Functional connectivity between red nucleus and putamen predicts clinlcal response of STN-DBS

doi:10.21203/rs.3.rs-2241108/v1

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Functional connectivity between red nucleus and putamen predicts clinlcal response of STN-DBS

https://doi.org/10.21203/rs.3.rs-2241108/v1

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Background:While deep brain stimulation (DBS) of subthalamic nucleus (STN) is proved effective in managing motor symptoms of Parkinson's disease, it has substantial individulized variability of clinlcal responses. Prediction of treatment outcomes is therefore beneficial for surgical planning. This study aims to examine the capability of preoperative resting state brain connectivity as a potential tool to predict the clinlcal response of STN-DBS.

Method: We collected the preoperative resting state functional Magnetic Resonance Imaging (MRI) of 41 participants who received DBS in the STN. The subcortical connectivity networks were estimated and correlated with postoperative exercise results. Linear regression was further used to predict the surgical improvements.

Results: Functional Connectivity (FC) between subcortical nuclei of interest and DBS response showed that FC from bilateral red nuclei to putamen was related to the overall changes of UPDRS-III (left: r = -0.44 p = 0.0056, right r = -0.46 p = 0.0029, p < 0.05 after FDR correction). Additionally, FC can predict the changes of UPDRS III at 1 year after DBS (r = 0.5 p = 0.0011 error rate = 0.175 ).

Cloclusions: The increased connectivity of the red nuclei in patients with Parkinson's disease may be a compensatory response to central nervous system damage. Functional MRI studies support the long-standing view that relatively intact cerebellar circuits can compensate for impaired basal ganglia function. Neuroplasticity is an adaptive mechanism that compensates for loss of function or maximizes residual function, leading to changes in brain function and morphology. This compensatory brain plasticity may be the reason why DBS improves the motor symptoms of Parkinson's disease.

Parkinson’s Diease

fMRI

Deep Brain Stimulation

Red Nucleus

Parkinson's disease(PD) is one of the most common neurodegenerative diseases characterized by resting tremor, rigidity, bradykinesia, and a spectrum of non-motor symptoms, and it affects increasing number of subjects as the worldwide population aging [1]. Dopaminergic medication such as levodopa (L-dopa), is the mainstay of symptomatic treatment of PD. However, it is complicated by movement fluctuations and dyskinesias, especially after years of treatment [2]. As an alternative surgical therapy, Deep Brain Stimulation (DBS) was introduced and has achieved great successes in managing motor symptoms. In the past 20 years, the subthalamic nucleus (STN) has become the most commonly used target for DBS [3–5]. STN-DBS has been proved to effectively restore motor function, reduce levodopa dosage and motor complications, and significantly improve the quality of life of patients with PD [6]. Despite its popularity, the physiological mechanism leading to the effectiveness of STN-DBS remains to be clarified. Additionally, inconsistent theraputical effects with substantial variability in behavior have been observed, making it important to predict the individualized clinical response before surgery [7–11].

The mechanisms underlying STN-DBS and the evaluation of its efficacy have been actively investigated over the years, ranging from the stimulation effect of local specific regions to the global changes of distributed brain networks [12–15]. In terms of local effects, STN-DBS may involve modulating brain activity in target and subcortical areas.

Alternatively, increasing attention has been recently paid on examining the changes on brain connectivity networks, and a number of prior studies have reported the altered connectivity patterns associated with STN-DBS. For instance, Younce et al. used data of two cohorts to verify the roles of functional connectivity for predicting the surgical effects of DBS [11]. In another study, the authors reported that the brain functional connection between the stimulated local area and the motor cortex is critical for estimating the outcomes of DBS surgery [16]. Such investigations gain additional insights on the evaluation of the DBS effects and may provide sensitive biomarkers for predicting the DBS outcomes.

However, how STN-DBS regulates brain connectivity on PD is far from reaching the concensus, which requires additional effort on further investigation. Resting state functional magnetic resonance imaging (rs-fMRI) is the commonly used technique for studying the brain connectivity networks, providing a unique opportunity to determine the effects of DBS on brain activity in vivo at the system level [17, 18]. Generally, it establishes the connectivity network by estimating the pairwise correlations between distant brain regions [19]. The changes of functional connection between the putamen and the midbrain cortex have been widely observed as a key phenomenon in occurrence of motor symptoms of Parkinson's disease [15, 20–22]. For instance, a number of studies have shown that the connectivity between the putamen and the auxiliary motor areas, thalamus and cerebellum are changed in PD [23, 24]. Therefore, we chose putamen as a seed point to analyze the potential compensatory mechanism of DBS activation for the improvement of motor symptoms in Parkinson's disease patients.

