Multi-scale investigation of the zona incerta subregions in Parkinson's Disease

300 

Abstract Submission 

Violet Liu¹, Ali Khan², Jonathan Lau³

¹Western Univeristy, London, MT, ²University of Western Ontario, London, Ontario, ³Department of Clinical Neurological Sciences, Division of Neurosurgery, London, ON

Violet Liu  
Western Univeristy
London, MT

Ali Khan  
University of Western Ontario
London, Ontario

Jonathan Lau  
Department of Clinical Neurological Sciences, Division of Neurosurgery
London, ON

Parkinson's Disease (PD) is the second most prevalent neurodegenerative disorder worldwide1. Deep brain stimulation (DBS), a neurosurgical procedure that delivers electric pulses to specific brain regions, demonstrates long-term success in alleviating tremors in PD, especially when targeting a subcortical region named the zona incerta (ZI)2. However, the mechanisms behind this therapeutic effect remain elusive.
Recent rodent research identifies a rostromedial ZI subregion, named the A13, that is uniquely enriched in dopaminergic neurons with connections to the nigrostriatal pathway3,4. Interestingly, this dopaminergic connectivity is preserved, yet undergoes re-configuration in animal PD models post-nigrostriatal degeneration3,5. Notably, inputs from the limbic and cortical regions are significantly downregulated, potentially contributing to the emotional processing deficit in PD3,5. Activation of the A13 dopaminergic neurons is also involved in nociceptive signaling, implicating this structure in PD-related chronic pain6,7. However, the A13 has not been identified in humans, impeding translation to clinical applications.
To address this challenge, we aim to identify the A13 region using 3T and 7T MRI, and investigate the transcriptomic changes in this subregion between healthy control and PD patients. By integrating multiscale information to characterize this structure, our findings on the A13 may provide clues to the underlying mechanisms in PD, and provide future therapeutic targets for symptom control in the clinical setting.

We enrolled a cohort of healthy individuals (n=41, age 20-70) and PD patients (n = 46, age 51 - 73) for 3T and 7T MR imaging, and leveraged publicly available microarray from the Allen Human Brain Atlas (AHBA, n=68). We previously established the ability to directly visualize the ZI in vivo in humans8, and now further expand on this pipeline to identify the A13 subregion in T1-map and quantitative susceptibility mapping (QSM) MR data in MNI space. Using QSM, an established technique sensitive to tissue iron deposits, and T1-map, sensitive to progressive neuronal changes in PD patients9,10, we will identify changes in MR characteristics, such as T1-score, susceptibility score, and volumetric changes, between healthy participants and PD patients, and establish spatial correspondence between MRI with transcriptomics. The microarray from AHBA is preprocessed using the Abagen toolbox to produce a sample x gene matrix, with each sample representing an MNI coordinate. Principal component analysis (PCA) is performed followed by K-mean clustering to identify regional subclusters in Python. Optimal number of clusters was identified using WCSS and the elbow method. Gene set enrichment analyses are performed using ClusterProfile in R-studio to dissect the functional and biological relevance of clusters and examine molecular networks within the ZI.

We have averaged and registered T1-map and quantitative susceptibility mapping (QSM) MR images from native to MNI space. Using the microarray data, PCA analysis (21 principal components, with a total of 81% variance explained) and K-mean clustering show 3 distinctive clusters along the rostral-caudal axis in the human ZI, corresponding to the caudal, rostral, and rostromedial regions. These clusters are enriched with significantly different cell type signatures, underscoring a unique organization within the ZI.

Understanding the molecular and MR characteristics of ZI in healthy and diseased states represents a crucial step in unlocking its full therapeutic potential. Our findings show distinctive molecular and cellular profiles within the ZI, providing clues to identifying the A13 region in humans. A more in-depth understanding of the A13 subregion will provide opportunities to impact treatment, enhance accurate targeting in a clinical context, and ultimately improve patient outcomes.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Transcriptomics

Image Registration and Computational Anatomy ²

Subcortical Structures

Neurophysiology of Imaging Signals

Cellular

CHEMOARCHITECTURE

Computational Neuroscience

Degenerative Disease

Movement Disorder

Neurotransmitter

Segmentation

STRUCTURAL MRI

Sub-Cortical

Other - Bioinformatics