Preoperative Attention/Memory Problem Affects the Quality of Life of Parkinson's Disease Patients after Deep Brain Stimulation: A Cohort Study

Objectives The aim of this study was to investigate the impact of nonmotor symptoms (NMS) on the quality of life (QoL) outcome after subthalamic nucleus deep brain stimulation (STN-DBS) at the 1-year follow-up. Methods Ninety-three patients diagnosed with Parkinson's disease (PD), who underwent subthalamic nucleus deep brain stimulation (STN-DBS) between April 2020 and August 2021, were included in this study. Demographic information was gathered through a self-designed questionnaire. The severity of both motor and non-motor symptoms, along with the quality of life (QoL), was assessed using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III), Nonmotor Symptoms Scale (NMSS), and 8-item Parkinson's Disease Questionnaire (PDQ-8), respectively. Results Significant differences were observed in the UPDRS-III score, NMSS summary index (SI), and subscores of six domains (sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, urinary, and sexual function) between the baseline and the 6- and 12-month follow-ups. The correlation analysis revealed positive correlations between the preoperative NMSS SI and subscores of seven domains (cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal, and urinary) and ΔPDQ-8. Moreover, the preoperative PDQ-8 SI (β = 0.869, P < 0.001) and the preoperative attention/memory subscore (β = −0.154, P = 0.026) were predictive of the postsurgery improvement in quality of life (QoL). Conclusion Deep brain stimulation (DBS) led to an improvement in the patients' nonmotor symptoms (NMS) at the 1-year follow-up, along with a correlation observed between NMS and the patients' quality of life (QoL). Notably, the severity of preoperative attention/memory problems emerged as the most significant predictor of NMS influencing the QoL outcome after STN-DBS at the 1-year follow-up.


Introduction
Parkinson's disease (PD) stands as the second most prevalent neurodegenerative condition worldwide, impacting approximately 2-3% of the population aged over 65 [1].Alongside motor symptoms such as tremors, rigidity, and bradykinesia, PD also gives rise to a range of nonmotor symptoms (NMS).Current evidence underscores the crucial infuence of NMS on the quality of life (QoL) of individuals with PD [1][2][3], emphasizing the importance of efective NMS management.
Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been demonstrated to alleviate motor symptoms, infuencing various nonmotor symptoms (NMS) to varying degrees, and enhancing the quality of life (QoL) of individuals with PD [3][4][5][6].Nevertheless, the substantial variability in the response to DBS among patients presents a signifcant challenge, underscoring the utmost importance of identifying preoperative factors that can predict QoL outcomes.
Prior studies have indicated the clinical signifcance of nonmotor symptoms (NMS) in relation to the quality of life (QoL) and have identifed NMS as a primary predictor of QoL enhancement after STN-DBS [7,8].However, these studies exhibited considerable heterogeneity among NMS items, thereby lacking external validity.
In this cohort study, our objective was to examine the nonmotor symptom (NMS) predictors that infuence the quality of life (QoL) outcomes after STN-DBS at the 1-year follow-up.We considered the NMS domains as factors in our analysis to potentially mitigate the impact of interindividual variability while maximizing the clinical relevance of predictors for the management of Parkinson's disease (PD).

Patients and Study Design.
A total of 160 Parkinson's disease (PD) patients who underwent subthalamic nucleus deep brain stimulation (STN-DBS) at the Department of Functional Neurosurgery in Ruijin Hospital, Shanghai, China, between April 2020 and August 2021 were enrolled in this study.From this group, 93 patients completed a 1-year follow-up and were fnally included in this retrospective study.Te inclusion criteria required a clinical diagnosis of PD and prior STN-DBS treatment.Te exclusion criteria encompassed mental retardation, organic mental disorder, drug abuse, inability to complete follow-up, surgical complications higher than grade I [9], and difculties understanding the questionnaires and scales at any stage of the study.All cognitive and psychiatric disorder diagnoses were made by experienced neurologists and psychiatrists.Te patients underwent preoperative assessments, and further evaluations were performed at 6 and 12 months postoperatively.Te study protocol received approval from the ethics committee, and written informed consent was obtained from all participating patients.

Clinical Assessment.
Demographic and disease-related information was gathered through a self-designed questionnaire, which included age, gender, disease duration, levodopa equivalent daily doses (LEDD), Hoehn-Yahr stage (H-Y stage), and the current status of motor symptoms.
Te quality of life (QoL) was evaluated using the short-form 8-item Parkinson's Disease Questionnaire (PDQ-8).Each item in the PDQ-8 represents a life situation with low quality and is rated on a 5-point Likert scale.Te summary score ranges from 0 to 32 points, with higher scores indicating lower QoL.Te questionnaire demonstrates good internal consistency, with a Cronbach's α of 0.874.
Motor symptoms were evaluated using the Unifed Parkinson's Disease Rating Scale-III (UPDRS-III).Tis scale, which is a subscale of the Unifed Parkinson's Disease Rating Scale (UPDRS), encompasses four categories of symptoms: tremor, rigidity, bradykinesia, and axial symptoms.Te total score on this scale ranges from 0 (indicating no impairment) to 108 (representing maximum impairment).

