Effects of high-frequency stimulation of the internal pallidal segment on neuronal activity in the thalamus in parkinsonian monkeys.

Deep brain stimulation of the internal globus pallidus (GPi) is a major treatment for advanced Parkinson's disease. The effects of this intervention on electrical activity patterns in targets of GPi output, specifically in the thalamus, are poorly understood. The experiments described here examined these effects using electrophysiological recordings in two Rhesus monkeys rendered moderately parkinsonian through treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after sampling control data in the same animals. Analysis of spontaneous spiking activity of neurons in the basal ganglia-receiving areas of the ventral thalamus showed that MPTP-induced parkinsonism is associated with a reduction of firing rates of segments of the data that contained neither bursts nor decelerations, and with increased burst firing. Spectral analyses revealed an increase of power in the 3- to 13-Hz band and a reduction in the γ-range in the spiking activity of these neurons. Electrical stimulation of the ventrolateral motor territory of GPi with macroelectrodes, mimicking deep brain stimulation in parkinsonian patients (bipolar electrodes, 0.5 mm intercontact distance, biphasic stimuli, 120 Hz, 100 µs/phase, 200 µA), had antiparkinsonian effects. The stimulation markedly reduced oscillations in thalamic firing in the 13- to 30-Hz range and uncoupled the spiking activity of recorded neurons from simultaneously recorded local field potential (LFP) activity. These results confirm that oscillatory and nonoscillatory characteristics of spontaneous activity in the basal ganglia receiving ventral thalamus are altered in MPTP-induced parkinsonism. Electrical stimulation of GPi did not entrain thalamic activity but changed oscillatory activity in the ventral thalamus and altered the relationship between spikes and simultaneously recorded LFPs.

Anatomical localization of Cav3.1 calcium channels and electrophysiological effects of T-type calcium channel blockade in the motor thalamus of MPTP-treated monkeys.

Conventional anti-Parkinsonian dopamine replacement therapy is often complicated by side effects that limit the use of these medications. There is a continuing need to develop nondopaminergic approaches to treat Parkinsonism. One such approach is to use medications that normalize dopamine depletion-related firing abnormalities in the basal ganglia-thalamocortical circuitry. In this study, we assessed the potential of a specific T-type calcium channel blocker (ML218) to eliminate pathologic burst patterns of firing in the basal ganglia-receiving territory of the motor thalamus in Parkinsonian monkeys. We also carried out an anatomical study, demonstrating that the immunoreactivity for T-type calcium channels is strongly expressed in the motor thalamus in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. At the electron microscopic level, dendrites accounted for >90% of all tissue elements that were immunoreactive for voltage-gated calcium channel, type 3.2-containing T-type calcium channels in normal and Parkinsonian monkeys. Subsequent in vivo electrophysiologic studies in awake MPTP-treated Parkinsonian monkeys demonstrated that intrathalamic microinjections of ML218 (0.5 µl of a 2.5-mM solution, injected at 0.1-0.2 µl/min) partially normalized the thalamic activity by reducing the proportion of rebound bursts and increasing the proportion of spikes in non-rebound bursts. The drug also attenuated oscillatory activity in the 3-13-Hz frequency range and increased gamma frequency oscillations. However, ML218 did not normalize Parkinsonism-related changes in firing rates and oscillatory activity in the beta frequency range. Whereas the described changes are promising, a more complete assessment of the cellular and behavioral effects of ML218 (or similar drugs) is needed for a full appraisal of their anti-Parkinsonian potential.

[Unilateral subthalamic stimulation for early-stage Parkinson's disease].

