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Iron Spatial Distributions in Deep Gray Nuclei are Related to Motor Outcomes of Subthalamic Nuclei Deep Brain Stimulation for Parkinson's Disease

Weiwei Zhao¹, Xi Wu², Chunhui Yang², Luguang Chen³, Yiqing Qiu², Chao Ma³, Gaiying Li¹, Yang Song⁴, Yi Wang⁵, and Jianqi Li¹
¹East Chian Normal University, Shanghai, China, ²Department of Neurosurgery, Changhai Hospital, Shanghai, China, ³Department of Radiology, Changhai Hospital, Shanghai, China, ⁴MR Scientific Marketing, Siemens Healthineers, Shanghai, China, ⁵Department of Radiology, Weill Medical College of Cornell University, New York, NY, United States

Synopsis

The objective of this study was to investigate the relationship between motor outcomes of subthalamic nuclei deep brain stimulation (STN-DBS) and spatial distribution of iron in the deep gray nuclei for patients with Parkinson's disease (PD). The first and second texture parameters were obtained from the preoperative QSM of 40 PD patients. Significant correlations were found between motor improvement after DBS and QSM texture parameters in substantia nigra (SN) and dentate nucleus (DN). Linear regression showed that second-order texture parameter angular second moment in SN (r = -0.449, p = 0.004) had the highest correlation with the STN-DBS motor outcomes.

Introduction

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor deficits in patients with advanced Parkinson's disease (PD), but improvement outcome varies across individuals ^1,2. The clinical predictors of the DBS motor outcome such as the levodopa challenge test, though have been extensively described, are still debated ³. Therefore, objective and unbiased predictive factors for DBS candidate selection are much desired in the pre-surgical process ^4–6. The iron deposition has been implicated in the pathogenesis of PD and resulted in spatial heterogeneous microstructural changes in deep gray matter in PD ⁷. Quantitative susceptibility mapping (QSM) and texture analysis can capture this difference ^8–11. In this study, we investigated whether the spatial distribution of iron in the substantia nigra (SN), subthalamic nucleus (STN) and dentate nucleus (DN) from preoperative QSM is useful for selecting PD candidates for STN-DBS.

Materials and Methods

This study was approved by the local ethical committee and all participants signed an Informed Consent form. Forty PD patients with a mean age of 63.30±7.45 years old (22 males and 18 females) were recruited in this study. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) ¹² scores were first assessed in the off-medication (med_OFF) and on-medication (med_ON) states 1 month before surgery. Postoperative MDS-UPDRS III scores were also obtained in the on-stimulation& off-medication (DBS_ON&med_OFF) state at 6-months follow-up. Motor improvements after DBS were calculated according to the formula:
$$Improvment_DBS(%)=(pre_op med_OFF - post_op DBS_ON&med_OFF)/(pre_op med_OFF )
All subjects were scanned on a clinical 3T MRI scanner (GE Signa HDxt) equipped with a 20-channel head coil. Susceptibility maps were generated from a 3D spoiled bipolar-readout multi-echo GRE sequence with the following parameters: TR = 28 ms, TE1 = 4.2 ms, ΔTE = 3.96 ms, number of echoes = 6, flip angle = 12˚, FOV = 240 × 240 mm², matrix size = 256 × 256, slice thickness = 0.9 mm, number of slices = 160, parallel imaging acceleration factor = 2, voxel size = 0.90 × 0.90 × 0.90 mm³.
QSM images were reconstructed using the Morphology Enabled Dipole Inversion with automatic uniform cerebrospinal fluid zero reference (MEDI+0) algorithm ¹³. Regions of interest (ROIs), including the bilateral SN, STN, and DN were drawn manually on the QSM images using ITK-SNAP (http://www.itk-snap.org). 3D first- and second-order texture analyses of the segmented ROIs were conducted using MaZda software (http://www.eletel.p.lodz.pl/programy/mazda/, Lodz, Poland). The first-order texture parameter was the mean susceptibility value. Second-order texture parameters included angular second moment (AngScMom), contrast, correlation, difference of variance (DifVarnc), inverse different moment (InvDfMom), entropy, sum of entropy (SumEntrp), difference of entropy (DifEntrp), sum of average (SumAverg), sum of variance (SumVarnc), and sum of squares (SumOfSqs).
Correlations between the motor improvement ratio and features of pre-operative susceptibility maps were assessed using Pearson and Spearman’s correlation coefficients (according to statistical distribution). All p-values reported are two-tailed and the adjusted p-values less than 0.05 were chosen to designate significant correlations. All statistical analyses were carried out using IBM SPSS Statistics 22.

Results

Significant correlations were found between total motor improvement ratio and texture parameters of deep grey matter nuclei (Fig. 1). The DBS outcome was significantly correlated with the AngScMom (r = -0.449, p = 0.004), Correlation (r = 0.326, p = 0.040), SumOfSqs (r = 0.402, p = 0.010), SumEntrp (r = 0.421, p = 0.007) and Entropy (r= 0.410, p = 0.009) of the SN (Fig. 2). In the DN, the mean susceptibility value was significantly negatively correlated with DBS response (r= -0.400, p = 0.012) (Fig. 3). No significant correlations were found between motor improvement outcome and the other texture parameters in the SN, STN and DN (p > 0.5).

Discussion

In this study, multiple second-order texture parameters of susceptibility maps within the SN were associated with the clinical motor improvement of STN-DBS in patients with PD. Interestingly, patients with a more homogeneous iron distribution throughout the SN as characterized by AngScMom responded worse to DBS treatment. A more homogeneous iron distribution may reflect clinically more severe motor impairment, which was agreed with a recent study ¹⁴. Iron induces oxidative damage through the production of reactive oxygen species and orchestrates “ferroptosis” ¹⁵, a recently identified form of iron-mediated cell death, and ferroptosis has been identified in PD patients ¹⁶. Uniform neurodegeneration associated with homogeneous iron distribution in SN seems to impede DBS outcome. Possible residual neurons associated with inhomogeneous iron distribution in SN seem to improve DBS outcome.
Motor improvement was negatively correlated with the mean susceptibility value in DN. This finding could be explained by that alterations in iron concentration in the DN were correlated with tremor severity in PD and may interrupt normal cerebello-thalamo-cortical (CTC) function ^17–19 and thus responded worse to DBS treatment.

Conclusions

In summary, texture features in preoperative susceptibility maps of SN and DN correlate with the motor outcomes of DBS in PD patients. These results provide a new insight into predictive biomarkers of DBS response: iron disposition spatial heterogeneity on QSM may predict the variability of DBS motor improvements and be useful for presurgical patient selection.

Acknowledgements

No acknowledgement found.

References

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Figures

Fig. 1. Heatmap representation of correlation coefficients between pre-operative QSM texture parameters and the improvement of total motor scores after DBS-STN.

Fig. 2. Scatter plots and regression lines show the relationship between texture parameters in SN and motor improvement in PD patients. The shaded region in each plot shows the 95% confidence interval. The P-value threshold was adjusted based on false discovery rate (FDR) correction.

Fig. 3. The scatter plot and regression line show the relationship between susceptibility values in DN and motor improvement in PD patients. The shaded region in the plot shows the 95% confidence interval. The P-value threshold was adjusted based on false discovery rate (FDR) correction.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)

3057

DOI: https://doi.org/10.58530/2022/3057