Determination of the Unilaterally Damaged Region May Depend on the Asymmetry of Carotid Blood Flow Velocity in Hemiparkinsonian Monkey: A Pilot Study.

The hemiparkinsonian nonhuman primate model induced by unilateral injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the carotid artery is used to study Parkinson's disease. However, there have been no studies that the contralateral distribution of MPTP via the cerebral collateral circulation is provided by both the circle of Willis (CoW) and connections of the carotid artery. To investigate whether MPTP-induced unilaterally damaged regions were determined by asymmetrical cerebral blood flow, the differential asymmetric damage of striatal subregions, and examined structural asymmetries in a circle of Willis, and blood flow velocity of the common carotid artery were observed in three monkeys that were infused with MPTP through the left internal carotid artery. Lower flow velocity in the ipsilateral common carotid artery and a higher ratio of ipsilateral middle cerebral artery diameter to anterior cerebral artery diameter resulted in unilateral damage. Additionally, the unilateral damaged monkey observed the apomorphine-induced contralateral rotation behavior and the temporary increase of plasma RANTES. Contrastively, higher flow velocity in the ipsilateral common carotid artery was observed in the bilateral damaged monkey. It is suggested that asymmetry of blood flow velocity and structural asymmetry of the circle of Willis should be taken into consideration when establishing more efficient hemiparkinsonian nonhuman primate models.

Long-Term Outcomes of Bilateral Subthalamic Nucleus Deep Brain Stimulation for Patients With Parkinson's Disease: 10 Years and Beyond.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) represents an effective treatment for severe Parkinson's disease (PD), but little is known about the long-term benefit. OBJECTIVE: To investigate the survival rate and long-term outcome of DBS. METHODS: We investigated all 81 patients including 37 males and 44 females who underwent bilateral STN DBS from March 2005 to March 2008 at a single institution. The current survival status of the patients was investigated. Preoperative and postoperative follow-up assessments were analyzed. RESULTS: The mean age at the time of surgery was 62 (range 27-82) years, and the median clinical follow-up duration was 145 months. Thirty-five patients (43%) died during the follow-up period. The mean duration from DBS surgery to death was 110.46 ± 40.8 (range 0-155) months. The cumulative survival rate is as follows: 98.8 ± 1.2% (1 year), 95.1 ± 2.4% (5 years), and 79.0 ± 4.5% (10 years). Of the 81 patients, 33 (40%) were ambulatory up to more than 11 years. The Unified Parkinson's Disease Rating Scale (UPDRS) score was significantly improved until 5 years after surgery although it showed a tendency to increase again after 10 years. The patient group with both electrodes located within the STN showed a higher rate of survival and maintained ambulation. CONCLUSION: STN DBS is a safe and effective treatment for patients with advanced PD. This study based on the long-term follow-up of large patient populations can be used to elucidate the long-term fate of patients who underwent bilateral STN DBS for PD.

Topographic connectivity and cellular profiling reveal detailed input pathways and functionally distinct cell types in the subthalamic nucleus.

The subthalamic nucleus (STN) controls psychomotor activity and is an efficient therapeutic deep brain stimulation target in individuals with Parkinson's disease. Despite evidence indicating position-dependent therapeutic effects and distinct functions within the STN, the input circuit and cellular profile in the STN remain largely unclear. Using neuroanatomical techniques, we construct a comprehensive connectivity map of the indirect and hyperdirect pathways in the mouse STN. Our circuit- and cellular-level connectivities reveal a topographically graded organization with three types of indirect and hyperdirect pathways (external globus pallidus only, STN only, and collateral). We confirm consistent pathways into the human STN by 7 T MRI-based tractography. We identify two functional types of topographically distinct glutamatergic STN neurons (parvalbumin [PV+/-]) with synaptic connectivity from indirect and hyperdirect pathways. Glutamatergic PV+ STN neurons contribute to burst firing. These data suggest a complex interplay of information integration within the basal ganglia underlying coordinated movement control and therapeutic effects.

