# Measuring Subthalamic Nucleus Volume of Parkinson’s Patients and Evaluating Its Relationship with Clinical Scales at Pre- and Postdeep Brain Stimulation Treatment: A Magnetic Resonance Imaging Study

Authors: Li Lu; Kai Xu; Lin Shi; Weiqiang Dou; Kai Liu; Hong Ma; Lixiang Xie; Chao Zhang; Cailuan Lu
Journal: BioMed Research International
 (2021)

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## Abstract

This study investigated potential imaging biomarkers for predicting the efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson’s disease (PD). A total of 59 PD patients and 50 healthy control subjects underwent high-resolution 3-dimensional T1-weighted brain magnetic resonance imaging. Bilateral STN volumes were compared between the 2 groups, and a correlation analysis was performed to assess the relationship between bilateral STN volumes or intracranial volume (ICV) and pre- or postoperative clinical scale scores. The results showed that the left STN volume differed significantly between PD patients and controls. In patients, the left STN volume was negatively correlated with pre- and postoperative quality of life scores and positively correlated with Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment scores; ICV was also positively correlated with the MMSE score. These findings indicate that changes in the left STN volume are a useful biomarker for evaluating the clinical outcome of PD patients following DBS.


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## Body

## 1. Introduction

Parkinson’s disease (PD) is a common movement disorder and neurodegenerative disease [1] characterized by the loss of dopaminergic neurons [2–5] mainly in the substantia nigra (SN). Drugs and invasive treatments are the main therapeutic options for PD. Given the limited efficacy of pharmacotherapy, stereotactic surgery is increasingly being considered for PD treatment in terms of the potential risks and benefits [6–10].Deep brain stimulation (DBS) is a widely used invasive procedure that has considered as an effective surgical treatment for movement disorders [11, 12]. The method involves implantation of electrodes into specific brain regions to stimulate neural circuits [13]. DBS has been used to treat various neurologic diseases including PD, dystonia, and essential tremor [14]. The target area for DBS in PD is usually the subthalamic nucleus (STN), which is an important node in the cortical–basal ganglia–thalamocortical loop [15–18]. Low-frequency DBS of the STN was shown to reduce gait freezing in PD patients [19]. DBS is thought to relieve motor symptoms by selectively activating white matter tracts or by normalizing aberrantly activated neural networks [20]. Although DBS has yielded promising results in PD treatment, the mechanisms underlying the observed effects are not fully understood [21, 22], especially in terms of how impaired neural circuitry is restored [23, 24].Changes in the regional brain volume can alter electrode targeting, reflect postoperative progression of subclinical dementia, or directly interfere with the therapeutic action of DBS [25]. Magnetic resonance imaging (MRI) is a noninvasive method that has been used to investigate structural and functional changes in PD [26–29] and predict motor outcomes following DBS based on thalamic and ventricular volumes [25]. However, few studies have focused on the relationship between STN volume and PD symptoms before and after DBS. The aim of the present study was to identify imaging biomarkers for predicting clinical outcome in PD patients treated by DBS by analyzing the relationship between STN volume and disease duration as well as pre-/postoperative clinical measures.


