Relationship Between Electrode Position and Clinical E cacy of Subthalamic Nucleus Deep Brain Stimulation and Motor Symptoms of Parkinson's Disease

Feng Zhang Beijing Neurosurgical Institute https://orcid.org/0000-0002-0898-7861 Feng Wang Ningxia Medical University Weiguo Li Shandong University Qilu Hospital Ning Wang Beijing Neurosurgical Institute Chunlei Han Beijing Neurosurgical Institute Shiying Fan Beijing Neurosurgical Institute Peng Li Hebei Medical University First A liated Hospital Lifeng Xu Hebei Medical University First A liated Hospital Jianguo Zhang Beijing Neurosurgical Institute Fangang Meng (  fgmeng@ccmu.edu.cn ) Beijing Neurosurgical Institute https://orcid.org/0000-0002-4030-7811


Introduction
Pakinson 's disease (PD) is a neurodegenerative disease common in middle-aged and elderly people, and deep brain stimulation (DBS) is an accepted treatment at an advanced stage [1][2]. Studies have shown that subthalamic nucleus (STN) DBS can improve dyskinesias and improve the quality of life (QOL) in PD patients [3][4][5][6].Every now, the STN is publicly preconceived the target of choice [4]. Studies have shown that the improvement in postoperative motor improvement depends in particular on age and disease duration [6] and preoperative response to dopaminergic drugs [7], this makes it critical to screen for the right DBS candidates. In the past, optimizing the parameters of DBS postoperative programming has been proved to be an important factor to improve the therapeutic effect on PD. However, the most important factors that determine the improvement of DBS on motor symptoms are precise stimulation targets and effective stimulation volume, that is, the position of the electrode active contact in STN and volume of tissue activated (VTA) [8][9].The purpose of this study was to observe the e cacy of motor symptoms in patients with PD receiving bilateral STN-DBS, and to study the relationship between the location of active contacts and VTA and the motor symptoms of Parkinson' disease (PD) patients.

Patient's selection
Evaluations were executed by neurologists specialized in movement disorders.All Patients met the diagnostic criteria for PD in China (2016 edition) and evaluation criteria for surgical treatment of PD [10]. All patients underwent preoperative testing and analyzed the levodopa challenge test, con rming that levodopa response needs to be improved by at least 30%,and those who had complete imaging and scoring data and could follow up regularly. Morphologic MRI is performed to exclude patients with severe cerebral atrophy,ischemic disease,and severe cognitive impairment and mental illness.

Surgical procedure
Articles describe surgical procedures [11][12]. For encircling patients, an image fusion procedure (3T MRI and 1.5T MRI), commonly drived out by our group. Images detach from 3T MRI plagiarized a day before the surgery were fused with CT (with a Leksell stereotactic frame) on the day of surgical procedure. The coordinates of the target and the entrance trajectory were de ned on stereotactic MR images by directly visualizing the STN. The STN coordinates were calculated using direct [based on MRI T2 DESS(double-ocho steady state)]and indirect (using statistical coordinates) methods. The rst operated side was the one contralateral to the most impaired body-side. The electrodes are implanted under local anesthesia, and targets are identi ed by a combination of neuroimaging, microelectrode recording (MER),and macrostimulation tests.The STN stimulation target was de ned using a combination of statistical coordinates of STN (4-6 mm inferior,2-3 posterior, and 11-13 mm lateral from midcomissural point) [12], and direct visualization on MRI where the STN was chosen at the anterior margin of red nucleus and 2 to 3 mm lateral from its external border.Enhanced T1-weighted images were used to visualize vessels to avoid injury of any vascular structure during surgery.Multi-track microelectrodes were inserted for electrophysiological mapping of the STN. Subsequent macro-stimulations were used to assess the e cacy and side effect pro le of the tested electrodes. The optimal track (best micro-recording and widen therapeutic window on macro-stimulation) was chosen for each side and quadripolar DBS leads (model L301, Stimulation programming [13] 1 month after operation, stimulator was turned on and programed. Monopolar screening was performed for the contacts on each electrode with a pulse width of 60 µm, a frequency of 130 Hz, and a voltage of 1.5-2.0 V.Thereafter, parameters such as voltage, pulse width or frequency are gradually adjusted according to the follow-up results until the best treatment effect was achieved, and adverse reactions were reduced as much as possible, and the position of the contact can be adjusted if necessary. Some patients use bipolar or double negative stimulation. Post-operative evaluation and volume of tissue activated estimation Patients were reassessed 1 month after surgery and 3 and 6 months after surgery at follow-up.(1)DBS electrode localisation:DBS leads were localized with the Lead-DBS toolbox [8,14]. (2) VTA:Volume of the STN in standard space was de ned by the DISTAL atlas. After veri cation of electrode locations, VAT was calculated [15].