In this paper, we explore the functional connectivity patterns associated with efficacy of STN-DBS using rs-fMRI, aiming to identify the connections that are most relevant to the clinical responses of PD and explain the potential bmechanism of STN-DBS therapy from the perspective of the putaminal connectivity.

Subjects

In this study, 41 patients with advanced Parkinson's disease (Hoehn-Yahr stage Ⅲ ~ IV, age 58.6 ±7.99 years, duration of disease 8.95 ±3.78 years) were enrolled. The selection criteria included more than 5 years of diagnosis of PD, eligibility for DBS surgery, and no taboos in MRI. All patients were treated with STN-DBS surgery. The details of the subjects' demographic and clinical characteristics are shown in Table 1. All patients were given informed written consent before participating the experiment and the study was approved by the local ethics board.

Table 1

Relevant values are reported as mean ± standard deviation. OFF-medication was defined as the practically defined OFF state with overnight medication withdrawal. Post-operative UPDRS-III values are ON-stimulation with bilateral clinical stimulation settings over first year after DBS.

Patient demographics and clinical characteristics
	pre-surgery	1 year follow up	P value
Age（years）	59.02±7.80	-	-
Disease duration(years)	9.10±3.72	-	-
UPDRS III baseline	57.04±12.28	52.31±15.98	0.137
UPDRS III "on" dopamine	29.73±11.12	36.12±19.97	0.056
UPDRS III "on" DBS	-	29.02±12.91	-
H-Y stage	3.57±0.78	3.20±0.53	<0.05
LEDD(mg)	642.68±384.40	467.57±240.85	<0.05
PDQ39	69.08±16.92	48.29±24.47	<0.0001

fMRI experiment

Functional and structural MRI data were acquired with a 3T GE (Achieva TX) MRI scanner on OFF medication state before DBS surgery, following 8-h period of medication withdrawal. Structural images were acquired using a sagittal magnetization prepared rapid gradient echo three-dimensional T1-weighted sequence (repetition time [TR] = 8.5 ms, echo time [TE] = 3.2 ms, inversion time [TI] = 450 ms, flip angle [FA] = 12◦). Functional MRI images were obtained using the following SE-EPI sequence: repetition time = 2,000 ms, echo time = 30 ms, slice thickness/gap = 3.6/0 mm, axial slices = 38 layers, flip angle = 90◦, FOV = 256 × 256 mm, matrix size = 64 × 64, and scanning time = 242s.

DBS surgery

All patients underwent standard frame-based DBS implantation. Two quadrupole DBS electrodes (L301C electrode of Beijing Pins Medical Co., Ltd., China) and a LFP sensing nerve stimulator (G102R, Beijing Pins Medical Co., Ltd.) were received. Accurate electrode placement was confirmed by intraoperative microelectrode recording, intraoperative motor response to stimulation, and postoperative CT. The stimulation was started one month after the operation, and regular return visits were conducted to adjust the stimulation parameters.

Clinical evaluation

Each patient underwent two clinical evaluations: UPDRS-III was measured during the pre-surgical inpatient on and during postoperative DBS programming clinical visits. The preoperative score was collected within 1 week prior to DBS, and the postoperative ON stimulation score was collected 12 months after DBS placement. All UPDRS-III scores were evaluated on OFF medication state, after at least 8 hours of medication withdrawal. At the end of each visit, the ON-stimulation rating was performed after the completion of DBS settings. We calculated the preoperative off-medication and postoperative off-medicine and on-stimulation score changes to determine the effect of DBS. The average score during the entire postoperative period was used to mitigate random fluctuations and to represent the actual performance of each subject after receiving DBS.

Date preprocessing

MRI data were analyzed using Data Processing & Analysis for Brain Imaging open-source package（DPABI V6.0_210501, based on SPM8 and MATLAB）[25]. The standard pre-processing included：(a) Remove the first five volumes to stabilize magnetization；(b) Slice timing correction and realignment to correct the time differences existed in each slice on the same volume；(c) Reorient functional and structural images by manually alignement；(d) Co-register of structural images and functional images, and segment the structural images into gray matter, white matter, and cerebrospinal fluid; (e) Regress nuisance covariates including Friston 24 head motion parameters, white matter, and cerebrospinal ﬂuid signals；(f) Normalize the functional images to Montreal Neurological Institute (MNI) space based on the diffeomorphic anatomical registration by exponentiated lie algebra, and resample the images to 3.0x3.0x3.0 mm; (g) Spatial smoothing using a Gaussian kernel with 6mm FWHM; (h) Temporal filtering to 0.01-0.08Hz.

