2.1.3. Targeting Accuracy

The theoretical assumption of STN DBS under GA surgery is that the accuracy in targeting STN is not less and the results are better than STN DBS surgery under LA using MER. Kochanski et al. analyzed MER trajectories after STN DBS using 227 iCTs and found that 1.2 ± 0.2mm of radial error occurred in comparison with the location of the intended targets [68]. These errors may be related to the mechanical errors related with the frame, arc, guide tube, and frame, which can lead to lead deviation [69]. In a large-scale study of DBS patients who underwent surgery using iCT, there were greater Euclidean error and greater medial deviation in the trajectory targeting Vim. The authors found that there are systematic tendencies in stereotactic error that differ with respect to the structure targeted [70]. In the study analyzing stereotactic accuracy of iMRI, the DBS lead placement using iMRI guidance showed a radial targeting error of 0.6–1.2 mm, while the error using iCT was 0.8–1.24 mm [22,25,27,28,31,37,71]. STN DBS surgery under GA using confirmatory iCT is based on the assumption that CT-MRI merge was performed correctly, but there may be some errors in the fusion of imaging modality, which may lead to suboptimal targeting [38,72,73]. The advantage of STN DBS surgery with iMRI guidance is that it has less dependence on image fusion and can reflect brain shift after dura opening. Analysis of the iMRI study revealed that the deep brain structure moves about 2 mm after opening the dura [74].

### *2.2. Using Microelectrode Recording*

### 2.2.1. Is MER Mandatory for STN DBS Surgery?

In the standard STN DBS procedure under LA, MER is used during surgery to obtain a signal to identify the deep structure [75]. The final site of electrode implantation is determined by considering both MER and intraoperative test stimulation [7–9,11,13–15]. Sedative drugs, such as propofol, dexmedetomidine, and remifentanil, are given to patients when it is not necessary for them to be

awake [76,77]. The goal of using MER in STN DBS surgery is to obtain high accuracy in radiographic and neurophysiological targeting. Theoretically, the ideal target should be one and the same, but several important factors can lead to errors in targeting, resulting in inconsistency between optimal radiographic and neurophysiological targets. In the report on awake STN DBS, about 25% (38/150) of the electrodes were found very accurately located on the intended target very accurately with an error of less than 1mm, but electrophysiological recording did not match with the target in MER and/or intraoperative stimulation, or showed an unacceptably low side-e ffect threshold by stimulation [68]. Although these findings may be explained by brain shifts, these cases indicate that MER is essential for target confirmation during DBS surgery. Even small merge error combined with brain shift can lead to discrepancies between optimal radiographic and neurophysiological targets [38,72,74,78–80]. The advantage of this method is that it is possible to observe the changes inMER related to passive motion during surgery, and immediately evaluate the e ffects and side e ffects through test stimulation [9,81]. By reflecting this result and modifying the electrode position, the e ffect can be maximized while the complications of stimulation can be minimized.

MER signals may be mixed with many noises which may be caused by snoring or movements of the patient. The reliability and usefulness of MER during STN DBS surgery under LA are still being investigated. However, awake surgery may not be possible for some patients with severe anxiety, fear, reduced cooperation, severe pain, respiration di fficulties and so on.

MER may increase the risk of intracranial hemorrhage and cognitive decline [82]. Binder et al. reported a bleeding rate of 3.3% and a risk of permanent defects 0.6% [83]. The number of MER trajectory was found slightly higher in patients with hemorrhage without statistical significance than the patients without hemorrhage [84]. Some researchers have also questioned whether MER has a real significant impact on target refinement [8]. They argued that a short MER-determined STN length alone cannot predict the occurrence of stimulation-related side e ffect [18]. Moreover, the MER procedure increases both surgical time and the cost [8,85].

Macrostimulation test cannot be performed if the patients are asleep during the operation. There is also controversy about whether intraoperative stimulation is needed during DBS surgery. Some researchers believe that it is necessary to confirm the e ffectiveness of the stimulus. On the other hand, some argued that discontinuation of the drug in LA makes the results less reliable, especially if it is not located in the correct position within the STN, the e ffect can be easily observed and di fficult to distinguish from the lesion e ffect [86].