Clinical outcome prediction from analysis of microelectrode recordings using deep learning in subthalamic deep brain stimulation for Parkinson`s disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for improving the motor symptoms of advanced Parkinson's disease (PD). Accurate positioning of the stimulation electrodes is necessary for better clinical outcomes. OBJECTIVE: We applied deep learning techniques to microelectrode recording (MER) signals to better predict motor function improvement, represented by the UPDRS part III scores, after bilateral STN DBS in patients with advanced PD. If we find the optimal stimulation point with MER by deep learning, we can improve the clinical outcome of STN DBS even under restrictions such as general anesthesia or non-cooperation of the patients. METHODS: In total, 696 4-second left-side MER segments from 34 patients with advanced PD who underwent bilateral STN DBS surgery under general anesthesia were included. We transformed the original signal into three wavelets of 1-50 Hz, 50-500 Hz, and 500-5,000 Hz. The wavelet-transformed MER was used for input data of the deep learning. The patients were divided into two groups, good response and moderate response groups, according to DBS on to off ratio of UPDRS part III score for the off-medication state, 6 months postoperatively. The ratio were used for output data in deep learning. The Visual Geometry Group (VGG)-16 model with a multitask learning algorithm was used to estimate the bilateral effect of DBS. Different ratios of the loss function in the task-specific layer were applied considering that DBS affects both sides differently. RESULTS: When we divided the MER signals according to the frequency, the maximal accuracy was higher in the 50-500 Hz group than in the 1-50 Hz and 500-5,000 Hz groups. In addition, when the multitask learning method was applied, the stability of the model was improved in comparison with single task learning. The maximal accuracy (80.21%) occurred when the right-to-left loss ratio was 5:1 or 6:1. The area under the curve (AUC) was 0.88 in the receiver operating characteristic (ROC) curve. CONCLUSION: Clinical improvements in PD patients who underwent bilateral STN DBS could be predicted based on a multitask deep learning-based MER analysis.

Bilateral Subthalamic Nucleus Deep Brain Stimulation under General Anesthesia: Literature Review and Single Center Experience.

Bilateral subthalamic nucleus (STN) Deep brain stimulation (DBS) is a well-established treatment in patients with Parkinson's disease (PD). Traditionally, STN DBS for PD is performed by using microelectrode recording (MER) and/or intraoperative macrostimulation under local anesthesia (LA). However, many patients cannot tolerate the long operation time under LA without medication. In addition, it cannot be even be performed on PD patients with poor physical and neurological condition. Recently, it has been reported that STN DBS under general anesthesia (GA) can be successfully performed due to the feasible MER under GA, as well as the technical advancement in direct targeting and intraoperative imaging. The authors reviewed the previously published literature on STN DBS under GA using intraoperative imaging and MER, focused on discussing the technique, clinical outcome, and the complication, as well as introducing our single-center experience. Based on the reports of previously published studies and ours, GA did not interfere with the MER signal from STN. STN DBS under GA without intraoperative stimulation shows similar or better clinical outcome without any additional complication compared to STN DBS under LA. Long-term follow-up with a large number of the patients would be necessary to validate the safety and efficacy of STN DBS under GA.

Effect of unilateral subthalamic deep brain stimulation in highly asymmetrical Parkinson's disease: 7-year follow-up.

