Effect of subthalamic nucleus lesions in a 6-hydroxydopamine-induced rat parkinsonian model: behavioral and biochemical studies

OBJECT: The purpose of this study was to determine whether subthalamic nucleus (STN) ablation caused by kainic acid can restore dopaminergic neurotransmission and improve motor deficits in a 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonian model. METHODS: The authors investigated behavioral changes in rats displaying parkinsonian symptoms (6-OHDA-lesioned rats) after an STN lesion was created using kainic acid. They also measured levels of dopamine and its metabolites following tissue dissection. The results of this study showed that STN ablation led to behavioral improvement in parkinsonian motor deficits. Increased levels of dopamine were also observed in the striatum and globus pallidus externus (GPE). CONCLUSIONS: The results indicate that creation of an STN lesion in this hemiparkinsonian rat model may counteract some of the neurochemical changes within the striatum and GPE caused by the 6-OHDA, and influence striatal dopaminergic metabolism.     

Prevention of neurotoxin damage of 6-OHDA to dopaminergic nigral neuron by subthalamic nucleus lesions.

OBJECT: To investigate the possibility that subthalamic nucleus (STN) ablation could prevent the toxicity of the selective dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA). METHODS: Sixty rats were divided into 6 groups (n = 10). The control group received a unilateral microinjection of 6-OHDA into the right ventral tegmental area (VTA) and the right median forebrain bundle (MFB). Group 1 received an administration of kainic acid (KA) into the right STN and, 1-week later, an injection of 6-OHDA in the right VTA and MFB. Groups 2-5 received an injection of 6-OHDA in the right VTA and MFB, 1 h, 2 h, 3 days, and 7 days before KA in the right STN respectively. Four weeks later, the changes of tyrosine hydroxylase (TH)-positive (dopaminergic) neurons in the SNc were investigated with immunocytochemical and morphometrical methods. RESULTS: The number of TH-positive cells in the SNc on the injected side of treated groups (groups 1-5) and control group were 71.46 +/- 6.84, 57.07 +/- 5.54, 51.09 +/- 4.85, 12.68 +/- 2.67, 4.15 +/- 1.60 and 3.40 +/- 1.54/slice, which decreased to 96.7, 72.9, 69.8, 17.2, 5.6 and 4.4% of the non-injected side, respectively. The number of TH-positive neurons in groups 1-4 significantly increased in comparison with the controls (p < 0.05, 0.01). In group 5, there were no remarkable differences in contrast to the number of TH-positive neurons of the controls (p > 0.05). The difference in the number of TH-positive neurons between groups 1-5 was statistically significant (p < 0.01). CONCLUSION: The results indicate that STN ablation can provide antiglutamate-based neuroprotection of the dopaminergic nigrostriatal pathway against 6-OHDA toxicity.     

Neurotransmitter release from high-frequency stimulation of the subthalamic nucleus

OBJECT: High-frequency stimulation (HFS) delivered through implanted electrodes in the subthalamic nucleus (STN) has become an established treatment for Parkinson disease (PD). The precise mechanism of action of deep brain stimulation (DBS) in the STN is unknown, however. In the present study, the authors tested the hypothesis that HFS within the STN changes neuronal action potential firing rates during the stimulation period by modifying neurotransmitter release. METHODS: Intracellular electrophysiological recordings were obtained using sharp electrodes in rat STN neurons in an in vitro slice preparation. A concentric bipolar stimulating electrode was placed in the STN slice, and electrical stimulation (pulse width 50-100 microsec, duration 100-2000 msec, amplitude 10-500 microA, and frequency 10-200 Hz) was delivered while simultaneously obtaining intracellular recordings from an STN neuron. High-frequency stimulation of the STN either generated excitatory postsynaptic potentials (EPSPs) and increased the action potential frequency or it generated inhibitory postsynaptic potentials and decreased the action potential frequency of neurons within the STN. These effects were blocked after antagonists to glutamate and gamma-aminobutyric acid were applied to the tissue slice, indicating that HFS resulted in the release of neurotransmitters. Intracellular recordings from substantia nigra pars compacta (SNc) dopaminergic neurons during HFS of the STN revealed increased generation of EPSPs and increased frequency of action potentials in SNc neurons. CONCLUSIONS: During HFS of STN neurons the mechanism of DBS may involve the release of neurotransmitters rather than the primary electrogenic inhibition of neurons.     

