Emotional symptoms and cognitive function outcomes of subthalamic stimulation in Parkinson's disease depend on location of active contacts and the volume of tissue activated

Abstract Background Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), that can improve patients' motor and non‐motor symptoms. However, there are differences in the improvement of patients' emotional symptoms and cognitive function. Objective To investigate the impact of active contact location and the volume of tissue activated (VTA) on patients' emotional symptoms and cognitive function in STN‐DBS in PD. Methods A total of 185 PD patients were included in this study. We evaluated them using the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale, Hamilton Anxiety Scale (HAM‐A), Hamilton Depression Scale (HAM‐D), Montreal Cognitive Assessment (MoCA), and Mini‐Mental State Examination (MMSE) scales at the preoperative, 1‐ and 12‐month postoperative time points. Leads were positioned in standard space using the Lead‐DBS toolbox, and VTA was calculated for analysis. Results When the lead active contact was closer to the ventral side of the STN, the patients' HAM‐A improvement rate was higher, and when the active contact was closer to the anterior and dorsal sides of the STN, the patients' MoCA improvement rate was higher. Stimulation of the sensorimotor zone was more favorable to the improvement of HAM‐A and HAM‐D in patients. And, the stimulation of the associative zone was more favorable to the improvement of MoCA in patients. Conclusion Our results provide evidence that the 12‐month outcomes of cognitive function and emotional symptoms in PD patients with STN‐DBS were closely related to the specific location of the active contacts in the STN and influenced by the VTA.


| INTRODUC TI ON
In 1817, James Parkinson described a progressive neurological disease characterized by tremor, compulsion, and slowness of movements. Charcot later referred to the disease as Parkinson's disease (PD) in the 19th century. 1 In 1987, Benabid et al. 2 first described the application of deep brain stimulation (DBS) of targeting thalamic nucleus ventralis intermedius in order to treat PD patients at Grenoble university in France. Subsequently, subthalamic nucleus DBS (STN-DBS) was confirmed to be effective to treat the symptoms of PD patients. It proved to be superior in controlling tremors, rigidity, and dyskinesia in patients with advanced stages of PD. 3,4 Although STN-DBS has been proven to improve motor symptoms in PD patients, [5][6][7] the effect of emotional symptoms and cognitive function has not been confirmed. [8][9][10][11][12] In 2018, Kelley et al. 13 experimentally confirmed that 4 Hz deep brain stimulation by STN that STN-DBS may cause some psychiatric problems, such as depression and mania. However, they did not find a significant decrease in social cognitive function in patients through social-behavioral cognitive tests. Therefore, researchers currently believe that the effects of STN-DBS on cognitive function, emotion, and behavior are still controversial. 15 These studies neglected differences in location of active contacts and the volume of tissue activated (VTA). Therefore, we analyzed the data of STN-DBS patients in our center and hypothesized that clinical outcomes of STN-DBS in patients with PD depend on location of active contacts and the volumes of STN tissue, which was stimulated by the generated VTA (STN-VTA).

| Patients and ethical approval
Parkinson's disease diagnosis was based on the MDS clinical diagnostic criteria 2015, 16

| Surgical procedures
All patients underwent standard frame-based stereotaxic DBS surgery with bilateral STN (01/2018-12/2021). These patients received preoperative 3.0T MRI and high-resolution CT examinations, and the Leksell-SurgiPlan (version 10.1) surgical system was used to fuse the images for visual localization of the bilateral STN targets.
Intraoperative electrophysiological mapping with micro-electrode recordings was performed to further determine the location of the implanted targets. Patients were given appropriate parameter adjustments 1 month after surgery to achieve maximum symptom improvement, and proper placement of stimulation lead was confirmed by high-resolution CT.

| Imaging data processing
We processed patients' imaging data using the Lead-DBS toolbox (www.lead-dbs.org) as described by Horn et al. 22 First, preoperative MRI and postoperative CT were registered, and brainshift was corrected. Then, images were nonlinearly normalized into standard space (MNI ICBM 2009b NLIN, Asym) using advanced normalization tools. The pre-reconstructed DBS leads were calculated using the PaCER or TRAC/CORE algorithm, and deviations were manually refined. The Lead-Group was used to display 3D images of patients in the standard space. After that, the locations of activated contacts F I G U R E 1 Patient selection and research process.
were displayed and the coordinates in the MNI space were counted.
Finally, the VTA was calculated based on their stimulation parameters. 23 All computational work was carried out with MATLAB 2022a.

| Statistical analysis of clinical outcomes
All statistical analyses were performed using SPSS 22

| Patient characteristics and clinical outcomes
A total of 185 patients were included from the database, including 100 males and 85 females, with an age of 63.2 ± 8.15 years and a disease duration of 9.6 ± 5.62 years at the time of surgery. Amedian Hoehn and Yahr score was 3.0 (interquartile range from 2.0 to 3.0).
We found that motor symptoms, anxiety, and depression improved significantly after stimulation at the 1-month follow-up and the 12-month follow-up compared to baseline. At the 12-month follow-up, the patients' MoCA and MMSE scores did not change significantly from baseline, but an explorative analysis of MoCA domains showed a significant improvement in the Delayed free recall, which is shown in Table 1. We

| Influence of the location of active contacts on clinical outcomes
In  Table 2).
It's worth noting that we got similar results in the Location-    Table 3). After matching the patient's active contact coordinate points with the patient's MoCA symptom improvement rate, we draw the improvement distribution map in the spatial coordinate, which was used to reflect the coordinate spatial distribution of patients with different improvement rates ( Figure 3C).

| The effect of VTA on the improvement rate of cognitive symptoms
Based on the parameters of the patients at the 12-month follow-up,

TA B L E 3
Comparison of symptom improvement rates in different zones of STN.
the improved group than in the aggravated group and was mainly reflected in the left hemisphere (p = 0.040) ( Table 4).

| The clinical predictive model
In order to better predict the 12-month outcome of cognitive and emotional symptoms in PD patients with STN-DBS, we first con-

| DISCUSS ION
In this study, we report the effect of STN-DBS on clinical symptoms in 185 PD patients followed for 12 months. We found a significant Interestingly, during the study, patients' cognitive function changes were more closely related to the left cerebral hemisphere.
Some studies have suggested that there are anatomical and functional differences between the left and right cerebral hemispheres.
The left cerebral hemisphere is more dominant in language, attentional, and analytical functions. 33

TA B L E 4
The VTA of different STN and its zones in the MoCA-based cohort.
Some limitations must be considered in our study. First, all assessments were performed during med-on, and although we counted the medications taken by patients, we did not take into account the variability between medication doses, which may have some impact on the results. Second, the sample size still needs further expansion. We are currently collecting further data for further study.

| CON CLUS ION
The results given here in our study provide evidence that the 12month outcomes of cognitive and emotional symptoms in PD patients with STN-DBS were closely related to the specific location of active contacts in the STN and influenced by the VTA.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.