Statistical Analysis.
Diferences between the baseline scores (x1) and the scores at the 12-month follow-up (x2) after STN-DBS were calculated for each outcome parameter (Δx � x2 − x1).To assess the diference in outcome parameters for each stage, we employed a one-way analysis of variance (ANOVA).Subsequent post hoc comparisons were conducted using Tamhane's T2 test.Te p value was corrected using the Bonferroni correction method.When appropriate, independent samples t-test or Mann-Whitney U test were used to compare subgroups.Pearson's correlation analysis was performed between the outcome parameters.To predict the postoperative improvement in quality of life (QoL), we conducted multivariate linear regression, with ΔPDQ-8 as the dependent variable, and the factors found signifcant in Pearson's correlation analysis as independent variables, while also controlling for sex and age.Te statistical analysis was carried out using SPSS version 20 (SPSS, Inc., Chicago, IL, USA), with the signifcance level set at 0.05.

Demographic Information.
Ninety-three patients diagnosed with Parkinson's disease (PD) were enrolled in this study.Demographic and disease-related information is presented in Table 1.All the information of patients was obtained during their of conditions.Additional specifc characteristics can be found in Supplementary Table 1.

Te Efects of STN-DBS on NMS and
QoL.To investigate the impact of DBS on patients' nonmotor symptoms (NMS) and quality of life (QoL), we compared the PDQ-8 index and NMSS score across nine domains at three time points: before DBS and at 6-and 12-month follow-ups.Univariate analysis (Table 2 and Figure 1) revealed a signifcant diference in the PDQ-8 index and in the scores for the sleep/fatigue, mood/ cognition, perceptual problems/hallucinations, attention/ memory, urinary, and sexual function domains, as well as the NMSS total score.Post hoc tests were conducted to further elucidate the signifcant diferences observed in the variables at the three time points.

Te Relationship between NMS and QoL Improvement.
As previously mentioned, there were signifcant diferences in PDQ-8 indexes at each time point.ΔPDQ-8 was used to represent the changes in quality of life (ΔPDQ-8 � PDQ-8 baseline − PDQ-8 12M ).Correlation analysis was performed to 2 Parkinson's Disease examine the association between ΔPDQ-8 and various demographic and disease factors, including age, gender, disease duration, levodopa equivalent daily doses (LEDD), UPDRS-III score, Hoehn-Yahr level (H-Y level), preoperative NMSS score, and PDQ-8 index before DBS.Te results, as shown in Table 3, revealed positive correlations between ΔPDQ-8 and the preoperative PDQ-8 index, as well as seven subscores of NMSS before DBS (cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal, and urinary), along with the preoperative NMSS total score.

Te Nonmotor Predictors for QoL Improvement after STN-DBS.
Multivariate linear regression analysis was conducted to investigate the predictors of quality of life (QoL) improvement following STN-DBS.Based on the regression model, the preoperative PDQ-8 index (β � 0.867, P < 0.001) and the preoperative attention/memory score (β � −0.158, P � 0.024) were found to be signifcant predictors of QoL improvement at the 12-month follow-up (Table 4).

Discussion
In this retrospective cohort study, we investigated the impact of STN-DBS on nonmotor symptoms (NMS) and quality of life (QoL), while also identifying the correlation between these two parameters.Te fndings indicated that DBS led to an improvement in patients' NMS at the 1-year follow-up, and a correlation was observed between NMS and patients' QoL.Notably, the severity of preoperative attention/memory problems emerged as the most prominent predictor of NMS infuencing the QoL outcome after STN-DBS at the 1year follow-up.
4.1.Nonmotor Symptoms.STN-DBS showed signifcant relief in the burden of nonmotor symptoms (NMS) and improvement in patients' quality of life (QoL), which is in line with the fndings of Dafsari et al. [10,11].Notably, seven domains of NMSS exhibited signifcant improvement at both the 6-and 12-month follow-ups when compared to the baseline.[12].Consistent with these fndings, our study also observed a signifcant diference in the NMSS sleep/fatigue domain at the 6-month follow-up [10,13].
Although the degree of improvement decreased, the sleep/ fatigue domain showed signifcant enhancement at the 12-month follow-up compared to the 6-month follow-up.Physiologically, dopaminergic neurons in the ventral tegmental area of the midbrain are regulated by orexin neurons from the hypothalamus, forming a descending loop that infuences arousal and wakefulness from the cortex and thalamus to the pontine nuclei and reticular formation [14].Subthalamic nucleus (STN) neurons have neural projections in regulatory regions, such as the cortex, thalamus, and pedunculopontine nucleus, which are involved in sleep regulation.Terefore, STN may be part of the regulatory networks governing sleep and arousal functions, potentially infuencing sleep disorders [15].Te observed improved sleep after STN-DBS in our patients may also be associated with the alleviation of nocturnal dyskinesia, reduced nocturia, and pain relief.Additionally, as sleep disturbances in PD patients contribute to fatigue, the improvement in sleep may also lead to the relief of fatigue in these patients [16].