Delta opioid peptide augments functional effects and intrastriatal graft survival of rat fetal ventral mesencephalic cells

Delta enkephalin analogue [D-Ala(2),D-Leu(5)]enkephalin (DADLE) has been shown to protect dopamine transporters from methamphetamine-induced neurotoxicity. In the present study, we demonstrate that exposure of embryonic ventral mesencephalic cells to DADLE (0.01 g/ml), prior to intrastriatal transplantation, enhanced functional recovery and graft survival in 6-hydroxydopamine-induced hemiparkinsonian rats. At 6 and 8 weeks posttransplantation, animals that received DADLE-treated cell grafts exhibited significantly higher (near normal) spontaneous locomotor behaviors, as well as trends of greater reversal of motor asymmetrical behaviors compared with animals that received nontreated cell grafts. Histological examination revealed that animals transplanted with DADLE-treated cell grafts exhibited about twice the number of surviving tyrosine hydroxylase-immunoreactive grafted neurons compared with those animals that received nontreated cell grafts. These results suggest that DADLE should be considered as an adjunctive agent for neural transplantation therapy in Parkinson's disease.     

Effect of ipsilateral subthalamic nucleus lesioning in a rat parkinsonian model: study of behavior correlated with neuronal activity in the pedunculopontine nucleus

OBJECT: The purpose of this study was to investigate the spontaneous behavioral changes and the alteration of neuronal activities in the pedunculopontine nucleus (PPN) after ipsilateral subthalamic nucleus (STN) lesioning by kainic acid in a rat parkinsonian model created by lesioning with 6-hydroxydopamine (6-OHDA). METHODS: Assumptions about the mechanisms mediating the effects of lesioning of the nigrostriatal dopaminergic pathway by 6-OHDA and the effects of STN lesioning were examined behaviorally by means of apomorphine-induced rotational behavior and forepaw-adjusting steps. The authors subsequently investigated the alteration of neuronal activities in the PPN to compare them with the behavioral changes in rat parkinsonian models. CONCLUSIONS: The results demonstrated that STN lesioning induced behavioral improvement in rat parkinsonian models. This result, which confirms previously held assumptions, may account for the therapeutic effect of STN stimulation in Parkinson disease. The alteration of the neuronal activities in the PPN units also indicates that the PPN units are responsible for the improvement in motor symptoms observed after STN lesioning in rat parkinsonian models.     

Progressive and extensive dopaminergic degeneration induced by convection-enhanced delivery of 6-hydroxydopamine into the rat striatum: a novel rodent model of Parkinson disease

OBJECT: A striatal dopamine lesion induces progressive nigral degeneration in rodents; however, intrastriatal injection of 6-hydroxydopamine (6-OHDA) causes only limited lesions due to spontaneous regeneration of the neurons that survive. To make an extensive lesion, the authors used a convection-enhanced delivery (CED) method for intrastriatal infusion of 6-OHDA and evaluated the animals for a model of Parkinson disease (PD). METHODS: Different doses of 6-OHDA were infused into the unilateral striatum in rats by using the CED method. The dopaminergic neuronal degeneration was evaluated based on morphological, biochemical, and behavioral measurements until 8 weeks postlesion. Due to the wide distribution of the drug, CED of 20 microg of 6-OHDA into the striatum was sufficient to obtain a progressive and extensive nigrostriatal lesion as defined by morphological (> 80% cell loss in the substantia nigra [SN]) and biochemical (> 95% decrease in striatal dopamine) criteria. The extent of the lesion manifested as a stable turning behavior with amphetamine (> 6 turns/minute) and apomorphine (> 4 turns/minute). It also appeared that at I week postlesion the apoptotic markers were maximal in neurons of the SN. CONCLUSIONS: A rat model of PD with a progressive and extensive dopamine lesion was successfully made by intrastriatal CED of 6-OHDA. In this model, the therapeutic value can be assessed using behavioral, biochemical, and histochemical measurements. The delay of nigral neuronal death with respect to the time of 6-OHDA administration may provide a therapeutic window for testing neuroprotective strategies.     