According to evidenced-based criteria, surgical treatment with subthalamic stimulation is indicated for advanced Parkinson's disease with severe motor complications. Currently, the treatment is indicated for patients in whom medical treatment has failed even if the patient is still in an early stage. This study investigated the efficacy and safety of unilateral subthalamic stimulation for patients with early-stage Parkinson's disease. We evaluated the Unified Parkinson's Disease Rating Scale (UPDRS) and the Schwab England ADL score before and 6 months after this treatment in 6 patients with early-stage Parkinson's disease demonstrating predominantly unilateral parkinsonian symptoms. We implanted a stimulation electrode (model 3387 or 3389) unilaterally on the side showing dominate symptoms, using both MRI and electrophysiological guidance. Six months after the beginning of stimulation, the UPDRS motor score without medication was improved by 64% and the Schwab England ADL score was improved by 23%. There were no adverse events except for asymptomatic intra-ventricular hemorrhage in one patient. Unilateral subthalamic stimulation is a useful treatment for patients with early-stage Parkinson's disease showing predominantly unilateral parkinsonian symptoms. However, long-term results of subthalamic stimulation for early-stage patients remain unclear.

Thalamocortical and intracortical connections of monkey cingulate motor areas.

Although there has been an increasing interest in motor functions of the cingulate motor areas, data concerning their input organization are still limited. To address this issue, the patterns of thalamic and cortical inputs to the rostral (CMAr), dorsal (CMAd), and ventral (CMAv) cingulate motor areas were investigated in the macaque monkey. Tracer injections were made into identified forelimb representations of these areas, and the distributions of retrogradely labeled neurons were analyzed in the thalamus and the frontal cortex. The cells of origin of thalamocortical projections to the CMAr were located mainly in the parvicellular division of the ventroanterior nucleus and the oral division of the ventrolateral nucleus (VLo). On the other hand, the thalamocortical neurons to the CMAd/CMAv were distributed predominantly in the VLo and the oral division of the ventroposterolateral nucleus-the caudal division of the ventrolateral nucleus. Additionally, many neurons in the intralaminar nuclear group were seen to project to the cingulate motor areas. Except for their well-developed interconnections, the corticocortical projections to the CMAr and CMAd/CMAv were also distinctively preferential. Major inputs to the CMAr arose from the presupplementary motor area and the dorsal premotor cortex, whereas inputs to the CMAd/CMAv originated not only from these areas but also from the supplementary motor area and the primary motor cortex. The present results indicate that the CMAr and the caudal cingulate motor area (involving both the CMAd and the CMAv) are characterized by distinct patterns of thalamocortical and intracortical connections, reflecting their functional differences.

Hemorrhagic complication of stereotactic surgery in patients with movement disorders.

OBJECT: Small, asymptomatic hemorrhages are easier to detect during stereotactic surgery when magnetic resonance (MR) imaging is used for targeting rather than when traditional approaches, such as ventriculography, are performed with contrast material. In the present study the authors examined the actual incidence of intraoperative hemorrhages in patients with movement disorders who had undergone MR imaging-targeted surgery, microelectrode recording (MER)-guided implantation of deep brain stimulation (DBS) electrodes, or radiofrequency-induced coagulation surgery performed. METHODS: Ninety-six consecutive patients underwent a total of 116 stereotactic operations for movement disorders (57 operations for radiofrequency-induced coagulation and 59 for DBS electrode implantation) between January 1998 and November 2002. The authors investigated the correlation between hemorrhages and other factors including the location of the hemorrhage and the type of surgery performed. Postoperative computerized tomography scans demonstrated the occurrence of intraoperative hemorrhages at 12 locations during 11 procedures (9.5% of all procedures). Nine hemorrhages occurred during 57 coagulation operations (15.8%). Within this group, the frequency of hemorrhages was highest during thalamotomy (five [21.7%] of 23 procedures) and lower during pallidotomy (four [11.8%] of 34 procedures). In contrast, only two intraventricular hemorrhages developed during 59 operations in which DBS electrodes were implanted (3.4%). In no case was hemorrhage detected in the main DBS target, that is, the subthalamic nucleus. CONCLUSIONS: When small, asymptomatic hemorrhages were included in the estimation, the actual rate of hemorrhage was higher than that previously reported. Judging from the incidence of hemorrhage during coagulation and DBS surgeries, the authors suggest that the heat induced by coagulation may play a larger role than microelectrode penetration in the development of hemorrhage.