## 2. Materials and Methods

### 2.1. Subjects

This study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University. A total of 200 patients with clinically confirmed primary PD were recruited between April 2016 and November 2017. Written consent was obtained from each patient prior to their participation in the study. All patients were evaluated for nonmotor symptoms and with the Geriatric Depression Scale, Beck self-rating form, rapid eye movement sleep behavior disorder self-rating form, sleepiness scale, 39-item Parkinson’s Disease Questionnaire scale, end-of-agent questionnaire, dyskinesia questionnaire, new frozen gait questionnaire, Mini-mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton Anxiety Scale, and Hamilton Depression Scale (HAMD). According to the 2012 China DBS expert consensus, 2 neurologists with 15 and 10 years of experience collected patient information and assessed disease course, levodopa response, and comorbidities. The preoperative inclusion criteria were as follows [30, 31]. (1) The patient met the United Kingdom Parkinson’s Disease Society brain bank or Chinese diagnostic criteria for primary PD, had hereditary or one of the many genotypes of PD, and showed good response to levodopa. (2) The patient had PD for >5 years, with tremor as the main symptom that was not alleviated by standard drug treatment and seriously affected the patient’s quality of life; if the patient strongly requested symptom alleviation through early surgery, the postoperative evaluation was extended to 3 years. (3) The patient was ≤75 years old; for older patients with severe tremor, the age limit was appropriately extended. (4) The patient responded to levodopa but the symptoms were not completely abolished, and quality of life remained low, or the patient was intolerant to the drug. (5) Disease severity was determined as a Hoehn and Yahr (HY) scale score of 2.5–4 in the “off” period of the drug (i.e., med-off). (6) Patients were not suitable for surgery because of the following conditions: severe cognitive dysfunction that could affect activities of daily living, severe refractory depression, anxiety, or schizophrenia, or other illnesses that could affect surgery or survival. Based on these criteria, 62 patients were included in the study and underwent DBS surgery. None of the patients had contraindications for MRI examination. However, because of head motion artifacts and incomplete MRI measurements, data for 3 patients were excluded (Figure 1).Figure 1
Flow chat of patient selection. 200 patients, clinically confirmed with primary PD, were recruited, and 141 patients were excluded due to different reasons including treatment with medication, PD history less than five years, 1-2 HY stage, head motion artifacts, or incomplete MRI data.Ultimately, 59 PD patients (33 males and 26 females, mean age:65.72±7.53 years, age range: 43–77 years) were included in the study. Each patient underwent pre- and postoperative assessment with the Unified Parkinson’s Disease Rating Scale (UPDRS) III and HY staging. The HY stage of the 59 patients was between 2.5 and 5. Preoperative med-on and med-off UPDRS III scores, postoperative med-on/DBS-on, postoperative med-off/DBS-off, and postoperative med-off/DBS-on UPDRS III scores were assessed. The control group comprised 50 healthy volunteers (23 males, 27 females, mean age: 59.84±7.14 years). There were no significant differences in the age or sex ratio between the 2 groups. All study participants were right-handed.


### 2.2. MRI Examination

A 3.0 T whole-body scanner (750w; GE Healthcare, Cleveland, OH, USA) with a standard birdcage head transmitter and receiver coil was used for MRI. All subjects were scanned in the supine position. A foam material was placed on both sides of the subject’s head to prevent head movement. The scan consisted of a high-resolution 3-dimensional T1-weighted (T1W) gradient echo-based sequence with the following parameters:repetitiontime=7.0ms, echotime=3.0ms, flipangle=12°, fieldofview=256×256mm2, matrixsize=256×256, slicethickness=1mm, and numberofslices=192; the scanning time was 4 min 15 s.


### 2.3. STN Volume Measurement

FreeSurfer v5.1.0 software (http://surfer.nmr.mgh.harvard.edu) [32] was used for subcortical volume segmentation. Preprocessing consisted of the following steps: (1) removal of nonbrain tissues, (2) automatic Talairach conversion, 3) separation of white and gray matter volumes, (4) signal normalization and registration to outline gray/white matter boundaries, (6) automatic topologic correction, (7) surface deformation, and (8) registration of the subject’s brain to a standard template. All of the steps were performed in FreeSurfer and manually adjusted as necessary. The STN was identified based on the DBS Intrinsic Template Atlas [33] (http://www.lead-dbs.org/). The mask of the bilateral STN standard space was extracted from the automated anatomic atlas template and binarized. Individual T1W images were registered into the standard space MNI152 template to obtain a registered parameter matrix. The resultant matrix was then inverted from the standard into the individual space to obtain the transformation parameters. The STN in the standard space was transformed accordingly into the individual space, and the voxel number was calculated and used to calculate the volume of each STN. Intracranial volume (ICV) was determined in the same manner and used as a covariate in STN volume comparisons. A general linear model was used to analyze bilateral STN volumes, with the group as a fixed factor, ICV as a covariate, and bilateral STN volumes as a dependent variable.


### 2.4. Statistical Analysis

Data were analyzed using SPSS v20.0 software (IBM, Armonk, NY, USA). Bilateral STN volumes were compared between patients and controls with the 2-tailedt test at a significance level of p<0.025 ([0.05/2]). Pearson correlation analysis was performed to evaluate the relationship between bilateral STN volumes and UPDRS III or 39-item Parkinson’s Disease Questionnaire (PDQ-39) score. Bonferroni correction (p<0.025, [0.05/2]) was applied to multiple comparisons in the correlation analysis.


### 2.5. Postoperative DBS Programming

For all patients, interventions were programmed 1 month after the operation by a neurologist experienced in movement disorders. Monopolar stimulation was used for programming at each contact under the state of drug withdrawal. Initial stimulus parameters were a pulse width of 60μs and frequency of 130 Hz. All DBS electrodes in the ventral to dorsal direction were first tested with a voltage of 2.5 V. The motor function was evaluated based on the postoperative UPDRS III score. Stimulus parameters were then modified for each patient according to the medication and fluctuation of symptoms. The optimal stimulation site was programmed with the lowest threshold for symptom reduction and highest threshold for side effects. All patients were evaluated with clinical scales 6 months after the operation.