Due to the improved image quality of preoperative imaging, determining the final electrode location by imaging alone without MER does not negatively a ffect motor improvement and LEDD, and does not aggravate surgical complications [24,26,29,42,87]. The UPDRS III reduction rate at postoperative 3 months was higher in the group of STN DBS under LA with MER cohort (*p* = 0.006), but there was no significant di fference at 1 year (*p* = 0.18), as well as in dysarthria, capsular, oculomotor, and sensory side e ffects [87]. Chen et al. also reported that there was no di fference in the UPDRS III reduction rate and score 6 months after STN DBS surgery between the MER group and the non-MER group [42]. In addition to frequently used imaging sequences, direct targeting can be used with quantitative susceptibility mapping (QSM) and di ffusion tensor imaging (DTI) [68].

### 2.2.2. Is MER Possible Under GA?

STN DBS under GA has traditionally been used in patients who are unable to tolerate awake surgery including pediatric patients, or in patients who do not require clinical testing, such as obsessive-compulsive disorder or epilepsy. The biggest concern with STN DBS surgery under GA for movement disorder is the possibility of diminution of MER signals. A few small-sized retrospective studies have reported that MER obtained from STN, GPi, substantia nigra in STN DBS surgery under GA with both volatile and intravenous anesthetics in PD and dystonia patients showed no significant di fference compared with patients awake during the procedure [54,88–91]. Notably, the neural activity of typical burst pattern disappeared when higher anesthetic doses were used. However, the results of these studies are controversial given the small sample size and heterogeneity of the anesthetic used. A prospective, double-blinded study is needed to compare the effects of anesthetic agents on MER quality in patients undergoing STN DBS surgery under GA.

The next concern is that since intraoperative stimulation cannot be performed under GA, immediate response of clinical effects and adverse effects associated with stimulation cannot be assessed during the STN DBS surgery. Several trials of MER in deep sedation have been performed without intraoperative stimulation [32,33,89]. In these studies, propofol or remifentanil tended to interfere with the electrophysiological signal, but there were no significant differences in terms of exact targeting, clinical effectiveness, and adverse event profiles. Other authors also reported that although there was significant MER signal attenuation in deep sedation with propofol, it did not interfere with the optimal approach to the target [32,33,92,93].

Although a few studies have previously investigated the effects of anesthetics on MER over the past 20 years, the exact effect has not been fully elucidated. Most studies were retrospective analyses with heterogeneity in the anesthesia protocol used and the patient population, and thus, no definitive conclusions could be drawn [77]. Therefore, most of the knowledge revealed to date is derived from the case reports or small case series. During MER, background neuronal discharges and spike activity patterns are an important part of the precise localization of the target nucleus. Anesthetics have been shown to affect background activity and neuronal spike activity in a dose-dependent manner, primarily through activation of γ-aminobutyric acid (GABA) receptors. In addition, anesthetics do not have the same effect on neuronal activity in various target nucleus. Since most anesthetics enhance the inhibitory action of GABA, this difference in GABA-input of the target nucleus plays an important role [94,95].

MER from STN in PD patients was successfully obtained under sedation with low-dose anesthetics. The anesthesia techniques used during MER ranged from conscious sedation with propofol, dexmedetomidine with no airway manipulation to GA with intravenous or inhalation anesthetics. Although anesthetics have been shown to reduce the spike activity, localization of the target areas was proven possible in most studies. Nevertheless, most studies did not mention the exact effect on the background activity, degree of suppression of spike activity, and the number of trajectories used for localization [34,58,80,89].

Under desflurane inhalation, Lin et al. observed that MER could be performed with a typical neuronal firing pattern and motion-related firing of STN, and the clinical results were similar in both groups [34,96].

Our group performed MER and implantation by administering propofol and fentanyl for sedation under LA, and reported the effects of propofol and fentanyl on MER and the clinical outcome. The locations of all electrodes were positioned within the STN. The postoperative 6-months UPDRS II and III, total "off" scores, Hoehn and Yahr (H&Y) scale, Schwab-England ADL scale scores, and LEDD have been greatly improved [92,93].

