HiDiver – The Future of Neurology

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Abstract

Neurodegenerative diseases and brain cancers, such as Alzheimer’s and Parkinson’s diseases, as well as gliomas and medulloblastomas, present ongoing challenges for global healthcare. Despite therapeutic advancements, prevention remains essential. Brain imaging technology is pivotal in unraveling the intricacies of the human brain and its disorders. This report delves into current brain imaging techniques, including Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), functional MRI (fMRI), and Diffusion Tensor Imaging (DTI), outlining their strengths and limitations in addressing neurodegenerative diseases and brain cancers. Emerging innovations like tau-specific PET tracers hold promise for early detection. The HiDiver project at Duke University introduces a novel fusion of Magnetic Resonance Histology (MRH) and Light Sheet Microscopy (LSM), bolstered by a detailed brain structure reference atlas, to yield precise 3D brain images. This pioneering approach is poised to uncover cellular insights and synaptic dynamics relevant to these conditions, leveraging multimodal imaging and data alignment. HiDiver’s potential in early detection, intervention, and uncharted exploration is emphasized, underscoring its role in advancing disease understanding, prevention, and treatment strategies for neurodegenerative diseases and brain cancers.

Introduction

Neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Amyotrophic lateral sclerosis (ALS), and Parkinson’s disease, alongside nervous system cancers like gliomas, craniopharyngiomas, medulloblastomas, and meningiomas, continue to impose significant burdens on global healthcare systems and the affected individuals. Despite notable advancements in treating these afflictions, encompassing approaches such as microglial targeting for progressive diseases and immunotherapy1 for mitigating brain tumors, the primary strategy for combatting these conditions remains rooted in prevention.

Brain imaging plays a pivotal role in understanding the human brain’s structure, function, and connectivity2. Advancements made in the field revolutionized scientists’ ability to study neurological disorders. For instance, Positron Emission Tomography (PET) techniques have evolved significantly with the development of novel radiotracers. Tau-specific PET tracers allow for the early detection of neurodegenerative disorders by visualizing tau protein deposition in the brain3. The early diagnosis, monitoring, and timely intervention made possible by brain imaging have a vital role in disease management.

In this context, the HiDiver research project at Duke University shows promise. Initiated in 2020, HiDiver aims to create highly detailed and integrated brain images that combine high-resolution Magnetic Resonance Histology (MRH) and Light Sheet Microscopy (LSM), while also incorporating a reference atlas of detailed brain structures for accurate alignment4. HiDiver has been tested on mice as of 2022, to create highly detailed 3D images of the mouse brain that provide insights into cellular and synaptic levels of brain architecture.

This scientific report will further explain what current brain imaging technology has accomplished and its limitations. By bridging gaps in complex imaging data, HiDiver could catalyze a shift in preventing and treating neurodegenerative diseases and neurological cancers.

Current Limitations

Brain imaging technology has significantly transformed our understanding of the human brain. This field is crucial for understanding the complicated nature of neurodegenerative diseases and brain cancers5. Disorders such as Alzheimer’s, Parkinson’s, and ALS, and brain tumors like gliomas, craniopharyngiomas, medulloblastomas, and meningiomas pose challenges to both patients and medical researchers6,7. While recent advancements have brought about remarkable progress in diagnosis and treatment strategies, the intricacies of these disorders demand more refined and comprehensive imaging techniques8. It is crucial to explore current brain imaging technologies9, their strengths, limitations, and potential for further enhancement to address the pressing issues posed by neurodegenerative diseases and brain cancers10.

Figure 1: Inaccurate Abnormalities found using MRIs (Doe et al., 2018)
  • Magnetic Resonance Imaging (MRI) MRI is a non-invasive method that employs strong magnetic fields and radio waves to create detailed images of the brain’s internal structures. This technology excels at producing high-resolution pictures that assist in spotting abnormalities in brain anatomy, and tumors6, and alterations in brain size. However, while MRI is adept at displaying the physical arrangement of brain components, it may lack the ability to identify subtle cellular or molecular changes associated with the initial stages of neurodegenerative diseases. Furthermore, MRIs have a history of inaccurately portraying abnormalities in the brain, most of which were not confirmed.
  • Positron Emission Tomography (PET) PET involves introducing a mildly radioactive substance, called a tracer, into the body. This tracer collects in regions with heightened metabolic activity or specific molecular markers. PET can visualize brain functions and molecular modifications by detecting emitted gamma rays from the tracer. This capability makes PET valuable for studying neurodegenerative illnesses and brain tumors6. Nevertheless, PET’s spatial resolution can sometimes be restricted, making it challenging to identify the locations of irregularities precisely.
  • Functional MRI (fMRI) fMRI gauges variations in blood circulation to identify active regions within the brain. This technique is widely used to explore brain function, connectivity, and modifications in neural activity linked to cognitive tasks or diseases. Although fMRI provides valuable insights into functional changes, it may not capture the underlying cellular transformations related to neurodegeneration (Smith et al., 2019)11,12.
  • Based on MRI, diffusion Tensor Imaging (DTI) DTI evaluates the brain’s white matter pathways by measuring the movement of water molecules. It plays a pivotal role in understanding disruptions in connectivity caused by diseases5. However, DTI might not consistently offer the required sensitivity to identify subtle alterations in brain structure.
  • Tau-Specific PET Tracers Emerging PET tracers are designed to specifically target tau proteins, which are characteristic markers of several neurodegenerative disorders. These tracers allow for the early detection and monitoring of tau protein accumulation in the