## 2.1. Subjects

This study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University. A total of 200 patients with clinically confirmed primary PD were recruited between April 2016 and November 2017. Written consent was obtained from each patient prior to their participation in the study. All patients were evaluated for nonmotor symptoms and with the Geriatric Depression Scale, Beck self-rating form, rapid eye movement sleep behavior disorder self-rating form, sleepiness scale, 39-item Parkinson’s Disease Questionnaire scale, end-of-agent questionnaire, dyskinesia questionnaire, new frozen gait questionnaire, Mini-mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Hamilton Anxiety Scale, and Hamilton Depression Scale (HAMD). According to the 2012 China DBS expert consensus, 2 neurologists with 15 and 10 years of experience collected patient information and assessed disease course, levodopa response, and comorbidities. The preoperative inclusion criteria were as follows [30, 31]. (1) The patient met the United Kingdom Parkinson’s Disease Society brain bank or Chinese diagnostic criteria for primary PD, had hereditary or one of the many genotypes of PD, and showed good response to levodopa. (2) The patient had PD for >5 years, with tremor as the main symptom that was not alleviated by standard drug treatment and seriously affected the patient’s quality of life; if the patient strongly requested symptom alleviation through early surgery, the postoperative evaluation was extended to 3 years. (3) The patient was ≤75 years old; for older patients with severe tremor, the age limit was appropriately extended. (4) The patient responded to levodopa but the symptoms were not completely abolished, and quality of life remained low, or the patient was intolerant to the drug. (5) Disease severity was determined as a Hoehn and Yahr (HY) scale score of 2.5–4 in the “off” period of the drug (i.e., med-off). (6) Patients were not suitable for surgery because of the following conditions: severe cognitive dysfunction that could affect activities of daily living, severe refractory depression, anxiety, or schizophrenia, or other illnesses that could affect surgery or survival. Based on these criteria, 62 patients were included in the study and underwent DBS surgery. None of the patients had contraindications for MRI examination. However, because of head motion artifacts and incomplete MRI measurements, data for 3 patients were excluded (Figure 1).Figure 1
Flow chat of patient selection. 200 patients, clinically confirmed with primary PD, were recruited, and 141 patients were excluded due to different reasons including treatment with medication, PD history less than five years, 1-2 HY stage, head motion artifacts, or incomplete MRI data.Ultimately, 59 PD patients (33 males and 26 females, mean age:65.72±7.53 years, age range: 43–77 years) were included in the study. Each patient underwent pre- and postoperative assessment with the Unified Parkinson’s Disease Rating Scale (UPDRS) III and HY staging. The HY stage of the 59 patients was between 2.5 and 5. Preoperative med-on and med-off UPDRS III scores, postoperative med-on/DBS-on, postoperative med-off/DBS-off, and postoperative med-off/DBS-on UPDRS III scores were assessed. The control group comprised 50 healthy volunteers (23 males, 27 females, mean age: 59.84±7.14 years). There were no significant differences in the age or sex ratio between the 2 groups. All study participants were right-handed.


## 2.2. MRI Examination

A 3.0 T whole-body scanner (750w; GE Healthcare, Cleveland, OH, USA) with a standard birdcage head transmitter and receiver coil was used for MRI. All subjects were scanned in the supine position. A foam material was placed on both sides of the subject’s head to prevent head movement. The scan consisted of a high-resolution 3-dimensional T1-weighted (T1W) gradient echo-based sequence with the following parameters:repetitiontime=7.0ms, echotime=3.0ms, flipangle=12°, fieldofview=256×256mm2, matrixsize=256×256, slicethickness=1mm, and numberofslices=192; the scanning time was 4 min 15 s.