Mood/Cognition.
In the current study, we observed signifcant diferences in the NMSS mood/cognition domain at both the 6-and 12-month follow-ups, which diverged from some previous fndings [10,17].Nevertheless, our results were consistent with several other studies.For instance, Elizabeth et al. reported that unilateral STN-DBS led to improved depression in patients at the 6-month follow-up [18], and similar fndings were reported by Li et al. [19].A   [29].Another study showed that 21 male patients reported signifcant improvements in their sexual life after STN-DBS.However, in our study, the average level of sexual function at the 12month follow-up remained similar to that at the 6-month follow-up.On the other hand, Jost et al.only reported a signifcant diference in sexual function at the 36-month follow-up compared to baseline, but the changing trend of sexual function during the 36-month follow-up was not reported [17].Terefore, we concluded that the efect of STN-DBS on PD patients' sexual function was mainly concentrated in the short postoperative period.
4.1.7.Miscellaneous.In our study, the NMSS miscellaneous domain, which includes pain, abnormal olfaction, altered weight, and hyperhidrosis, demonstrated a signifcant improvement at the 6-month follow-up, consistent with the fndings of Jost et al. [17].Surprisingly, at the 12-month follow-up, the miscellaneous domain deteriorated signifcantly compared to the 6-month follow-up.However, the miscellaneous burden at the 12-month follow-up was still signifcantly relieved compared to baseline, indicating an unstable long-term efect of STN-DBS on the miscellaneous domain.Furthermore, previous studies have reported varied results regarding specifc components of the miscellaneous domain.For instance, Wolz et al. found no immediate Parkinson's Disease improvement in excessive sweating and pain after STN-DBS [30].In contrast, Cury et al. demonstrated that STN-DBS surgery improved patients' pain [31].Te efects of STN-DBS on olfaction may be mediated through modulation of the orbitofrontal and primary olfactory cortices, and Kola et al. found deterioration of olfaction in patients after STN-DBS [32].Additionally, Strowd et al. reported weight gain in PD patients after STN-DBS [33].In the study by Bjerknes et al., the trends of autonomic symptoms after STN-DBS were similar to our present study, initially showing signifcant improvement and then worsening over time.Autonomic symptoms in PD patients tend to worsen with age and disease progression [34].Contrary to the observed improvement in the miscellaneous domain, we found no signifcant improvement in the cardiovascular and gastrointestinal domains at either the 6-or 12-month follow-up.
4.1.8.Cardiovascular.In our study, the NMSS cardiovascular domain remained unchanged at both the 6-and 12month follow-ups, which aligns with the fndings of Dafsari et al. [10].Similarly, Wolz et al. did not report any immediate improvement in dizziness after STN-DBS [30].Although no signifcant diference was observed, the average level of the cardiovascular domain slightly worsened at the 12-month follow-up compared to the 6-month follow-up.Tus, we concluded that STN-DBS has little infuence on cardiovascular symptoms.
4.1.9.Gastrointestinal.In our study, the NMSS gastrointestinal domain showed no signifcant diferences at both the 6-and 12-month follow-ups.Tis result was consistent with the fndings of Dafsari et al. and Jost et al. [10,17].Gastrointestinal symptoms in PD may be caused by extracerebral lesions in patients, such as dysphagia which may be due to muscle wasting, abnormal peristalsis, or esophageal contractions [35].However, Arai et al. demonstrated that STN-DBS improves gastric emptying dysfunction in PD patients, and this phenomenon might be caused by altering the neural system controlling gastrointestinal function.
Although the underlying mechanism was unclear, the activation of nerve fbers projecting from or to the hypothalamus and crossing the subthalamic nucleus was a possible route [36].Wolz  Conversely, the preoperative PDQ-8 summary index positively correlated with ΔPDQ-8, suggesting that PD patients with a low preoperative QoL experienced more signifcant improvement in QoL after STN-DBS.Tis fnding aligns with the results of Jost et al. [7].Daniels et al. also reported that the change in PD patients' QoL had correlations with preoperative parameters, including positive mood changes, which did not show a signifcant correlation in our study [38].Tis could be related to the diferent scales evaluating patients' mood used in Daniels' study and this one.Tus, gaining an in-depth understanding of the type of PD patient who would beneft most from STN-DBS and elucidating the mechanisms by which STN-DBS improves NMS would be valuable.It would also aid physicians and surgeons in predicting the benefts for PD patients after STN-DBS and providing more precise management recommendations.