No participant had a head motion of more than 1.5 mm maximum displacement in any of the x, y, or z directions or 1.5 of any angular motion throughout the course of the scan, and data greater than this threshold were excluded from further analysis.

Brain connectivity estimation

PD25 template with 16 Region of Interests (ROIs) which was specifically defined based on a Parkinson’s disease cohort was used to construct the FC matrix. The average time course of each ROI was calculated, and the functional connection was generated by computing the Pearson’s correlation coefﬁcients between each pair of ROIs. Fisher z-transformation was used to convert r value to z value to increase the normality of correlation distribution. Connectivity between the putamen and other 15 ROIs was chosen for further analysis.

Statistical Analysis

Connectivity between the putamen and other ROIs was correlated with the overall changes in UPDRS-III in order to explore the relationship between preoperative resting-state functional connectivity and postoperative motor improvement. The level of significance was set at p<0.05. The False Discovery Rate (FDR) correction was used for multiple comparison correction. FDR correction was performed using Matlab. Demographic information, such as age at surgery, gender, and disease duration, were not assessed using a t-test, since our data were conducted for the same subject pre-surgery and post-surgery.

To investigate the predictive power of the corrections between FC and overall change in UPDRS-III, Leave-One-Out Cross-Validator (LOOCV) was adopted. Linear regression models were performed with Scikit-learning software using FC and other covariates, which included medication improvement rate and preoperative UPDRS-III. Among them, the improvement value means the difference between preoperative OFF-medication and postoperative OFF-medication and ON-stimulation scores. We also carried out a series of ablation studies on various factors. For example, generate linear models with and without medication improvement rate or baseline UPDRS-III. Mean absolute error was used to evaluate the validity of the linear regression model.

Subjects The demographic and clinical characteristics of all subjects are shown in Table 1. H-Y decreased from 3.57 to 3.20 after operation, and UPDRS-III score decreased significantly from 29.73 to 19.12. As expected, LEDD was decreased significantly as well, from 642.68 ±384.40 to 467.57 ±240.85 (P < 0.05). They demonstrated that DBS surgery significantly alleviated motor symptoms associated with Parkinson's disease while reducing drug doses.

Brain connectivity estimation The Functional Connectivity(FC) matrix between the subcortical ROI nuclei and the DBS response is shown in figure 2A, and the same matrix related to the changes in the UPDRS-III is shown in figure 2B for each FC relationship. FC from the bilateral red nuclei to the putamen correlated with overall changes in UPDRS-III (p < 0.05). It is worth noting that after FDR correction, there is still a significant correlation between the connectivity and the changes of UPDRS-III (r =-0.46, p < 0.05). There was no significant correlation between FC and the decrease of LEDD or the change of UPDRS-IV dyskinesia score after DBS.

Linear regression analysis FC from the bilateral red nucleus to the putamen correlated with the overall changes of UPDRS-III as shown in Figure 4 (left: r= 0.35, p <0.005; right: r= 0.42, p <0.01). When preoperative scale and drug improvement rate were used as covariables, the prediction capability of improvement rate was improved (left:R = -0.60 p <0.001; r= 0.58 p <0.001).

In this paper, we evaluated the resting state putaminal connections with the subcortical nucleus before surgery based on the PD25 template, and investigated their relationship with STN-DBS motor results. One year after DBS surgery, the H-Y score decreased from 3.57 ± 0.78 to 3.20 ± 0.53 (p < 0.05), the levodopa equivalent dose (LEDD) decreased from 642.68 ± 384.40 to 467.57 ± 240.85 (p < 0.05), and PDQ-39 significantly improved from 69.05 ± 16.92 to 48.29 ± 24.47 (p < 0.0001), indicating the efficacy of DBS surgry. Functional Connectivity(FC) between subcortical nuclei of interest and DBS response showed that FC from the bilateral red nuclei to the right putamen was related to the overall changes of UPDRS-III (left: r = -0.44 p = 0.0056, right r = -0.46 p = 0.0029, p < 0.05 after FDR correction). The results demonstrate that FC can predict the changes of UPDRS III at 1 year after DBS surgry (r = 0.5, p = 0.0011, error rate = 0.175 ).