## 2.3. STN Volume Measurement

FreeSurfer v5.1.0 software (http://surfer.nmr.mgh.harvard.edu) [32] was used for subcortical volume segmentation. Preprocessing consisted of the following steps: (1) removal of nonbrain tissues, (2) automatic Talairach conversion, 3) separation of white and gray matter volumes, (4) signal normalization and registration to outline gray/white matter boundaries, (6) automatic topologic correction, (7) surface deformation, and (8) registration of the subject’s brain to a standard template. All of the steps were performed in FreeSurfer and manually adjusted as necessary. The STN was identified based on the DBS Intrinsic Template Atlas [33] (http://www.lead-dbs.org/). The mask of the bilateral STN standard space was extracted from the automated anatomic atlas template and binarized. Individual T1W images were registered into the standard space MNI152 template to obtain a registered parameter matrix. The resultant matrix was then inverted from the standard into the individual space to obtain the transformation parameters. The STN in the standard space was transformed accordingly into the individual space, and the voxel number was calculated and used to calculate the volume of each STN. Intracranial volume (ICV) was determined in the same manner and used as a covariate in STN volume comparisons. A general linear model was used to analyze bilateral STN volumes, with the group as a fixed factor, ICV as a covariate, and bilateral STN volumes as a dependent variable.


## 2.4. Statistical Analysis

Data were analyzed using SPSS v20.0 software (IBM, Armonk, NY, USA). Bilateral STN volumes were compared between patients and controls with the 2-tailedt test at a significance level of p<0.025 ([0.05/2]). Pearson correlation analysis was performed to evaluate the relationship between bilateral STN volumes and UPDRS III or 39-item Parkinson’s Disease Questionnaire (PDQ-39) score. Bonferroni correction (p<0.025, [0.05/2]) was applied to multiple comparisons in the correlation analysis.


## 2.5. Postoperative DBS Programming

For all patients, interventions were programmed 1 month after the operation by a neurologist experienced in movement disorders. Monopolar stimulation was used for programming at each contact under the state of drug withdrawal. Initial stimulus parameters were a pulse width of 60μs and frequency of 130 Hz. All DBS electrodes in the ventral to dorsal direction were first tested with a voltage of 2.5 V. The motor function was evaluated based on the postoperative UPDRS III score. Stimulus parameters were then modified for each patient according to the medication and fluctuation of symptoms. The optimal stimulation site was programmed with the lowest threshold for symptom reduction and highest threshold for side effects. All patients were evaluated with clinical scales 6 months after the operation.


## 3. Results

### 3.1. Clinical Information of the Subjects

Of the 59 patients, electrodes were implanted into bilateral STN in 57 patients and in bilateral internal globus pallidus (GPi) in 2 patients (Table1). The history of PD in the patients ranged from 1 to 23 years, with a mean duration of 8.16±4.32 years. In 15 patients, tremors first manifested in the left limb and gradually spread to the right limb, while in 44 patients, the pattern was reversed. All patients underwent follow-up assessment with clinical scales at 6 months postsurgery.Table 1
Clinical information of PD patients and control subjects.
PDControlTest statisticp valueAge, years (mean±SD)65.72±7.5359.84±7.140.0260.872Sex1.9360.586Male3323Female2627Disease duration, years≥ 1019—5–1022—≤ 518—Onset (affected area)Left limb15—Right limb44—Electrode implantationBilateral STN57—Bilateral GPi2—GPi: internal globus pallidus; PD: Parkinson’s disease; SD: standard deviation; STN: subthalamic nucleus.


### 3.2. Comparison of STN Volumes between PD Patients and Control Subjects

PD patients had a smaller left STN volume than control subjects (70.757±10.448 vs 73.162±9.883 mm3; F=5.624, p=0.02 with Bonferroni correction), but a comparable right STN volume (46.448±9.358 vs 46.041±6.636 mm3; F=0.007, p=0.932) (Figure 2). There was no significant difference in ICV between PD patients and controls (1388.1±164.9 vs 1323.9±156.6 cm3; p>0.05).Figure 2
STN volumes in PD patients and controls. The Left STN volume was significantly lower in PD patients than in control subjects. The error bars representmean±standarddeviation.


### 3.3. Correlation between STN Volume/ICV and Disease Duration

We performed a correlation analysis between the STN volume or ICV and duration of PD. Neither STN volume nor ICV was correlated with disease duration (p>0.05).


