Multimodal mapping of the human zona incerta via ultra-high field MRI, histology and transcriptomics
Poster No:
1758
Submission Type:
Abstract Submission
Authors:
Violet Liu1, Marie Tsai2, Bradley Karat1, Wataru Inoue3, Tallulah Andrews4,5, Ali Khan6,7,8, Jonathan Lau6,9,10
Institutions:
1Neuroscience Graduate Program, Western University, London, Ontario, Canada, 2Clinical Anatomy Graduate Program, Western University, London, Ontario, Canada, 3Department of Physiology and Pharmacology, Western University, London, Ontario, Canada, 4Department of Biochemistry, Western Univeristy, London, Ontario, Canada, 5Department of Computer Science, Western University, London, Ontario, Canada, 6Department of Neuroscience, Robarts Research Institute, Western University, London, Ontario, Canada, 7School of Biomedical Engineering, Robarts Research Institute, Western University, London, Ontario, Canada, 8Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada, 9School of Biomedical Engineering, Western University, London, Ontario, Canada, 10Division of Neurosurgery, Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada
First Author:
Co-Author(s):
Wataru Inoue, PhD
Department of Physiology and Pharmacology, Western University
London, Ontario, Canada
Department of Physiology and Pharmacology, Western University
London, Ontario, Canada
Tallulah Andrews, PhD
Department of Biochemistry, Western Univeristy|Department of Computer Science, Western University
London, Ontario, Canada|London, Ontario, Canada
Department of Biochemistry, Western Univeristy|Department of Computer Science, Western University
London, Ontario, Canada|London, Ontario, Canada
Ali Khan
Department of Neuroscience, Robarts Research Institute, Western University|School of Biomedical Engineering, Robarts Research Institute, Western University|Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University
London, Ontario, Canada|London, Ontario, Canada|London, Ontario, Canada
Department of Neuroscience, Robarts Research Institute, Western University|School of Biomedical Engineering, Robarts Research Institute, Western University|Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University
London, Ontario, Canada|London, Ontario, Canada|London, Ontario, Canada
Jonathan Lau
Department of Neuroscience, Robarts Research Institute, Western University|School of Biomedical Engineering, Western University|Division of Neurosurgery, Department of Clinical Neurological Sciences, Western University
London, Ontario, Canada|London, Ontario, Canada|London, Ontario, Canada
Department of Neuroscience, Robarts Research Institute, Western University|School of Biomedical Engineering, Western University|Division of Neurosurgery, Department of Clinical Neurological Sciences, Western University
London, Ontario, Canada|London, Ontario, Canada|London, Ontario, Canada
Introduction:
Subcortical integrative hubs unify neural systems with distinct functions and anatomical features, playing a central role in diverse brain functions (van den Heuvel & Sporns, 2011). The zona incerta (ZI) exemplifies many of these characteristics (Fratzl & Hofer, 2022; Haber et al., 2023), and serves as an effective neuromodulatory target. Stimulation of the caudal ZI alleviates motor symptoms in Parkinson's disease (PD, Fratzl & Hofer, 2022), while its rostral region may serve as a putative target for treating obsessive-compulsive disorder (Haast et al., 2024; Haber et al., 2023). Rodent studies also identify a dopaminergic rostromedial ZI, where stimulation reverses PD-related motor deficits (Kim et al., 2023). These findings support the diversity of therapeutic potential of ZI subregions.
The unclear boundaries of the human ZI and its subregions has posed a challenge for visualization using conventional MRI, hindering clinical translation. To address this, our lab developed a ZI atlas using 7T MRI, that has facilitated accurate visualization (Lau et al., 2020). Building on this work, we aim to:
1) Characterize the rostromedial, rostral, and caudal ZI subregions by integrating transcriptomics and 7T MRI.
2) Refine delineation of the ZI and surrounding regions through histology-derived myeloarchitecture and 15.2T MRI.
The unclear boundaries of the human ZI and its subregions has posed a challenge for visualization using conventional MRI, hindering clinical translation. To address this, our lab developed a ZI atlas using 7T MRI, that has facilitated accurate visualization (Lau et al., 2020). Building on this work, we aim to:
1) Characterize the rostromedial, rostral, and caudal ZI subregions by integrating transcriptomics and 7T MRI.
2) Refine delineation of the ZI and surrounding regions through histology-derived myeloarchitecture and 15.2T MRI.