Xenografting human T2 sympathetic ganglion from hyperhidrotic patients provides short-term restoration of catecholaminergic functions in hemiparkinsonian athymic rats

Previous studies have suggested that allografting peripheral sympathetic ganglia, such as superior cervical ganglia, partially relieves clinical or behavioral deficits in parkinsonian patients and animals. However, removal of these ganglia can cause Homer's syndrome, which limits the utilization of this approach. Hyperhidrosis, a disease of excessive sweating, is commonly seen in young Orientals. Treatment of hyperhidrosis often involves surgical removal of the second thoracic sympathetic ganglia (T2G), which contain catecholaminergic neurons. The purpose of our study was to investigate behavioral responses and tyrosine hydroxylase (TH) immunoreactivity in hemiparkinsonian rats at different time points after transplantation of human T2G from hyperhidrotic patients. Athymic Fisher 344 rats were injected unilaterally with 6-hydroxydopamine into the medial forebrain bundle to destroy the nigrostriatal dopaminergic (DA) pathway. The effectiveness of lesions was tested by measuring methamphetamine (MA)-induced rotations. These unilaterally lesioned rats were later transplanted with T2G or T2 fiber tract (T2F) obtained from adult hyperhidrotic patients. Animals grafted with T2G showed a reduction in MA-induced rotation by 2 weeks; however, rotation returned to the pregrafting levels by 3 months. Animals receiving T2F grafts did not show any reduction of rotation over a 3-month period. Animals were later sacrificed for TH immunostaining at different time points. Tyrosine hydroxylase-positive [TH(+)] cell bodies and fibers were found in the lesioned striatum 2-4 weeks after T2G grafting, suggesting the survival of transplants. Two to 3 months after grafting, TH(+) fibers were still found in almost all the recipients. However, TH(+) cell bodies were found in only three of seven rats studied. Animals receiving T2F grafting did not show any TH immunoreactivity in the lesioned striatum over the 3-month period. These data indicate that T2G transplants from adult hyperhidrotic patients can survive and provide transient normalization of the motor behavior in the hemiparkinsonian athymic rats. Because of the short-term improvement in behavior after grafting, the use of T2G in human trials should be cautious at the present time. Further laboratory research is required.     

Implantation of xenografts into the parkinsonian rat brain after portal venous administration of xenogeneic donor spleen cells