Although the effects of short-acting opioid receptor agonists, such as remifentanil, on MER are not well known, some data sugges<sup>t</sup> that GABAergic neurons may play a central role [76,77,97]. A few reports showed that anesthesia using propofol reduces the firing rate of basal ganglia in a few reports [95,98], while one study showed no significant difference in firing rate compared to LA when administered with propofol and fentanyl [92]. Monitored anesthesia using propofol appears to be a safe technique for DBS procedure [99]. In some studies, MER was properly performed without affecting the surgical outcome only when remifentanil administration was discontinued and propofol was carefully monitored [32,54,100]. However, the spontaneous firing patterns of STN and substantia nigra remained similar to those under LA [14,100]. Chen et al. also reported that there was no significant difference between the GA and LA groups in terms of MER trajectory, recorded STN depths, postoperative coordinates, and overall incidence of stimulation-related side effect [55]. Under remifentanil or ketamine anesthesia, no significant differences were found in number of spikes detected, mean firing rate, pause index, and burst index compared to LA [57]. However, Moll et al. observed a long interburst between abnormally long group discharges under propofol and remifentanil [89].

Benzodiazepines are direct GABA-agonists, which can completely eliminate MER and cause dyskinesia. Dexmedetomidine may be a better alternative for anxiety relief. The effect of dexmedetomidine on neural activity has not been fully elucidated, but it seems to be a reasonable option due to the non-GABA-mediated mechanism of action. Several studies to date have shown minimal e ffects of low-dose dexmedetomidine on MER in STN and GPi [101–104]. Some authors reported that low doses of dexmedetomidine (<0.5 μg/kg/h) did not significantly a ffect the quality of MER in STN or GPi [76,99,103]. Although dexmedetomidine may a ffect the MER result, it does not a ffect target localization [50].

### 2.2.3. Clinical Experiences of STN DBS Using MER under GA

Some authors performed STN DBS surgery on PD patients under GA and reported favorable clinical outcomes (Table 1). Hertel et al. reported that patients' daily o ff phases decreased from 50% to 17%, while the Unified Parkinson's Disease Rating Scale (UPDRS) III score was reduced from 43 (preoperative; medication o ff) to 19 (stimulation on; medication o ff) and 12 (stimulation on; medication on) [32]. Yamada et al. also reported that UPDRS II, III, IV on and o ff scores were significantly lower in the LA and GA groups at 3 months postoperatively, and the activities of daily living(ADL)s and motor symptoms, such as bradykinesia, tremor, rigidity, and axial symptoms, have improved significantly [54]. In this study, a reduction in dyskinesia duration (*p* < 0.001), disability (*p* = 0.009) and o ff period duration, and improvement of sleep disorders were observed. Other authors also reported significant improvement in o ff-medication UPDRS, levodopa-equivalent daily dose (LEDD), and quality of life [29,35]. Harries et al. reported a long-term clinical outcome of more than 5 years [49]. In their study, not only the UPDRS II and III o ff score, but also the total UPDRS o ff scores at postoperative 1 year improved significantly, and the total UPDRS score continued to improve for up to 7 years.

Previously, authors have suggested the use of bispectral analysis (BIS) of the electroencephalogram in STN DBS surgery under GA using MER. An appropriate MER signal can be easily obtained by adjusting the anesthesia depth using BIS [100,105]. BIS of 65–85 and 40–65 is recommended for sedation and GA, respectively [106]. In the case of sedation using dexmedetomidine, it has been reported that the MER signal does not di ffer from the nonsedated state if the BIS value is maintained below 80 [80].

### *2.3. Intraoperative Imaging vs. MER in STN DBS under GA*

Recent meta-analysis reported that no significant di fference was found in the improvement of UPDRS III score or LEDD between LA and GA cohort (Tables 2–4) [16,33,46,54,55,107]. Lefaucheur et al. reported that the rate of reduction in UPDRS III axial, gait, postural stability, and rigidity subscores tended to be greater when performed under LA compared to GA, but the di fference was not statistically significant [33]. On the other hand, Chen et al. reported that the LA cohort showed greater improvement in posture and walking than the GA cohort (*p* = 0.054), while the GA cohort showed a significant decrease in cognitive function (*p* = 0.017) [55].