OBJECTIVEFor patients with highly asymmetrical Parkinson's disease (PD), unilateral subthalamic nucleus (STN) deep brain stimulation (DBS) has been suggested as a reasonable treatment. However, the results of a previous 2-year follow-up study involving patients with prominently asymmetrical PD who had unilateral STN DBS suggested that simultaneous bilateral surgery should be performed. In the present study, the authors analyze 7-year follow-up data from the same patient group to examine changes in motor benefit from unilateral STN DBS over time and the interval between initial unilateral surgery and a second (contralateral) STN DBS surgery.METHODSEight patients with highly asymmetrical parkinsonism who underwent unilateral STN DBS were evaluated. The factors measured were scores on the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III), Hoehn and Yahr (HY) stage, and levodopa equivalent daily dose (LEDD). Evaluations occurred at 3, 6, and 12 months after the initial surgery and annually thereafter.RESULTSThe mean follow-up period was 91.5 months (range 36-105 months). Three years after the initial unilateral surgery, motor benefits on the contralateral side continued; however, an aggravation of the ipsilateral parkinsonism attenuated the improvement in total UPDRS III scores, which reverted to baseline. Axial motor score, LEDD, and HY stage did not differ from the baseline. Seven of 8 patients (87.5%) were considered candidates for a second surgery to offer additional motor benefits. Of the 7 candidates, 4 patients (50% of total patients) underwent the second surgery at 58.5 ± 11.6 (mean ± SD) months after the initial surgery. Three patients were not able to have the second surgery: one patient died of gastric cancer, one patient was severely immobilized by an accident, and one patient could not afford the second surgery. One patient remained content with the initial unilateral surgery throughout the follow-up period.CONCLUSIONSSeven of 8 patients with unilateral STN DBS became candidates for second surgery before battery replacement surgery of the first implanted device. Baseline asymmetry alone may not predict appropriate candidates for unilateral STN DBS. This study provides further evidence that, from a long-term perspective, initial simultaneous bilateral STN DBS should be considered for PD patients with prominently asymmetrical motor symptoms.

Correlation of electrode position and clinical outcomes in globus pallidus stimulation for dystonia.

BACKGROUND: The correlation between the electrode location and the clinical outcome for internal globus pallidus (GPi) deep brain stimulation (DBS) has not been fully elucidated. OBJECTIVE: The aim of this study was to determine the discrepancies between the theoretical target planned by magnetic resonance imaging (MRI) and the actual electrode location in postoperative MRI, as well as to find the correlation between the final electrode locations and the clinical outcome after GPi DBS. METHODS: Thirty-six patients who underwent GPi DBS for dystonia were included in this retrospective study. The X coordinate was defined as the lateral distance from the midline, the Y coordinate as the anterior distance from the midcommissural point, and the Z coordinate as the inferior distance from the intercommissural line. RESULTS: All coordinates showed a significant difference between theoretical and actual values for all electrode locations (p < 0.05). In particular, greater differences were exhibited for Y than for the X and Z coordinates. There was no significant difference in the accuracy of the localization of the left-side versus the right-side electrode for any coordinates. The patients whose electrodes were located within or near the posteroventral GPi showed better clinical outcomes. CONCLUSIONS: The actual electrode location was slightly more posterior to the theoretically planned target. Electrodes concentrated near the posteroventral GPi tended to yield favorable outcomes.

Bilateral Deep Brain Stimulation of the Subthalamic Nucleus under Sedation with Propofol and Fentanyl.

Awakening during deep brain stimulation (DBS) surgery may be stressful to patients. The aim of the current study was to evaluate the effect on MER signals and their applicability to subthalmic nucleus (STN) DBS surgery for patients with Parkinson's disease (PD) under sedation with propofol and fentanyl. Sixteen consecutive patients with PD underwent STN-DBS surgery with propofol and fentanyl. Their MER signals were achieved during the surgery. To identify the microelectrodes positions, the preoperative MRI and postoperative CT were used. Clinical profiles were also collected at the baseline and at 6 months after surgery. All the signals were slightly attenuated and contained only bursting patterns, compared with our previous report. All electrodes were mostly located in the middle one third part of the STN on both sides of the brain in the fused images. Six months later, the patients were improved significantly in the medication-off state and they met with less dyskinesia and less off-duration. Our study revealed that the sedation with propofol and fentanyl was applicable to STN-DBS surgery. There were no significant problems in precise positioning of bilateral electrodes. The surgery also improved significantly clinical outcomes in 6-month follow-up.

Long-Term Clinical Outcome of Internal Globus Pallidus Deep Brain Stimulation for Dystonia.

