaluations in any of the parameters evaluated. Complications due to stimulation were minor. CONCLUSIONS: DBS of the STN provides a significant and persistent anti-parkinsonian effect in advanced Parkinson's disease 4 years after surgery.

Activities of Daily Living↗

PubMed2004

Subthalamic nucleus stimulation reduces abnormal motor cortical overactivity in Parkinson disease.

BACKGROUND: Based on the basal ganglia model, it has been hypothesized that the efficacy of high-frequency stimulation of the subthalamic nucleus (STN) against parkinsonian symptoms relies on the activation of cortical premotor regions. In previous positron emission tomography activation studies, STN high-frequency stimulation was associated with selective activation of midline premotor areas during hand movements but mainly reduced the regional cerebral blood flow in movement-related areas, peculiarly at rest. OBJECTIVE: To investigate with positron emission tomography the role of regional cerebral blood flow reduction in the clinical improvement provided by STN high-frequency stimulation. METHODS: Seven patients with advanced Parkinson disease, who were markedly improved by bilateral STN high-frequency stimulation, underwent positron emission tomography with H2(15)O while the right STN electrode was turned off. The patients were studied at rest and during right-hand movements in 3 electrode conditions: no stimulation, inefficient low-frequency stimulation, and efficient high-frequency stimulation. RESULTS: The main effect of high-frequency stimulation was to reduce regional cerebral blood flow in the left primary sensorimotor cortex, the lateral premotor cortex, the right cerebellum, and the midline premotor areas. The selective activation of the anterior cingulate cortex and the left primary sensorimotor cortex during hand movement under STN high-frequency stimulation was attributed to decreased regional cerebral blood flow at rest, rather than increased activation induced by STN high-frequency stimulation. Akinesia was correlated with the abnormal overactivity in the contralateral primary sensorimotor cortex and the ipsilateral cerebellum. CONCLUSION: High-frequency stimulation of the STN acts through the reduction of abnormal resting overactivity in the motor system, allowing selective cortical activation during movement.

Aged↗

PubMed2006

Subthalamic nucleus stimulation in Parkinson's disease : anatomical and electrophysiological localization of active contacts.

OBJECTIVES: 1 - To assess the anatomical localization of the active contacts of deep brain stimulation targeted to the subthalamic nucleus (STN) in Parkinson's disease patients. 2 - To analyze the stereotactic spatial distribution of the active contacts in relation to the dorsal and the ventral electrophysiologically-defined borders of the STN and the stereotactic theoretical target. METHODS: Twenty-eight patients underwent bilateral high-frequency stimulation of the STN (HFS-STN). An indirect anatomical method based on ventriculography coupled to electrophysiological techniques were used to localize the STN. Clinical improvement was evaluated by Unified Parkinson's Disease Rating Scale motor score (UPDRS III). The normalized stereotactic coordinates of the active contact centres, dorsal and ventral electrophysiologically-defined borders of the STN were obtained from intraoperative X-rays images. These coordinates were represented in a three-dimensional stereotactic space and in the digitalized atlas of the human basal ganglia. RESULTS: HFS-STN resulted in significant improvement of motor function (62.8%) in off-medication state and levodopa-equivalent dose reduction of 68.7% (p < 0.05). Most of the active contacts (78.6%) were situated close to (+/- 1.6 mm) the dorsal border of the STN (STN-DB), while 16% were dorsal and 5.4% were ventral to it. Similar distribution was observed in the atlas. The euclidean distance between the STN-DB distribution center and the active contacts distribution center was 0.31 mm, while the distance between the active contacts distribution center and the stereotactic theoretical target was 2.15 mm. Most of the space defined by the active contacts distribution (53%) was inside that defined by the STN-DB distribution. CONCLUSION: In our series, most of the active electrodes were situated near the STN-DB. This suggests that HFS-STN could influence not only STN but also the dorsal adjacent structures (zona incerta and/or Fields of Forel).

Action Potentials↗