### 3.4. Correlation between STN Volume and Pre-/Postoperative Clinical Scores

The correlation between the STN volume and pre- or postoperative clinical measures was also evaluated. In the preoperative assessment, the left STN volume was negatively correlated with quality of life score (r=−0.532, p=0.009) and positively correlated with the MMSE and MoCA scores (r=0.665 and 0.695, respectively; p<0.05) in PD patients. Moreover, ICV was positively correlated with the MMSE score (r=0.443, p=0.030). No significant correlations were observed between the left or right STN volume or ICV and med-on/med-off UPDRS III scores (all p>0.05; Figure 3).Figure 3
Correlation analysis between the STN volume and preoperative clinical measures in PD patients. The left STN volume was negatively correlated with preoperative PDQ-39 (a) and positively correlated with MMSE (b) and MoCA (c) scores. ICV was positively correlated with the MMSE score (d).
(a)(b)(c)(d)In the postoperative assessment, the left STN volume was negatively correlated with quality of life score (r=−0.480, p=0.028) and HAMD score (r=−0.570, p=0.021); the right STN volume was also negatively correlated with the HAMD score (r=−0.534, p=0.033) (Figure 4). There was no significant correlation between the left or right STN volume, ICV, and med-on/DBS-on, med-off/DBS-on, or med-off/DBS-off UPDRS III scores (all p>0.05).Figure 4
Correlation analysis between the STN volume and postoperative clinical measures in PD patients. The left STN (L-STN) volume was negatively correlated with postoperative PDQ-39 (a) and HAMD (b) scores, and the right STN (R-STN) volume was negatively correlated with the HAMD score (c).
(a)(b)(c)


## 3.1. Clinical Information of the Subjects

Of the 59 patients, electrodes were implanted into bilateral STN in 57 patients and in bilateral internal globus pallidus (GPi) in 2 patients (Table1). The history of PD in the patients ranged from 1 to 23 years, with a mean duration of 8.16±4.32 years. In 15 patients, tremors first manifested in the left limb and gradually spread to the right limb, while in 44 patients, the pattern was reversed. All patients underwent follow-up assessment with clinical scales at 6 months postsurgery.Table 1
Clinical information of PD patients and control subjects.
PDControlTest statisticp valueAge, years (mean±SD)65.72±7.5359.84±7.140.0260.872Sex1.9360.586Male3323Female2627Disease duration, years≥ 1019—5–1022—≤ 518—Onset (affected area)Left limb15—Right limb44—Electrode implantationBilateral STN57—Bilateral GPi2—GPi: internal globus pallidus; PD: Parkinson’s disease; SD: standard deviation; STN: subthalamic nucleus.


## 3.2. Comparison of STN Volumes between PD Patients and Control Subjects

PD patients had a smaller left STN volume than control subjects (70.757±10.448 vs 73.162±9.883 mm3; F=5.624, p=0.02 with Bonferroni correction), but a comparable right STN volume (46.448±9.358 vs 46.041±6.636 mm3; F=0.007, p=0.932) (Figure 2). There was no significant difference in ICV between PD patients and controls (1388.1±164.9 vs 1323.9±156.6 cm3; p>0.05).Figure 2
STN volumes in PD patients and controls. The Left STN volume was significantly lower in PD patients than in control subjects. The error bars representmean±standarddeviation.


## 3.3. Correlation between STN Volume/ICV and Disease Duration

We performed a correlation analysis between the STN volume or ICV and duration of PD. Neither STN volume nor ICV was correlated with disease duration (p>0.05).


## 3.4. Correlation between STN Volume and Pre-/Postoperative Clinical Scores

The correlation between the STN volume and pre- or postoperative clinical measures was also evaluated. In the preoperative assessment, the left STN volume was negatively correlated with quality of life score (r=−0.532, p=0.009) and positively correlated with the MMSE and MoCA scores (r=0.665 and 0.695, respectively; p<0.05) in PD patients. Moreover, ICV was positively correlated with the MMSE score (r=0.443, p=0.030). No significant correlations were observed between the left or right STN volume or ICV and med-on/med-off UPDRS III scores (all p>0.05; Figure 3).Figure 3
Correlation analysis between the STN volume and preoperative clinical measures in PD patients. The left STN volume was negatively correlated with preoperative PDQ-39 (a) and positively correlated with MMSE (b) and MoCA (c) scores. ICV was positively correlated with the MMSE score (d).
(a)(b)(c)(d)In the postoperative assessment, the left STN volume was negatively correlated with quality of life score (r=−0.480, p=0.028) and HAMD score (r=−0.570, p=0.021); the right STN volume was also negatively correlated with the HAMD score (r=−0.534, p=0.033) (Figure 4). There was no significant correlation between the left or right STN volume, ICV, and med-on/DBS-on, med-off/DBS-on, or med-off/DBS-off UPDRS III scores (all p>0.05).Figure 4
Correlation analysis between the STN volume and postoperative clinical measures in PD patients. The left STN (L-STN) volume was negatively correlated with postoperative PDQ-39 (a) and HAMD (b) scores, and the right STN (R-STN) volume was negatively correlated with the HAMD score (c).
(a)(b)(c)