BACKGROUND: GPi (Internal globus pallidus) DBS (deep brain stimulation) is recognized as a safe, reliable, reversible and adjustable treatment in patients with medically refractory dystonia. OBJECTIVES: This report describes the long-term clinical outcome of 36 patients implanted with GPi DBS at the Neurosurgery Department of Seoul National University Hospital. METHODS: Nine patients with a known genetic cause, 12 patients with acquired dystonia, and 15 patients with isolated dystonia without a known genetic cause were included. When categorized by phenomenology, 29 patients had generalized, 5 patients had segmental, and 2 patients had multifocal dystonia. Patients were assessed preoperatively and at defined follow-up examinations postoperatively, using the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) for movement and functional disability assessment. The mean follow-up duration was 47 months (range, 12-84). RESULTS: The mean movement scores significantly decreased from 44.88 points preoperatively to 26.45 points at 60-month follow up (N = 19, P = 0.006). The mean disability score was also decreased over time, from 11.54 points preoperatively to 8.26 points at 60-month follow up, despite no statistical significance (N = 19, P = 0.073). When analyzed the movement and disability improvement rates at 12-month follow up point, no significant difference was noted according to etiology, disease duration, age at surgery, age of onset, and phenomenology. However, the patients with DYT-1 dystonia and isolated dystonia without a known genetic cause showed marked improvement. CONCLUSIONS: GPi DBS is a safe and efficient therapeutic method for treatment of dystonia patients to improve both movement and disability. However, this study has some limitations caused by the retrospective design with small sample size in a single-center.

Patients' reluctance to undergo deep brain stimulation for Parkinson's disease.

BACKGROUND: Many patients with advanced Parkinson's disease (PD) are reluctant to undergo the subthalamic nucleus deep brain stimulation (STN-DBS) when surgery is warranted. Reasons for this reluctance have not been examined. We undertook to establish the rate and causes of this reluctance for STN-DBS in patients with advanced PD. METHODS: A reluctant group was defined as patients who were hesitant to undergo DBS. Clinical information included age, onset age, disease duration, the Unified Parkinson Disease Rating Scale, Hoehn and Yahr stage and levodopa equivalent dose when they were evaluated with a view to consider surgery. RESULTS: We enrolled 186 patients who underwent STN-DBS. 84 patients (45%) belonged to the reluctant group. Between the reluctant and the non-reluctant, there were no differences in preoperative characteristics. Main reasons for hesitation were fear of complications (74%) and economic burden (50%). The main reasons that they finally underwent the DBS were confidence in the doctor's decision (80%) and encouragement from their family (36%). CONCLUSIONS: Building trust between patients and physicians is an important factor in guiding patients to undergo this treatment. To reduce the reluctance to undergo DBS at the appropriate time, we need to find effective ways of reducing their psychological and economic burden.

Sudden loss of the deep brain stimulation effect with high impedance without macroscopic fracture: a case report and review of the published literature.

The number of deep brain stimulation (DBS) hardware complications has increased during the past decade. In cases of abnormally high lead impedance with no evidence of a macroscopic fracture, optimal treatment options have not yet been established. Here, we present the case of a 49-year-old woman with a 12-year history of Parkinson's disease who received bilateral subthalamic nucleus DBS in March 2006. The patient showed good control of parkinsonism until December 24, 2010, when she awoke with abrupt worsening of parkinsonian symptoms. At telemetric testing, lead impedances were found at >2,000 Ω in all four leads on the left side. Fracture of a lead or an extension wire was suspected. However, radiological screening and palpation revealed no macroscopic fracture. In June 2011, the implantable pulse generator (IPG) was changed under local anesthesia without any complications. Postoperatively, her parkinsonism immediately improved to the previous level, and the lead impedance readings by telemetry were also normalized. The disconnection of the neurostimulator connector block and the hybrid circuit board of the IPG was confirmed by destructive analysis. The present report illustrates that a staged approach that starts with simple IPG replacement can be an option for some cases of acute DBS effect loss with high impedance, when radiological findings are normal, thereby sparing the intact electrodes and extension wires.

Influence of propofol and fentanyl on deep brain stimulation of the subthalamic nucleus.