OBJECT: The purpose of the present study was to examine the effect of pretransplantation portal venous immunization with ultraviolet B (UVB)-treated donor spleen cells on neural xenograft transplantation. METHODS: Cells from a murine catecholaminergic cell line derived from the B6/D2 F1 mouse, CATH.a, were used as a xenograft. Thirty hemiparkinsonian rats were divided into three different treatment groups. Group 1 received saline in the dopamine-denervated striatum; Group 2 received xenograft cells; and Group 3 received portal venous administration of UVB-irradiated B6/D2 F1 splenocytes 7 days before receiving xenograft cells. Xenograft function was determined by reviewing apomorphine-induced rotation at 2-week intervals, and xenograft survival was examined at 4 and 12 weeks after transplantation by immunohistochemical staining for murine tyrosine hydroxylase (THase). Rotational behavior was improved in both xenograft-transplanted groups (Groups 2 and 3); however, the animals in Group 3 displayed a significantly reduced rotational behavior compared with Group 2. In Group 2, many inflammatory cells and a few THase-positive cells were found at the graft sites 4 weeks after transplantation. In Group 3, however, a large number of THase-positive cells were found with few inflammatory cells. The THase-positive cells disappeared in the Group 2 rats at 12 weeks, but remained in Group 3 animals. In Group 3 rats proliferation of spleen cells in a mixed lymphocyte reaction was suppressed in a donor-specific fashion. CONCLUSIONS: This work demonstrates improved neural xenograft survival and function by pretransplantation portal venous immunization with UVB-irradiated xenogeneic donor splenocytes. On the basis of these findings, the authors suggest the possibility of creating donor-specific immunological tolerance in the brain by administration of xenogeneic donor lymphocytes via the portal vein.     

Reduced xenograft rejection in rat striatum after pretransplant photodynamic therapy of murine neural xenografts

OBJECT: The goal of this study was to develop a method of reducing neural xenograft rejection by pretreating the graft with photodynamic therapy (PDT). METHODS: Xenograft cell suspensions were prepared from fetal mouse mesencephalon, after which they were incubated for 30 minutes with various concentrations of a photosensitizer, verteporfin for injection, and light exposure. The xenograft cell suspensions were injected into the dopamine-depleted striata of 40 hemiparkinsonian rats assigned to different treatment groups. Four weeks after transplantation, xenograft function (determined by methamphetamine-induced rotation) and survival (determined by immunohistochemical staining for murine neurons) were compared. Group 1 animals (xenografts pretreated with 25 ng/ml verteporfin) and Group 3 animals (no verteporfin pretreatment, but daily administration of cyclosporin A) had significantly better xenograft survival and function compared with control animals (no pretreatment with verteporfin). Group 2 animals (xenografts pretreated with 250 ng/ml verteporfin) had no significant improvement. CONCLUSIONS: This work demonstrates improved neural xenograft survival and function when using pretransplant PDT of the graft in a rodent model. The potential benefits of this new therapy are its convenience (one pretransplant treatment) and its compatibility with host immunosuppression.     

Combining neuroprotective treatment of embryonic nigral donor tissue with mild hypothermia of the graft recipient

Around 80-95% of the immature dopaminergic neurons die when embryonic ventral mesencephalic tissue is transplanted. Cell death occurs both during the preparation of donor tissue and after graft implantation, but the effect of combining successful neuroprotective treatments before and after transplantation has not been extensively investigated. We therefore treated embryonic rat mesencephalic tissue with a combination of the lipid peroxidation inhibitor tirilazad mesylate (3 microM) and the caspase inhibitor Ac.YVAD.cmk (500 microM) and transplanted the tissue into hemiparkinsonian rats kept hypothermic (32-33 degrees C) or normothermic (37 degrees C) during, and 90 min following, graft surgery. Suspension cell number did not differ between untreated or tirilazad/YVAD-treated preparations prior to transplantation. When graft survival was evaluated 6 weeks after implantation, both tirilazad/YVAD pretreatment and mild hypothermia increased the survival of transplanted dopaminergic neurons. Approximately 50-57% of the embryonic dopaminergic neurons survived the dissociation and grafting procedure in rats rendered hypothermic, but there was no significant additive effect on graft survival with a combined treatment. All groups of rats exhibited behavioral recovery in the amphetamine-induced rotation test. There was a significantly enhanced functional capacity of grafts placed in hypothermic as compared to normothermic rats. However, tirilazad/YVAD pretreated implants did not afford greater behavioral improvement than control-treated grafts. Our results suggest that neuroprotective treatments administered prior to and immediately after neural graft implantation may under certain conditions rescue, at least in part, the same subset of dopaminergic neurons. The study also emphasizes the importance of the immediate time after grafting for transplant survival, with relevance both for primary mesencephalic implants and stem cell grafts.     