brain, enabling timely intervention. Nevertheless, refining imaging techniques is crucial to differentiate various types of tau-related pathologies and quantify their distribution within the brain8,13,14

To address the complexities of neurodegenerative diseases and brain cancers, improvements in brain imaging technology are crucial15,16. Efforts should be directed toward enhancing spatial resolution, sensitivity, and specificity. Multimodal approaches, such as combining PET with MRI, could offer a comprehensive view of brain structure, function, and molecular changes17. Developing advanced contrast agents and radiotracers targeting specific disease markers can enable earlier and more accurate diagnoses. Furthermore, leveraging artificial intelligence and machine learning can aid in the automated analysis of large datasets18, enhancing the detection of subtle abnormalities and patterns.

MRH (Magnetic Resonance Histology)

Magnetic Resonance Histology (MRH) is an advanced imaging technique that uses high-resolution magnetic resonance imaging (MRI) to visualize the fine anatomical structures of biological tissues, particularly the brain19. MRH operates on the same fundamental principles as traditional MRI, leveraging the nuclear magnetic resonance (NMR) properties of hydrogen nuclei (protons) in water and fat molecules within the tissues. Here’s a summary of the key principles:

  1. Magnetic Field and Radiofrequency Pulses: A strong external magnetic field aligns the magnetic moments of hydrogen nuclei. Radiofrequency (RF) pulses are then applied to perturb this alignment.
  2. Signal Detection: As the hydrogen nuclei return to their equilibrium state, they emit RF signals detected by the MRI scanner.
  3. Spatial Encoding: Gradient magnetic fields encode spatial information, allowing for the reconstruction of a three-dimensional image of the tissue.
  4. High-Resolution Imaging: In MRH, higher magnetic field strengths and advanced imaging sequences are employed to achieve micron-level resolution, revealing detailed histological features without the need for physical sectioning of the tissue.

Unique Contributions of MRH to Brain Imaging

  • Non-destructive Imaging: MRH allows for detailed 3D visualization of brain structures without physically altering the tissue, preserving it for further studies.
  • High Contrast: MRH provides excellent contrast between different types of brain tissues, making it easier to distinguish fine anatomical details20.
  • Volume Imaging: It can image entire brain volumes, offering comprehensive insights into brain anatomy and pathology.

LSM (Light Sheet Microscopy)

Light Sheet Microscopy (LSM), also known as Selective Plane Illumination Microscopy (SPIM), is an optical imaging technique that uses a thin sheet of light to illuminate a specific plane of a sample21. The fundamental principles of LSM include:

  1. Orthogonal Illumination: A thin sheet of light is projected into the sample from the side, illuminating only a single plane at a time22.
  2. Detection Perpendicular to Illumination: The fluorescence emitted by the sample is collected by an objective lens placed perpendicular to the light sheet, minimizing out-of-focus light and improving contrast.
  3. Sectioning and Reconstruction: By moving the sample or the light sheet, different planes can be imaged sequentially and reconstructed into a 3D volume.

Unique Contributions of LSM to Brain Imaging

  • Optical Sectioning: LSM provides high-resolution optical sections with minimal phototoxicity and photobleaching, essential for live imaging and thick specimens.
  • Fast Imaging: The technique allows rapid acquisition of images, making it suitable for capturing dynamic processes in biological tissues.
  • Deep Tissue Imaging: By using cleared tissues and optimized light sheets, LSM can achieve significant imaging depths compared to traditional fluorescence microscopy22.