[Comparison and examination of stereotactic surgical complications in movement disorders].

The purpose of the present study was to determine exactly the incidence of surgical complications in patients for whom MRI-targeted, microelectrode recording (MER)-guided implantation of deep brain stimulation (DBS) or radiofrequency (RF)-coagulation surgery was performed. Between January, 1998 and September, 2002, a total of 110 stereotactic surgeries for movement disorders (57 RF-coagulations and 53 implantations of DBS) were performed. We investigated the type and number of complications for each of the following surgical targets; globus pallidus, thalamus, and subthalamic nucleus (STN). Twenty-four neurological complications in 22 patients and 16 radiological/instrumental complications in 16 patients were verified among the 110 surgeries. Among the neurological complications, hemiparesis and mental disturbances were observed at a high rate, while intraoperative hemorrhage frequently occurred among the radiological/instrumental complications. The rate of neurological and radiological/instrumental complications for each of the stereotactic targets; the globus pallidus, thalamus, and STN-targeted surgeries, was 32.4%, 16.7%, 18.8% and 16.2%, 20.0%, 12.5%, respectively. The reason for the high rate of intraoperative hemorrhage may be associated with technical problems resulting from the penetration of vessels by needles, as well as the destruction of small vessels due to heat ablation. As for the mental disturbances, visual hallucinations (VH) occurred a high rate, especially during STN-DBS. Peduncular damage and/or L-dopa toxicity due to STN-DBS may have been associated with VH, so the STN-DBS may therefore be thought to change the threshold of stimulus-induced hallucinations. We also found that the procedures for DBS surgery, especially in younger patients, have a lower risk of complication, while, on the other hand, coagulation surgery for elderly patients is accompanied by of high risks, from the standpoint of surgical complications.

[Variance in effects of subthalamic nucleus stimulation].

Chronic stimulation of subthalamus nucleus (STN) is effective in treating severe motor fluctuation and levodopa induced dyskinesia as well as parkinsonian motor symptoms. The improvement of peak-dose/diphasic dyskinesias of STN stimulation is considered to be due to the decrease in the daily dosage of antiparkinsonian drugs. However one report pointed out that STN stimulation improved directly levodopa induced dyskinesia. Moreover the timing of the improvement for levodopa induced dyskinesia is not yet obvious. In the present study, we have assessed variance in the latency of improvement of levodopa induced dyskinesia due to STN stimulation. In addition, we would clarify an issue which cite of STN stimulation improved parkinsonian symptoms and motor complication (motor dyskinesias and motor fluctuation). We have studied seven patients diagnosed with advanced idiopathic Parkinson's disease with motor fluctuations and levodopa induced dyskinesias. Before and after the implantation of stimulating electrode, patients were assessed by the Unified Parkinson's Disease Rating Scale and % 'OFF' motor state. The dosage of the antiparkinsonian medication was not modified for one month prior to implantation. Following implantation, dosage of the medication and strength of stimulation was adjusted, if necessary. Symptoms of motor fluctuation and dyskinesia improved in all patients six month after surgery. The mean off-time duration and dyskinesia disability improved compared with presurgical conditions. However, the time course of the improvement of dyskinesias was not the same among patients. Contralateral limb dyskinesias in three patients improved immediately after the stimulation without modification of medication. In contrast, the stimulation worsened contralateral limb dyskinesias in other three patients immediately following the surgery. In two of the three patients, dyskinesias gradually improved within one month after surgery without reducing the dosage of medication. Dyskinesias of the other patient improved following a reduction in the dosage of medication one month after the surgery. Improvement of parkinsonian symptoms of the patients with longer latency of stimulation effect for dyskinesias was better than that of the patients with shorter latency. Stimulation cite of the former group appeared to locate more central than that of the latter group. Latency and strength of the effects of STN stimulation are variable.