Early transplantation of an encapsulated glial cell line-derived neurotrophic factor-producing cell demonstrating strong neuroprotective effects in a rat model of Parkinson disease

OBJECT: Glial cell line-derived neurotrophic factor (GDNF) has been shown to confer neuroprotective effects on dopaminergic neurons. The authors investigated the effects of GDNF on 6-hydroxydopamine (6-OHDA)-treated dopaminergic neurons in vitro and in vivo. METHODS: First, the authors examined how 1, 10, or 100 ng/ml of GDNF, administered to cells 24 hours before, simultaneously with, or 2 or 4 hours after 6-OHDA was added, affected dopaminergic neurons. In a primary culture of E14 murine ventral mesencephalic neurons, earlier treatment with the higher dosage of GDNF suppressed 6-OHDA-induced loss of dopaminergic neurons better than later treatment. Next, the authors examined whether continuous infusion of GDNF at earlier time points would demonstrate a greater neuroprotective effect in a rat model of Parkinson disease (PD). They established a human GDNF-secreting cell line, called BHK-GDNF, and encapsulated the cells into hollow fibers. The encapsulated cells were unilaterally implanted into the striatum of adult rats 1 week before; simultaneously with; or 1, 2, or 4 weeks after 6-OHDA was given to induce lesions of the same striatum. With the earlier transplantation of a BHK-GDNF capsule, there was a significant reduction in the number of amphetamine-induced rotations displayed by the animals. Rats that had received earlier implantation of BHK-GDNF capsules displayed more tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and a tendency for glial proliferation in the striatum. CONCLUSIONS: These neuroprotective effects may be related to glial proliferation and signaling via the GDNF receptor alpha1. The results of this study support a role for this grafting technique in the treatment of PD.     

Movement-related neurons of the subthalamic nucleus in patients with Parkinson disease

OBJECT: The subthalamic nucleus (STN) is a target in the surgical treatment of Parkinson disease (PD). Little is known about the neurons within the human STN that modulate movement. The authors' goal was to examine the distribution of movement-related neurons within the STN of humans by using microelectrode recording to identify neuronal receptive fields. METHODS: Data were retrospectively collected from microelectrode recordings that had been obtained in 38 patients with PD during surgery for placement of STN deep brain stimulation electrodes. The recordings had been obtained in awake, nonsedated patients. Antiparkinsonian medications were withheld the night before surgery. Neuronal discharges were amplified, filtered, and displayed on an oscilloscope and fed to an audio monitor. The receptive fields were identified by the presence of reproducible, audible changes in the firing rate that were time-locked to the movement of specific joint(s). The median number of electrode tracks per patient was six (range two-nine). The receptive fields were identified in 278 (55%) of 510 STN neurons studied. One hundred one tracks yielded receptive field data. Fourteen percent of 64 cells tested positive for face receptive fields, 32% of 687 cells tested positive for upper-extremity receptive fields, and 21% of 242 cells tested positive for lower-extremity receptive fields. Sixty-eight cells (24%) demonstrated multiple-joint receptive fields. Ninety-three cells (65%) with movement-related receptive fields were located in the dorsal half of the STN, and 96.8% of these were located in the rostral two thirds of the STN. Analysis of receptive field locations from pooled data and along individual electrode tracks failed to reveal a consistent somatotopic organization. CONCLUSIONS: Data from this study demonstrate a regional compartmentalization of neurons with movement-related receptive fields within the STN, supporting the existence of specific motor territories within the STN in patients suffering from PD.     