Parkinson's disease is a chronic progressive dyskinesia of the central nervous system. The clinical defects of patients with Parkinson's disease are not only related to structural brain atrophy, but also related to the functional imbalance within and between brain networks [26]. Neuroimaging technology provides a better understanding of the mechanism underlying these functional abnormalities, and different methods have been used to evaluate the changes of BOLD signals in human brain at rest [27]. The most important methods are seed based and network-based approaches. With prior assumptions, seed based methods are usually chosen for imaging analysis with superior computational efficiency. It has been the most commonly used method to investigate striatal connectivity in PD. For instance, Yu et al. reproted that the connectivity between the putamen and Supplementary Motor Area (SMA) was enhanced in patients with Parkinson's disease [28]. In another study, significant decreased correlation between the striatum and thalamus, midbrain, pons and cerebellum in PD was identified [29]. These results indicate the alterations of striatal functional connectivity in PD, which is consistent with our prior knowledge that reduced Dopamine uptake in the putamen of patients with Parkinson's disease is a key factor leading to the main symptoms of Parkinson's disease [1]. The loss of substantia nigra cells in patients with Parkinson's disease leads to dopamine depletion in the striatum and affects the putamen. Additional studies reported that the uptake of 18F dopa in the putamen of patients with Parkinson's disease is related to the clinical severity of dyskinesia [30]. Therefore, in this study, we chose the putamen as the seed region to identify the potential connectome features for DBS surgery prediction. Our results show that the functional connectivity from the bilateral red nuclei to the putamen is negatively correlated with the overall changes of UPDRS-III, which is capable to predict the changes of UPDRS-III at 1 year after DBS.

The red nucleus is located from the dorsomedial tegmentum to the substantia nigra, and is composed of caudal large cells and rostral small cells. They provide efferent nerves for the rubrospinal tract and the central tegmental tract, respectively [31]. These two cell groups also receive inputs from cerebellum and cerebral cortex. Functionally, the red nucleus is considered to be a complement to the main corticospinal tract that controls trunk and limb movements. The red nucleus can not only directly receive motor stimulation from the cortex, but also the cerebellum can transmit signals to the thalamus through the red nucleus. When patients with Parkinson's disease change their behavioral state to perform motor tasks, the interactive connection between the basal ganglia and cerebellum is additionally activated [32]. Anatomical evidence from primates shows that cerebellar fibers project to the striatum in a multisynaptic manner, and the connection from the basal ganglia to the cerebellum is mediated by the red nucleus [33]. PET studies have shown that in order to maintain the integrity of the dopaminergic system, some changes have taken place at the synaptic level. Functional MRI studies support the long-standing view that relatively complete cerebellar circuits can compensate for impaired basal ganglia function. Previous studies have shown that the severity and longer duration of Parkinson's disease are associated with increased red nucleus volume . This volume change can be attributed to the compensatory role of the red nucleus as the intersection of primary and cerebellar motor pathways [34, 35].

The increase of red nucleus connectivity may be a compensatory response to the damage of central nervous system in patients with Parkinson's disease as shown in figure 5. Neuroplasticity is an adaptive mechanism to compensate for loss of function or maximize residual function, which can lead to changes in brain function and morphology. Motor cortex plasticity has been reported in patients with Parkinson's disease [21]. This compensatory brain plasticity may lead to increased functional connectivity of the red nucleus as we noticed.

Our results demonstrate the potential role of the putamnial connections for prediction of the DBS outcome. However, due to the strict quality control applied to the obtained data, a relatively small sample of subjects were included in this study. A larger sample size will be validated in our future study. allow identification. Addtionally, further prospective studies are warrented to determine the feasiblility of these features as indicators to predict the course of Parkinson's disease, and investigate the neuroplasticity of Parkinson's disease and its effect on brain morphology.

Declaration and Competing interests

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.

Ethical Approval

The study was reviewed and approved by Ethics Committee of The First Affiliated Hospital of USTC. The ethical approval code is 2022‐RE‐154.

Authors' contributions

Chen Ni responsible for experiments and article writing draft, Jin Yin involved in data statistical analysis, Chi Xiong for data management and investigation and made an important job, Jiang Manli also has carried on the data management and investigation, Peng Chen and JiaMing Mei is in charge of the patient management, article review made an important contribution to Bowen Chang, Aiping Liu and Chaoshi Niu are co-supervisors of the project and are responsible for the progress of the experiment

Funding

This paper is supported by the Special Fund Project for Guiding Local Science and Technology Development by the Central Government (No: 2019b07030001)

Availability of data and materials

The datasets used or analysed during the current study are available from the corresponding author on reasonable request.

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No competing interests reported.

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Functional connectivity between red nucleus and putamen predicts clinlcal response of STN-DBS

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