Statistical analyses
All statistical analyses were performed using SPSS 25.0 (IBM Corp, USA). Continuous variables that obey or approximately obey the normal distribution are expressed as mean ± standard deviation( ± s).The continuity data that does not obey the normal distribution was expressed by the median and quartile interval. The continuity data that does not obey the normal distribution was based on the Friedman test.The comparison between multiple groups used the rank sum test of the comparison of multiple groups, that was, the Kruskal-Wallis test. Categorical variables were expressed as constituent ratios or percentages, and chi-square tests were used for comparison between groups. Through the Pearson correlation analysize the relationship between the UPDRS-score and the drug improvement rate, LEDD change rate, PDQ-39 score improvement rate, the VTA, the coordinates of the electrode activate contacts, and the distance from the electrode activate contacts to the STN motor subregion, associative subregion,and limbic subregion were discussed.Statistical signi cance level was set at P < 0.05. Resultsx 1. DBS on PD patients with motor symptoms and its correlation analysis results: The follow-up results at 6 months after operation showed that compared with before operation, 57 patients had signi cantly improved UPDRS-scores, and the improvement rate of drug off-state was the highest [(55.4 ± 18.9)%, P < 0.001)]; The improvement rate of PDQ-39 scores were (47.4 ± 23.2)% (P < 0.005), indicating that the patient 's quality of life was also signi cantly improved under chronic high frequency stimulation; LEDD decreased by (40.1 ± 24.3)% (P < 0.005, Table 1, Fig. 1).The improvement rate of motor symptoms (UPDRS III score) (Med-off)in 57 patients 6 months after operation was positively correlated with the drug improvement rate (r = 0.262, P = 0.049) ( Fig. 2A). At 6 months after surgery, the improvement rate of the PDQ39 scores of 57 patients was positively correlated with the improvement rate of motor symptoms(Med-off) (r = 0.461, P < 0.001) (Fig. 2B); the decrease rate of LEDD was positively correlated with the improvement rate of motor symptoms(Med-off) ( r = 0.354, P = 0.007) (Fig. 2C).    Table 5).
(2)The VTA of the electrode active contacts in the MNI space of each group: In the MNI space, there was no statistically signi cant difference between the groups in the VTA of the electrode active contacts (all P > 0.05, Table 6) (Fig. 4C.D).   Discussion STN-DBS has a good effect on PD motor symptoms [16].In our stidy,compared to baseline,STN-DBS improved UPDRS III scores and major motor function, both Med-on and Med-off postoperatively. These results demonstrate that DBS has a unique advantage in relieving motor symptoms,the patient's scores in Med-on / Stim-on postoperatively were lower than the scores in Med-on preoperatively;it has a better effect on improving motor symptoms of PD patients. In addition, the most effective contacts were dorsal contacts, this is similar to reports that the contact selection is dorsal to the STN [17].In our study,we observed a large reduction in LEDD 6 months after operation, a reduction of more than 40% compared to the preoperative dose, which was related to the improvement of motor symptoms in DBS(UPDRS-scores reduced by 55.4%), Which was consistent with a 19-80.7% reduction in drug dose and 53-92% improvement in dyskinesia scores [18][19].The LEDD decement was positively correlated with the improvement rate of motor symptoms (r = 0.354,P = 0.007).We think that the better the effect of DBS on improving patients' motor symptoms, the more LEDD is reduced.Through the PDQ-39 assessment, the QOL (quality of Life) of our patients improved by 47.4% overall, which also proved the good effect of STN-DBS.This result is consistent with previous studies, with an improvement in quality of life from 30.2-50.6% [20].In our study the PDQ39 improvement was positively correlated with the improvement rate of motor symptoms, (r = 0.461,P < 0.001),the better the effect of DBS on improving motor symptoms, the better the QOL of patients.

Factors in uencing clinical e cacy: active contact location
We observed that electrode active contacts in STN-DBS patients were mainly distributed in dorsolateral STN. As we all know, the dorsolateral STN is involved in motor function, and the dorsolateral STN serves as the target region for STN-DBS in PD patients [21].Stimulation of the dorsolateral STN (sensory motor function area) is expected to disrupt pathological neuronal motor activity or afferent bers and improve clinical symptoms.In our study, with UPDRS-III score improvement rate of more than 50% was basically concentrated in the dorsolateral part of STN, the active contacts location of patients with UPDRS score improvement rate of 25-50% was more concentrated in the middle part of STN, the active contacts position of patients with UPDRS-III score improvement rate of less than 25% was more concentrated in the ventral part of STN. After statistical analysis, it was found that only the z-axis coordinate of the brain was signi cantly different.Optimal location of DBS stimulation within STN: the dorsolateral part of STN is traditionally considered to represent the optimal location of the motor region and stimulation [22]. So far, this part can only be con rmed by intraoperative electrophysiology, which shows an increase in βoscillation activity [23].The results of our study support the conclusion that the position of the electrode active contacts help to judge the motor effect of STN-DBS. This study found that the improvement rate of motor symptoms is related to the improvement rate of drugs, but the correlation coe cient is only 0.262,which needs further research.
Characterising clinical e cacy -VTA The effect of programmed parameters (voltage, pulse width, frequency) on the e cacy of DBS surgery is critical.The therapeutic effect is not only on the single contact, but also on the larger electric eld range than the contact. Therefore, Andreas Horn's method of VAT calculation [15] was used to analyze the stimulation parameters of postoperative active contacts and calculate the correlation between the volume of tissue activated (VTA) and the UPDRS motor scores. We used the VAT calculation to evaluate the clinical e cacy of STN-DBS in PD patients, although the difference between the VTA of the electrode activate contacts in the MNI space of each group was not statistically signi cant (all P > 0.05), however, it was found that the higher the VTA of the electrode activate contact of the patient in the STN motor subregion, the higher the improvement of motor symptoms. The difference is not statistically signi cant and may be related to the sample size of this study. Limitations: (1)It is a retrospective analysis of a small sample of 57 patients, the sample is small; (2)The average follow-up period is half a year and the time is short; (3)The treatment mechanism of DBS in this study has not been clari ed.Despite these limitations, our results further con rm that DBS electrode active contacts located dorsolateral to STN can achieve better clinical e cacy and are proportional to the percentage of VTA located in

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Availability of data and material The datasets generated and/or analysed during the current study are available in the Fangang Meng repository upon reasonable request.
Competing interests