Bridging nigrostriatal pathway with fibroblast growth factor-primed peripheral nerves and fetal ventral mesencephalon transplant recuperates from deficits in parkinsonian rats

Previous studies have indicated that the nigrostriatal dopaminergic (DA) pathway can be reconstructed in hemiparkinsonian rats with a bridge transplantation technique involving fetal ventral mesencephalic transplants and glial cell line-derived neurotrophic factor. In this study, we examined if the nigrostriatal pathway can be restored by combining peripheral nervous tissue with the fetal ventral mesencephalon transplants. Adult rats were injected with 6-hydroxydopamine into left median forebrain bundle. Those with marked rotational behavior, which has been previously shown to indicate complete DA dennervtion, were used for transplant treatments. One month after the lesion, fetal ventral mesencephalic cells were transplanted into the nigral region followed by nigral-striatal grafting of peripheral nerves as a bridge. The bridging nerves (sciatic or intercostals) were pretreated with basic fibrous growth factor (nerve+bFGF+) or Hank's saline (nerve+bFGF-). We found that (a) animals receiving transplants of VM and bFGF+ nerve had a reduction in rotational behavior; (b) animals receiving bFGF-- nerve bridge only had a partial improvement in rotation. Reinnervation of tyrosine hydroxylase (TH)-immunoreactive (ir) fibers into the striatum was found in both of the above groups with more innervation in the former than in the latter. No TH-ir fibers in lesioned striatum or reduction in rotational behavior were found in animals receiving VM only, or VM plus bFGF. Taken together, our data indicate that peripheral nerve, with the aid of bFGF, greatly facilitates the reconstitution of the TH pathway from nigra to striatum and improves motor function in hemiparkinsonian rats.     

Validity of Single Tract Microelectrode Recording in Subthalamic Nucleus Stimulation

In surgery for subthalamic nucleus (STN) deep brain stimulation (DBS), precise implantation of the lead into the STN is essential. Physiological refinement with microelectrode recording (MER) is the gold standard for identifying STN. We studied single tract MER findings and surgical outcomes and verified our surgical method using single tract MER. The number of trajectories in MER and the final position of lead placement were retrospectively analyzed in 440 sides of STN DBS in 221 patients. Bilateral STN DBS yielded marked improvement in the motor score, dyskinesia/fluctuation score, and reduced requirement of dopaminergic medication in this series. The number of trajectories required to obtain sufficient activity of the STN was one in 79.0%, two in 18.2%, and three or more in 2.5% of 440 sides. In 92 sides requiring altered trajectory, the final direction of trajectory movement was posterior in 73.9%, anterior in 13.0%, lateral in 5.4%, and medial in 4.3%. In 18 patients, posterior moves were required due to significant brain shift with intracranial air caused by outflow of CSF during the second side procedure. Sufficient STN activity is obtained with minimum trajectories by proper targeting and precise interpretation of MER findings even in the single tract method. Anterior–posterior moves rather than medial–lateral moves should be attempted first in cases with insufficient recording of STN activity.     

Deep brain stimulation in Parkinson’s disease: motor effects relative to the MRI-defined STN

This study aims to evaluate the improvements of cardinal motor symptoms depending on the stimulation site relative to a standardized, reconstructed three-dimensional MRI-defined subthalamic nucleus (STN.) This retrospective, clinical study includes 22 patients with idiopathic Parkinson’s disease, who consecutively underwent bilateral subthalamic nucleus stimulation. Intraoperative microelectrode recording and clinical testing were performed. The location of the best stimulation site, found intraoperatively, and the positions of the active electrode contacts 12 months after the operation were correlated to a standardized, reconstructed three-dimensional MRI-defined STN. Further, the impact of the stimulation site on rigidity, tremor and akinesia was analysed. Significant improvement of the contralateral akinesia was observed if the intraoperative stimulation site was located more lateral and superior in the MRI-STN. Furthermore, active electrode contacts located superior to or in the superior part of the MRI-STN had a significantly better effect on the tremor of the contralateral hand than in other locations inside the STN. For rigidity and akinesia, these correlations were statistically not significant. Although we found significantly better results for tremor suppression in superior and lateral aspects of the STN, for overall clinical improvement, several patients fared better with randomly distributed stimulation sites in medial, posterior or inferior parts of the MRI-defined STN. Locations of stimulation sites with the best improvements of motor symptoms were distributed randomly throughout the whole MRI-defined STN, indicating that MRI-based targeting alone is not sufficient, but intraoperative clinical testing is necessary to determine the optimal stimulation site for each individual patient.     