We investigated the effect of propofol and fentanyl on microelectrode recording (MER) and its clinical applicability during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. We analyzed 8 patients with Parkinson's disease, underwent bilateral STN DBS with MER. Their left sides were done under awake and then their right sides were done with a continuous infusion of propofol and fentanyl under local anesthesia. The electrode position was evaluated by preoperative MRI and postoperative CT. The clinical outcomes were assessed at six months after surgery. We isolated single unit activities from the left and the right side MERs. There was no significant difference in the mean firing rate between the left side MERs (38.7 ± 16.8 spikes/sec, n=78) and the right side MERs (35.5 ± 17.2 spikes/sec, n=66). The bursting pattern of spikes was more frequently observed in the right STN than in the left STN. All the electrode positions were within the STNs on both sides and the off-time Unified Parkinson's Disease Rating Scale part III scores at six months after surgery decreased by 67% of the preoperative level. In this study, a continuous infusion of propofol and fentanyl did not significantly interfere with the MER signals from the STN. The results of this study suggest that propofol and fentanyl can be used for STN DBS in patients with advanced Parkinson's disease improving the overall experience of the patients.

The clinical impact of precise electrode positioning in STN DBS on three-year outcomes.

Few studies have analyzed the clinical impact of subthalamic nucleus (STN) deep brain stimulation (DBS) as a function of the positioning of the inserted electrode. We investigated retrospectively the three-year outcomes in Parkinson's disease (PD) patients following bilateral STN DBS in terms of the electrode positions. Forty-one advanced PD patients were followed up for over three years following bilateral STN DBS. Patients were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr staging, Schwab and England Activities of Daily Living (ADL), and the Short Form-36 Health Survey (SF-36) before surgery and one, two, and three years after surgery. The patients were divided into two groups according to the electrode position based on the fused preoperative MRI and postoperative CT images: group I included patients who had both electrodes in the STN (n=30) while group II included patients who had one of the electrodes in the STN (n=11). The UPDRS, the Hoehn & Yahr staging, the Schwab and England ADL, and the SF-36 scores showed significant improvements with decreased l-dopa equivalent daily doses (LEDDs) in both groups as well as in the group as a whole for up to three years following bilateral STN DBS. However, the off-medication UPDRS total and motor (part III) scores significantly deteriorated with increased LEDDs for patients in group II three years after STN DBS compared to that of the group I patients. We conclude that more accurate electrode positioning in the STN leads to better long-term outcomes in advanced PD patients following DBS.

Electrode position and the clinical outcome after bilateral subthalamic nucleus stimulation.

We compared the surgical outcome with electrode positions after bilateral subthalamic nucleus (STN) stimulation surgery for Parkinson's disease. Fifty-seven patients treated with bilateral STN stimulations were included in this study. Electrode positions were determined in the fused images of preoperative MRI and postoperative CT taken at six months after surgery. The patients were divided into three groups: group I, both electrodes in the STN; group II, only one electrode in the STN; group III, neither electrode in the STN. Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr stage, and activities of daily living scores significantly improved at 6 and 12 months after STN stimulation in both group I and II. The off-time UPDRS III speech subscore significantly improved (1.6 ± 0.7 at baseline vs 1.3 ± 0.8 at 6 and 12 months, P < 0.01) with least L-dopa equivalent daily dose (LEDD) (844.6 ± 364.1 mg/day at baseline; 279.4 ± 274.6 mg/day at 6 months; and 276.0 ± 301.6 mg/day at 12 months, P < 0.001) at 6 and 12 months after STN deep brain stimulation (DBS) in the group I. Our findings suggest that the better symptom relief including speech with a reduced LEDD is expected in the patients whose electrodes are accurately positioned in both STN.

Fusion image-based programming after subthalamic nucleus deep brain stimulation.

OBJECTIVE: To propose fusion image-based programming to adjust patients with advanced Parkinson disease (PD) effectively after subthalamic nucleus (STN) deep brain stimulation (DBS). METHODS: Between January 2007 and July 2008, 38 patients with advanced PD were consecutively treated with STN DBS. The electrode positions and information regarding their contacts with STN were determined via fusion of the images of preoperative magnetic resonance imaging (MRI) and of postoperative computed tomography (CT) obtained 1 month after STN DBS. Postoperative programming was performed using the information of electrode positions based on the fused images. All patients were evaluated with a prospective protocol of the Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr Staging, Schwab and England Activities of Daily Living (SEADL), levodopa equivalent daily dose (LEDD), short-form-36 health survey (SF-36), and neuropsychological tests before and at 3 months and 6 months after surgery. RESULTS: There was a rapid and significant improvement of motor symptoms, especially tremor and rigidity, after STN stimulation, with low morbidity. Stimulation led to an improvement in the off-medication UPDSR III scores of the patients of approximately 55% at 3 months and 6 months after STN DBS. Dyskinesia was significantly improved (74% at 3 months and 95% at 6 months) after STN DBS. In addition, LEDD values decreased to 50% of the level observed before surgery within 1 month after STN DBS. CONCLUSIONS: Programming based on fused images of preoperative MRI and postoperative CT after STN DBS was performed quickly, easily, and efficiently.