Some studies have used MER in STN DBS surgery under GA (mean 1.92 ± 0.68) and LA cohort (mean 2.27 ± 1.31) with respect to the maximum error of each read (*p* = 0.557) despite the varying targets [33,52,55]. Ho et al. reported that there was no significant di fference between GA (mean 1.92 ± 0.68) and LA cohort (mean 2.27 ± 1.31) with respect to the maximum error of each lead (*p* = 0.557), but their study included a variety of targets [16]. The number of lead passes and the incidence of intracranial hemorrhage and infection were lower in STN DBS under GA, but treatment-related side e ffects based on the UPDRS IV "o ff" score were lower in DBS under LA (LA cohort 78.4% vs GA cohort 59.7%, *p* = 0.022) [16,35]. However, other studies showed no di fference in the UPDRS IV subscore between the GA and LA groups [24,107]. As for LEDD, some studies reported that the 6-months postoperative LEDD reduction was significantly greater in the LA group, while others

showed statistically similar reductions (LA cohort 38.27%, GA cohort 49.27%, *p* = 0.4447) [26,107]. Tsai et al. reported that symptoms of the patients with PD improved after DTN DBS in both LA and GA cohorts without significant di fferences in LEDD and UPDRS IV scores [52].

When the long-term outcome was investigated, the authors found that the probability of side e ffects by stimulation and lead revision was higher in the GA cohort without MER and test stimulation [68]. On the other hand, no di fference was observed in UPDRS III score, LEDD, stimulation parameters, coordination of targeting, STN recording length, and side e ffects in the two groups [108].

STN DBS surgery can be safely performed with a low complication rate in both LA and GA cohort, and the results of the studies to date show that there is no significant di fference in complication rates between the two groups. Some authors reported that overall DBS-related complications, such as intracranial hemorrhage (GA 0.3% vs LA 1.1%) and infection (GA 0.7% vs LA 1.4%), were significantly lower in GA cohort (*p* < 0.001) [16,35]. Martin et al. reported the incidence of hardware infection is due to electrode implantation after 10 years of MRI-guided STN DBS surgery [109]. In the study, the overall infection rate of 164 iMRI-guided surgeries with 272 electrodes implanted was 3.6%, which was similar to that reported in the previous STN DBS surgery under LA. The results of a systematic review on the incidence of complications, hospitalization time, and readmission rate of patients who underwent awake and asleep STN DBS surgery were recently published, and there was no statistical di fference in the complication rate, length of hospitalization, and readmission rate of LA and GA cohort [110].

The mean total cost of STN DBS surgery under GA and LA was similar at \$38,850 ± \$4830 in GA and \$40,052 ± \$6604 in LA, respectively, but the standard deviation in DBS under GA was significantly lower [111]. This indicates that there is no di fference in the total cost of DBS surgery under GA and LA, but the cost fluctuation is lower due to the lower incidence of unexpected variables in DBS surgery under GA. However, there are limitations to generalizing such result, since it is a single-center experience.


**Table 2.** Summary data of published literature comparing clinical outcome e ffect of after subthalamic nucleus deep brain stimulation under general anesthesia and local anesthesia in patients with Parkinson's disease: Baseline patient characteristics

Data are presented as: mean ± standard deviation GA, general anesthesia; LA, local anesthesia; GPi, Internal globus pallidus; STN, subthalamic nucleus; NR, Not reported \* Age of Onset.


*J. Clin. Med.* **2020**, *9*, 3044

Lefranc et al. NR No significant differences

Ho et al.

Tsai et al. Significantly less in GA

This study 1 required revision due to inappropriate lead

GA 1.4 ± 0.44 vs LA 2.1 ± 0.69 *p* = 0.006

*p* = 0.39 NR NR NR

*p* = 0.78

GA 253.7 ± 82.3 vs LA 272.4 ± 92.5 *p* = 0.748

Blasberg et al. NR No significant differences 1.00 1.00 0.31 Chen et al. NR NR NR NR GA 266.0 ± 60.6 vs LA 260.9 ± 57.6

NR %ICH/lead: GA 0.3 ± 0.0 vs LA 1.1 ± 0.3,

Liu et al. NR 0.94 0.64 NR 0.47

*p* = 0.04 Similar adverse effects NR NR NR

position in LA 1 IPG site infection treated by antibiotics in LA

MER, microelectrode recording; NR, not recorded; GA, general anesthesia; LA, local anesthesia; IPG, implantable pulse generator.

*p* < 0.001

%infection/lead GA 0.7 ± 0.0 vs LA 1.4 ± 0.0, *p* < 0.001