神经轴突二次损伤对健侧颈7神经根移位术疗效影响的实验研究

目的以大鼠健侧颈，神经根移位术为动物模型，比较健侧颈7神经根移位术后神经轴突一次和二次损伤对中枢神经元及周围神经的影响差异。方法清洁级雌性SD大鼠60只，随机分成3组。A组为健侧颈，神经根移位术二次完成组；B组为健侧颈7神经根移位术一次完成组；C组为正常对照组。术后通过脊髓神经元计数、肌电图检查、神经肌肉组织学检查、肌张力测定和运动终板形态学检查进行综合评价。结果健侧颈，神经根移位术后36周，脊髓前角α运动神经元和背根神经节感觉元的数目A组较B组减少。但A组的再生神经纤维数目增加，而肌电图检查潜伏期延长。2组间肌张力、肌湿重、肌纤维截面积等无明显差异。结论神经轴突二次损伤，可减少中枢神经元数目，但再生神经纤维增加，最终对肌肉形态与肌张力的恢复无明显影响。     

Subthalamic nucleus stimulation for Parkinson disease: benefits observed in levodopa-intolerant patients.

OBJECT: A blinded evaluation of the effects of subthalamic nucleus (STN) stimulation was performed in levodopa-intolerant patients with Parkinson disease (PD). These patients (Group I, seven patients) were moderately or severely disabled (Hoehn and Yahr Stages III-V during the off period), but were receiving only a small dose of medication (levodopa-equivalent dose [LED] 0-400 mg/day) because they suffered unbearable side effects. The results were analyzed in comparison with those obtained in patients with advanced PD (Group II, seven patients) who were severely disabled (Hoehn and Yahr Stages IV and V during the off period), but were treated with a large dose of medication (500-990 mg/day). METHODS: The patients were evaluated twice at 6 to 8 months after surgery. To determine the actual benefits afforded by STN stimulation to their overall daily activities, the patients were maintained on their medication regimen with optimal doses and schedules. Stimulation was turned off overnight for at least 12 hours. It was turned on in the morning (or remained turned off), and each patient's best and worst scores on the Unified Parkinson's Disease Rating Scale during waking daytime activity were recorded as on- and off-period scores, respectively. The order of assessment with respect to whether stimulation was occurring was determined randomly. The STN stimulation markedly improved daily activity and total motor scores in Group I patients. The percentage time of immobility (Hoehn and Yahr Stages IV and V) became 0% in patients who were intermittently immobile while not receiving stimulation. Improvements were demonstrated in tremor, rigidity. akinesia, and gait subscores. The STN stimulation produced less marked but still noticeable improvements in the daily activity and total motor scores in Group II patients. The percentage time of immobility as well as the LED was reduced in patients who displayed intermittent immobility with pronounced motor fluctuations while not receiving stimulation. Improvements were demonstrated in tremor, rigidity, and dyskinesia subscores in these patients. In contrast, STN stimulation did not improve the overall daily activities at all in patients who had become unresponsive to a tolerable dose of levodopa and were continuously immobile, even though these patients' tremor and rigidity subscores were still improved by stimulation. CONCLUSIONS: Consistent with earlier findings, the great benefit of STN stimulation in levodopa-intolerant patients is that STN stimulation can reduce the level of required levodopa medication. This suggests that STN stimulation could be a therapeutic option for patients with less-advanced PD by allowing levodopa medication to be maintained at as low a dose as possible, and to prevent adverse reactions to the continued use of large-dose levodopa.     