Methods:
A perfusion-fixed subcortical sample was imaged on a 15.2T MRI using 0.1mm³ T1-FLASH (TE/TR=8/30ms, flip angle=25°, 8 averages) and 0.1mm³ MP2RAGE (TE/TR=4.6/6500ms, flip angle=10°, 3 averages) to calculate the R1-map (Figure 1). The sample was sectioned (50µm) and stained with Luxol Fast Blue/Nissl, with blockface images captured for 3D reconstruction prior to distortion. Sections were aligned to the 3D blockface, registered to the subject and MNI152 space using antsLandmarkBasedTransformInitializer, landmark-based similarity transformation and deformable registration in 3D Slicer (Avants et al., 2014; Pinter et al., 2012). Segmentations were performed in ITK-SNAP (Yushkevich et al., 2006). Microarray data from the Allen Human Brain Atlas (n=6) were registered to MNI152 space (Shen et al., 2012), with dimensionality reduction identifying clusters and Ordinary Kriging interpolating expression. 7T MRI data from 42 healthy participants (aged 20–70) and 46 PD patients (aged 51–73) generated averaged T1-map images (Lau et al., 2020), with non-parametric tests assessing ZI subregion differences.
Results:
We present the first detailed segmentation of the human ZI and surrounding structures obtained using 15.2T MRI, revealing features previously difficult to discern, including boundaries between the STN and ZI, the H fields traversing through the rostral ZI, and small white matter tracts (i.e. fasciculus retroflexus, Figure 2A). Combining 7T MRI and transcriptomics, we identified five distinct clusters along the rostral-caudal axis, including a dopaminergic rostromedial cluster enriched in genes implicated in PD pathogenesis. We generated a transcriptomic-based parcellation of the rostromedial ZI, which is the first of its kind in humans to our knowledge. Additionally, the rostral ZI was significantly enriched in neurogenesis and axon guidance compared to the caudal ZI, suggesting functional specialization (Figure 2B). To illustrate pipeline applications, we compared T1-map values between healthy and PD patients, revealing an elevated rZI:cZI ratio in PD patients, suggesting potential disease-specific alterations (Figure 2C).
Conclusions:
By bridging multimodal data in both healthy and diseased subjects, we provide novel insight into the neuroanatomy of the ZI, characterizing its subregions and boundaries with surrounding structures. This workflow not only advances our understanding of the complex organization of the ZI, but also provides a versatile framework for investigating other subcortical regions and white matter tracts. These findings pave the way for optimizing neuromodulation strategies, holding potential to improve patient outcomes.
Brain Stimulation:
Deep Brain Stimulation
Genetics:
Transcriptomics
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Subcortical Structures 1
Neuroanatomy Other
Neuroinformatics and Data Sharing:
Workflows 2
Keywords:
Data Registration
Degenerative Disease
Myelin
STRUCTURAL MRI
Sub-Cortical
Workflows
Other - Zona Incerta; Integrative Hub; Multimodal; Histology
1|2Indicates the priority used for review
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Provide references using APA citation style.
Fratzl, A., & Hofer, S. B. (2022). The caudal prethalamus: Inhibitory switchboard for behavioral control? Neuron, 110(17), 2728–2742. https://doi.org/10.1016/j.neuron.2022.07.018
Haast, R. A., Kai, J., Taha, A., Liu, V., Gilmore, G., Guye, M., Khan, A. R., & Lau, J. C. (2024). Mapping the topographic organization of the human zona incerta using diffusion MRI (p. 2024.09.05.610266). bioRxiv. https://doi.org/10.1101/2024.09.05.610266
Haber, S. N., Lehman, J., Maffei, C., & Yendiki, A. (2023). The Rostral Zona Incerta: A Subcortical Integrative Hub and Potential Deep Brain Stimulation Target for Obsessive-Compulsive Disorder. Biological Psychiatry, 93(11), 1010–1022. https://doi.org/10.1016/j.biopsych.2023.01.006
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Lau, J. C., Xiao, Y., Haast, R. A. M., Gilmore, G., Uludağ, K., MacDougall, K. W., Menon, R. S., Parrent, A. G., Peters, T. M., & Khan, A. R. (2020). Direct visualization and characterization of the human zona incerta and surrounding structures. Human Brain Mapping, 41(16), 4500–4517. https://doi.org/10.1002/hbm.25137
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