Is MRI a reliable tool to locate the electrode after deep brain stimulation surgery? Comparison study of CT and MRI for the localization of electrodes after DBS.

PURPOSE: MRI has been utilized to localize the electrode after deep brain stimulation, but its accuracy has been questioned due to image distortion. Under the hypothesis that MRI is not adequate for evaluation of electrode position after deep brain stimulation, this study is aimed at validating the accuracy of MRI in electrode localization in comparison with CT scan. METHODS: Sixty one patients who had undergone STN DBS were enrolled for the analysis. Using mutual information technique, CT and MRI taken at 6 months after the operation were fused. The x and y coordinates of the centers of electrodes shown of CT and MRI were compared in the fused images to calculate average difference at five different levels. The difference of the tips of the electrodes, designated as the z coordinate, was also calculated. RESULTS: The average of the distance between the centers of the electrodes in the five levels estimated in the fused image of brain CT and MRI taken at least 6 months after STN DBS was 1.33 mm (0.1-5.8 mm). The average discrepancy of x coordinates for all five levels between MRI and CT was 0.56 ± 0.54 mm (0-5.7 mm), the discrepancy of y coordinates was 1.06 ± 0.59 mm (0-3.5 mm), and for the z coordinate, it was 0.98 ± 0.52 mm (0-3.1 mm) (all p values < 0.001). Notably, the average discrepancy of x coordinates at 3.5 mm below AC-PC level, i.e., at the STN level between MRI and CT, was 0.59 ± 0.42 mm (0-2.4 mm); the discrepancy of y coordinates was 0.81 ± 0.47 mm (0-2.9 mm) (p values < 0.001). CONCLUSIONS: The results suggest that there was significant discrepancy between the centers of electrodes estimated by CT and MRI after STN DBS surgery.

Data management system in a movement disorder center: technical report.

OBJECTIVE: We designed a specialized monitoring unit and data management system with systematic storage and easy access for a deep brain stimulation program of patients with movement disorders. METHODS: All patients were monitored and evaluated in a specialized 24-hour monitoring system whenever it was needed, postoperatively as well as preoperatively. We digitized all the data and developed a data management system that allowed for systematic storage and easy access to the data on demand by users in the offices and outpatient clinics. CONCLUSION: We describe our data management system and how it provides benefit to patients in order that others may use it as a template for designing their own data management system.

Reprogramming guided by the fused images of MRI and CT in subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: To evaluate the usefulness of the visual information about the location of the contacts in deep brain stimulation (DBS) programming, we compared the outcomes of subthalamic nucleus (STN) stimulation before and after reprogramming guided by the fused images of MRI and CT. METHODS: Of the 65 patients with Parkinson's disease, who underwent bilateral STN-DBS surgery between March 2005 and September 2006 and had been managed for at least 6 months with conventional programming which was only based on the physiological responses from the patients, 54 patients were reprogrammed based on the 3D anatomical location of the contacts revealed by the fused images of pre-operative MRI and post-operative CT scans taken at 6 months after surgery. A total 51 patients completed the evaluation after reprogramming. RESULTS: Reprogramming significantly improved the UPDRS part III scores during the on- and off-medication condition. The daily levodopa-equivalent dose was significantly reduced. Improvement in the UPDRS part III scores after reprogramming was greater in the patients with electrodes in the STN than the patients with electrodes off the STN. CONCLUSIONS: CT-MR fusion images helped to reprogram stimulation parameters with ease and confidence in a time-saving manner and resulted in further clinical improvement. This method could complement the conventional method of adjusting stimulation parameters after bilateral STN-DBS.