# Volumetric optical connectome microscopy of human cerebellar circuitry

> **NIH NIH R00** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $248,993

## Abstract

Project Summary/Abstract
The goal in seeking a K99/R00 Pathway to Independence Award is to establish myself as an independent
principal investigator to study the structural-functional relationship of the brain circuitry in normal and brain
disorders. The proposed project, driven by the need for understanding the human brain with high-resolution
high-throughput tools and my extensive experience in biomedical optics for neuroimaging, aims to establish a
versatile tool to reconstruct the circuitry and neuronal architecture in human cerebellum, understand the
disruptive impacts of cerebellar degenerative disease, and combine with MRI models to seek novel biomarkers
that will potentially influence the clinical assessment.
Despite the tremendous advances of light microscopy since Santiago Ramón y Cajal's pioneering work in
drafting axonal tracts, our knowledge on how the 80-100 billions of neurons connect together to form complex
functions in human brain is still limited. Presently, there is no volumetric microscopy technique that can map
the circuitry and architecture of human brain with high integrity. Here I propose to develop a volumetric optical
connectome microscopy (VOCM), for reconstructing the human cerebellum with unprecedented resolution and
scales, and mapping the connectivity and neuronal architectures from a global perspective. VOCM is based on
a polarization sensitive optical coherence tomography and a vibratome slicer to image large-scale ex vivo brain
at a micrometer-scale resolution. Importantly, this technology allows volumetric reconstruction preserving an
ultra-high accuracy without tissue distortions; therefore overcomes the 100 years challenge of all histology
based methods in tracing long fiber tracts and inspecting sophisticated cortical folding in the human brain. The
high-quality data generated by VOCM will be fit into MRI models to construct an ultra-high resolution atlas of
human cerebellum to provide anatomical labels that are not available in current MRI tools.
By applying VOCM, the project further explores 3D pathological patterns of cerebellar disorder. Multiple system
atrophy cerebellar type (MSA-C) is a fatal neurodegenerative disease manifested by severe cerebellar and
brainstem atrophy. Despite its rare incidence, MSA-C shares common phenotypic characteristics with other
neurological diseases. Studying the neuroanatomical substrates and pathological trajectory of MSA-C could
advance our understanding of the impact of cerebellar disorders and cerebellar affected diseases. Particularly,
the project will characterize the architecture and circuitry disruptions associated with neurodegeneration in
MSA-C. We will then use the high-resolution ex vivo dataset to make predictions in vivo, and allow an MRI
assessment that would not be possible otherwise.
The proposed research is conducted at Martinos Center, Massachusetts General Hospital (MGH), which is an
ideal environment developing cutting edge biomedical technologies and...

## Key facts

- **NIH application ID:** 10245316
- **Project number:** 5R00EB023993-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Hui Wang
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $248,993
- **Award type:** 5
- **Project period:** 2020-08-08 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245316

## Citation

> US National Institutes of Health, RePORTER application 10245316, Volumetric optical connectome microscopy of human cerebellar circuitry (5R00EB023993-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245316. Licensed CC0.

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