## 4. Discussion

This study investigated the relationship between the STN volume and duration of PD and pre-/postoperative clinical measures in order to evaluate the clinical utility of MRI findings in PD patients. We found that the left STN volume was reduced in PD patients, and that the STN volume was negatively correlated with pre- and postoperative quality of life scores. The left STN volume of PD patients in our study was70.757±10.448 mm3. A previous study found no statistically significant difference between males and females in terms of the size of the STN, which was determined from length and width measurements [34]; meanwhile, another reported an STN volume of about 150 mm3 that was calculated from front-to-back, inside-to-outside, and ventral-to-dorsal distances to the anterior-posterior commissure line [35]. As the STN has a double-lens shape, we think that its volume cannot be accurately determined by applying a geometric algorithm. Additionally, differences in left and right STN volumes have not been previously reported. In the present study, we separately measured left and right STN volumes as well as the whole brain volume and examined their correlations with clinical measures of PD. The lower left STN volume in PD patients compared to controls may be explained by the fact that77.9% of our patients (46/59) had disease onset in the right limb, with progressive left limb involvement; moreover, most patients exhibited more severe right limb symptoms.PD motor symptoms typically manifest on one side of the body and gradually spread to the opposite side, with asymmetric symptom presentation over the course of the disease. Damage to subnuclei of the SN pars compacta is the most important hallmark of PD and leads to dopamine deficiency in the striatum. The loss of dopaminergic input into the striatum results in changes in basal ganglia circuitry; for example, direct inhibitory input to the GPi—the main output nucleus—is decreased while indirect excitatory input is increased, resulting in an overall reduction in thalamic activity and attenuation of cortical excitability. Histopathologic studies have shown that 50%–70% of SN neurons have undergone apoptosis by the time motor symptoms appear. Asymmetric loss of dopaminergic neurons in bilateral SN may explain the symptom asymmetry [5, 36]. Over half of PD patients show obvious differences in UPDRS III scores between the left and right limbs. Studies using fluorine-18-labeled fluorodopa (18F-dopa) positron emission tomography and single-photon emission computed tomography have demonstrated that uptake of the tracer was decreased in the striatum corresponding to the side of the body more severely affected by PD symptoms [37]. A pathologic analysis of 21 cases of PD asymmetry found that neurodegeneration in the SN occurred asymmetrically, with greater neuronal loss on the side contralateral to the initially affected side [36]. It has been suggested that the reduced duration of levodopa response in PD patients with dyskinesia is attributable to decreases in the number of nigrostriatal dopaminergic neuron terminals and in the dopamine storage capacity of the striatum, specifically on the contralateral side. As most patients in our study had right-limb symptom onset, we speculate that there was greater loss of neurons and decreased dopamine storage capacity in the SN and STN on the left side, with a corresponding reduction in the left STN volume [24].The left STN volume in PD patients was also negatively correlated with pre-/postoperative PDQ-39 scores. The STN is an important structure in the surgical treatment of PD [15, 16]; both the STN and GPi are part of a neural network that includes the frontal striatum and cortical (motor cortex) and subcortical (basal ganglia/thalamus) regions and are part of the indirect and direct pathways, respectively, through the basal ganglia. Stimulation of both regions has been shown to improve PD symptoms [38, 39]. We found that increased neurodegeneration in the left STN of PD patients—as reflected by lower left STN volume—was associated with lower pre- and postoperative quality of life and higher neurocognitive assessment scores. Thus, with progressive disease, patients experienced a decline in life quality and corresponding increase in symptoms of depression; postoperatively, neuropsychological symptoms improved while no change was observed in patient’s quality of life.There were some limitations to this study. Firstly, we did not perform manual segmentation in calculating STN volume from T2W images. In future studies, high-resolution MR images will be acquired for a thinner STN layer (<2 mm), and the accuracy of automatic vs manual segmentation of STN measurements will be compared. Secondly, as each patient had undergone DBS surgery, the HY stage was relatively high in our cohort, and the patients were in the mid-to-late stage of disease; therefore, we did not examine the correlation between HY stage and STN volume.


## 5. Conclusions

In conclusion, the results of this study demonstrate that the left STN volume was reduced in PD patients compared to healthy control subjects. Moreover, the STN volume was negatively correlated with pre- and postoperative PDQ-39 scores. These results indicate that the STN volume is closely associated with the clinical status of PD patients and can serve as a biomarker for evaluating clinical outcome following DBS surgery.



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