Limitations.
Nevertheless, the present study has several limitations.First, subgroup analysis was not performed in the univariate analysis of QoL and NMS.Te changes in specifc domains of NMSS after STN-DBS may be infuenced by other factors, such as age, gender, and disease duration.Subgroup analysis could help elucidate signifcant factors by comparing the target parameters of diferent subgroups divided by a specifc potential factor.Terefore, the current study cannot provide further insights into the postoperative changes in each NMS.Second, considering the advanced age of our cohort, the scale questions in the NMSS sex function domain were difcult to answer or were not fully applicable to PD patients.Tis discrepancy between the scale and the cohort might have led to low-quality data and may have infuenced the study results.Tird, the samples in our study were from a single center, which could introduce a systematic bias.Tus, future studies involving multiple centers with larger sample sizes, multiple evaluation tools, and exhaustive data analysis are anticipated.Fourth, this study lacks further evaluation of patient attention and memory function.In the future, more comprehensive tools are needed for detailed evaluation.Lastly, new onset impulse control disorders were not evaluated in the samples of this study.Given the potential impact of new-onset impulse control disorders on NMS and patients' QoL, we look forward to further consideration of these disorders in future related studies.

Conclusions
Tis retrospective cohort study with 6-and 12-month follow-ups provides evidence for the improvement of QoL and NMS burden by STN-DBS.We demonstrated signifcant improvement in seven domains of NMSS at both 6-and 12-month follow-ups: sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, urinary, sex function, and miscellaneous.Apart from the total NMS burden and preoperative QoL, the improvement in QoL through STN-DBS was signifcantly correlated with the cardiovascular, sleep/fatigue, mood/ cognition, perceptual problems/hallucinations, attention/ memory, gastrointestinal, and urinary domains.Moreover, the improvement in QoL could be predicted by the preoperative attention/memory domain and preoperative QoL, which might aid in the prediction of prognosis and clinical management of patients.

Figure 1 :
Figure 1: NMSS domains at baseline (blue), 6-month follow-up (orange), and 36-month follow-up (red) in a bar chart (a) and radar chart (b).(a) Sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, and urinary domain signifcantly improved at both 6-and 12-month follow-ups compared to the baseline.Sexual function and miscellaneous domain showed signifcant improvement at 6-month follow-up.However, the sexual function domain stayed unchanged at 12-month follow-up, while the miscellaneous domain worsened signifcantly at the 12-month follow-up.(b) NMSS domain scores were illustrated as percentages of each maximum score.Te NMS burden was overall mitigated at both 6-and 12-month follow-ups compared to the baseline.* indicates P < 0.05, * * indicates P < 0.01, * * * indicates P < 0.001.

Table 2 :
Outcome parameters assessed at preoperative baseline and at postoperative 6-and 12-month follow-ups for a total of 93 participants (N � 93).

Table 3 :
Te correlations between the test scores at the preoperative baseline and the 12-month change scores of quality of life (N � 93).
[17]26]t study indicated that STN-DBS has a short-term (<3 months) benefcial efect on apathy, but in the long term, it could exacerbate the condition[22].4.1.3.Perceptual Problems/Hallucinations.Our observations indicated a signifcant improvement in the NMSS perceptual problems/hallucinations domain at both the 6-and 12-month follow-ups, which is in agreement with the fndings of Dafsari et al. and Yoshida et al.[10,23].However, Jost et al. did not report any signifcant change in this domain from baseline to the 36-month follow-up[17].Due to the limited number of studies focusing on this specifc issue, further research is required to elucidate the correlation between STN-DBS and outcomes related to perceptual problems or hallucinations.patients[25,26].Additionally, according to Kim et al., there is no evidence to suggest that STN-DBS is a risk factor for cognitive deterioration in PD patients when compared to medical therapy[27].Moreover, only 3 items exist in the NMSS evaluating patient's attention and memory function, which demonstrates that more systematic tools are needed to assess patient's attention and memory function.cortexactivation[28].Furthermore, this improvement was sustained at the 12-month follow-up, aligning with the fndings of the long-term study conducted by Jost et al.[17].4.1.6.Sexual Function.In our study, we observed a signifcant improvement in the NMSS sexual function domain at the 6-month follow-up.Tis fnding aligns with the results of a study by Castelli et al., which involved a cohort of 31 PD patients (21 males and 10 females)