Integration of MRH and LSM in the HiDiver Project

The HiDiver project aims to integrate MRH and LSM to leverage the strengths of both techniques, providing a comprehensive view of brain anatomy and function with unprecedented detail23. The integration process involves several key steps:

  1. Sample Preparation: The brain tissue is prepared and possibly cleared using techniques like CLARITY or iDISCO to make it more transparent for optical imaging.
  2. MRH Imaging: The prepared sample undergoes high-resolution MRH to obtain a detailed 3D map of its macroscopic and mesoscopic structures.
  3. Alignment and Registration: The MRH data serves as a reference for the subsequent LSM imaging. Advanced computational algorithms align and register the MRH and LSM datasets, ensuring precise correlation between the modalities.
  4. LSM Imaging: The same sample is imaged using LSM, capturing high-resolution optical sections at different depths.
  5. Data Integration: The datasets from MRH and LSM are integrated using sophisticated image processing techniques, creating a unified high-resolution 3D model of the brain.

Advantages of Integration

  1. Resolution: The integration of MRH and LSM significantly enhances the overall resolution. MRH provides high-resolution volumetric data, while LSM offers superior optical sectioning at finer scales, combining to give a detailed multi-scale view.
  2. Alignment: Using MRH as a reference for LSM ensures precise alignment of the datasets, allowing accurate correlation between structural and functional data across scales.
  3. Imaging Depth: While MRH can image entire brain volumes non-destructively, LSM excels in providing high-resolution images at specific depths. Combined, they offer comprehensive coverage from surface to deep structures.

Specific Advantages Compared to Traditional Methods

  • Comprehensive Multiscale Imaging: Traditional methods often require separate imaging techniques for different scales and depths, leading to potential misalignment and loss of context. The HiDiver approach provides a seamless integration across scales24,22,19.
  • Enhanced Contrast and Detail: By combining the high contrast of MRH with the fine detail of LSM, the integrated approach reveals subtle anatomical and pathological features that might be missed by single-modality imaging.
  • Non-destructive and Efficient: Traditional histology involves physical sectioning and staining, which can be time-consuming and destructive. The HiDiver method preserves the sample and allows for repeated or complementary analyses.

HiDiver

HiDiver’s unique approach holds promise for advancing our understanding of neurodegenerative diseases and brain cancers, offering significant advantages over traditional imaging methods. The innovative fusion of high-resolution Magnetic Resonance Histology (MRH) and Light Sheet Microscopy (LSM) within a comprehensive brain structure reference atlas empowers HiDiver with distinctive capabilities conducive to addressing the complexities of these conditions. HiDiver’s integration of MRH and LSM enables the creation of highly detailed and accurately aligned 3D brain images. This meticulous level of detail is particularly valuable for deciphering the subtle structural changes associated with neurodegenerative diseases and brain cancers. The ability to visualize cellular and synaptic architecture provides insights into disease progression at unprecedented levels of granularity. Furthermore, HiDiver’s multimodal approach allows researchers to combine multiple imaging techniques, resulting in a holistic understanding of brain structure, function, and molecular changes. This comprehensive view facilitates the identification of correlations between various imaging parameters, offering a more complete picture of disease mechanisms. This is especially pertinent for neurodegenerative diseases and brain cancers, which often involve complex interactions across different levels of brain organization.

HiDiver’s incorporation of a detailed brain structure reference atlas ensures accurate alignment of diverse imaging data. This alignment is vital for comparing findings across different studies, subjects, and modalities. The precise spatial context provided by HiDiver enhances the reliability of detecting abnormalities and tracking disease progression. Moreover, the high-resolution images generated by HiDiver have the potential to aid in the early detection of pathological changes associated with neurodegenerative diseases and brain cancers. By capturing subtle alterations at their inception, HiDiver contributes to the possibility of early intervention strategies, enhancing treatment outcomes and quality of life. Currently, HiDiver researchers are using 3D imaging to capture the brains of adult mice.

Figure 2 / Detailed Reference Atlas of an Adult Mouse ((The Allen Institute for Brain Science. Adult mouse brain atlases.))

Similarly, HiDiver’s integrative approach has the potential to uncover previously unexplored areas of knowledge. By combining MRH, LSM, and a reference atlas, researchers can investigate the intricate relationships between the brain’s cellular, molecular, and structural aspects. This may lead to breakthroughs in understanding disease mechanisms, identifying novel biomarkers,25 and guiding the development of targeted therapies26. The wealth of information generated by HiDiver’s multimodal imaging approach can be harnessed through advanced data analysis techniques, such as artificial intelligence and machine learning. These tools can uncover patterns, correlations, and predictive indicators that might not be discernible through traditional analysis methods.

Conclusion

In summary, HiDiver’s synergy of advanced imaging technologies, precision alignment, and multimodal insights positions it as a transformative tool in the realm of neurodegenerative diseases and brain cancers. Its potential to unveil cellular and synaptic nuances, coupled with its capacity for early detection and exploration of uncharted territories, holds the promise of revolutionizing our approach to these intricate disorders. As our understanding of neurobiology and pathology deepens through HiDiver, the door to innovative therapeutic interventions and breakthroughs in neurological science stands wide open.

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