Neurophysiological refinement of subthalamic nucleus targeting

OBJECTIVE: Advances in image-guided stereotactic surgery, microelectrode recording techniques, and stimulation technology have been the driving forces behind a resurgence in the use of functional neurosurgery for the treatment of movement disorders. Despite the dramatic effects of deep brain stimulation (DBS) techniques in ameliorating the symptoms of Parkinson's disease, many critical questions related to the targeting, effects, and mechanisms of action of DBS remain unanswered. In this report, we describe the methods used to localize the subthalamic nucleus (STN) and we present the characteristics of encountered cells. METHODS: Twenty-six patients with idiopathic Parkinson's disease underwent simultaneous, bilateral, microelectrode-refined, DBS electrode implantation into the STN. Direct and indirect magnetic resonance imaging-based anatomic targeting was used. Cellular activity was analyzed for various neurophysiological parameters, including firing rates and interspike intervals. Physiological targeting confirmation was obtained by performing macrostimulation through the final DBS electrode. RESULTS: The average microelectrode recording time for each trajectory was 20 minutes, with a mean of 5.2 trajectories/patient. Typical trajectories passed through the anterior thalamus, zona incerta/fields of Forel, STN, and substantia nigra-pars reticulata. Each structure exhibited a characteristic firing pattern. In particular, recordings from the STN exhibited an increase in background activity and an irregular firing pattern, with a mean rate of 47 Hz. The mean cell density was 5.6 cells/mm, with an average maximal trajectory length of 5.3 mm. Macrostimulation via the DBS electrode yielded mean sensory and motor thresholds of 4.2 and 5.7 V, respectively. CONCLUSION: The principal objectives of microelectrode recording refinement of anatomic targeting are precise identification of the borders of the STN and thus determination of its maximal length. Microelectrode recording also allows identification of the longest and most lateral segment of the STN, which is our preferred target for STN DBS electrode implantation. Macrostimulation via the final DBS electrode is then used primarily to establish the side effect profile for postoperative stimulation. Microelectrode recording is a helpful targeting adjunct that will continue to facilitate our understanding of basal ganglion physiological features.     

Stimulation of the subthalamic nucleus in Parkinson's disease does not produce striatal dopamine release

OBJECTIVE: The subthalamic nucleus (STN) is a target in the surgical treatment of Parkinson's disease (PD). The mechanism by which electrical stimulation of the STN ameliorates symptoms of PD remains unknown. One consistent aspect of STN stimulation is the ability to reduce the dosage of dopaminergic medications; sometimes they can be eliminated altogether. Furthermore, nigrostriatal projection axons are apposed to the dorsal surface of the STN and are likely affected by the application of current in this region. We sought to determine whether STN stimulation could release endogenous striatal dopamine. METHODS: Five patients with PD, who had previously undergone surgical implantation of bilateral STN stimulators, underwent [(11)C]raclopride positron emission tomographic scanning. l-dopa was withheld for 12 hours, and both stimulators were turned off 9 hours before scanning. We assayed for striatal dopamine release by measuring radioligand displacement as a consequence of turning on the right STN stimulator after 45 minutes of a 90-minute [(11)C]raclopride infusion. Patients were evaluated with the motor section of the Unified Parkinson's Disease Rating Scale before and after the studies. RESULTS: Comparisons between the right and left striata, before and after right STN stimulation, demonstrated no significant differences in [(11)C]raclopride binding, despite significant improvements in Unified Parkinson's Disease Rating Scale motor scores with unilateral stimulation (mean improvement, 26.0 +/- 16.4%; P < 0.05). This finding was also noted when the striatum was partitioned into dorsal and ventral caudate and putamen and the four regions were analyzed separately. CONCLUSION: Our results suggest that STN stimulation does not mediate its anti-PD effects via the release of dopamine, as assessed with [(11)C]raclopride displacement.