The Human Brain Project: Bridging Micro and Macro Understandings of the Brain

The Human Brain Project (HBP) team has adopted an exceptional multi-tiered strategy, incorporating a variety of experimental procedures to explore the intricate structure of the brain’s connectome. They have blended methods like anatomical and diffusion magnetic resonance imaging, two-photon fluorescence microscopy, and 3D Polarized Light Imaging to visualize and comprehend nerve fibers at various spatial scales. Their results, indexed in the Julich Brain Atlas, shed new light on the connections and functionality of various brain regions.

Researchers from the Human Brain Project employed a multi-tiered strategy, merging diverse imaging techniques to understand the connectome, the interconnected framework of the human brain, from the molecular to the macroscopic level. They utilized 3D Polarized Light Imaging to visualize nerve fibers, situating their discoveries within the Julich Brain Atlas for spatial referencing, revealing new perspectives about the brain’s structure and operation.

To comprehend the workings of our brain, it is crucial to explore how nerve fibers connect different brain regions. The HBP researchers provide a review in the Science journal, offering insights into the brain’s connectome structure at various spatial scales, from the molecular and cellular to the macroscopic level. They also discuss the current methods and future necessities for understanding the complex organization of the connectome.

Katrin Amunts, the author and HBP Scientific Director, stresses the need to examine brain connectivity using more than one method. She adds that understanding the connectome’s nested structure requires examining several spatial scales simultaneously through a multi-tiered strategy, integrating data into multilevel atlases like the Julich Brain Atlas.

Markus Axer from Forschungszentrum Jülich and the University of Wuppertal’s Physics Department, the Science article’s first author, and his team at INM-1 have crafted a unique method called 3D Polarized Light Imaging to visualize nerve fibers at a microscopic resolution. They aim to develop a 3D fiber atlas of the entire human brain by tracing three-dimensional fiber routes across serial brain sections.

HBP researchers from Neurospin in France and the University of Florence in Italy, collaborated with Axer and his team to image the same tissue block from a human hippocampus using several different techniques: anatomical and diffusion magnetic resonance imaging, two-photon fluorescence microscopy, and 3D-PLI.

Microscopy techniques like TPFM provide high-resolution images of small brain volumes revealing the brain’s cerebral cortex microstructures. However, these techniques struggle to unravel fibers connecting distant brain regions, building deep white matter structures. On the other hand, dMRI enables whole-brain level tractography but cannot resolve individual fibers or small tracts.

“3D-PLI acts as a bridge between minute and macroscopic techniques,” says Amunts. It resolves fiber architecture at high resolution and simultaneously permits imaging of entire brain sections, allowing 3D reconstruction to trace fiber connections.

The integration of dMRI, TPFM, and 3D-PLI data was possible only by imaging the same tissue sample, explains Axer. This sample of human hippocampus traversed from Germany to France, back to Germany, and finally to Italy, getting processed and imaged in different laboratories using specialized equipment.

The researchers used the Julich Brain Atlas to anchor their data in an anatomical reference space. This three-dimensional atlas, containing over 250 cytoarchitectonic brain area maps, is the core of the HBP’s Multilevel Human Brain Atlas. “Our brain atlas allows us to precisely identify where in the brain these microstructures are found,” explains Amunts. The dataset is openly accessible via the HBP’s EBRAINS infrastructure and can be explored in an interactive atlas viewer.

The researchers’ multi-tiered strategy, which combines various modalities at different spatial scales, provides thrilling new insights into the human brain’s operation.

Despite the hippocampus reconstruction being a landmark project, there are several ongoing (or about to start) international endeavors that need coordination at an open atlas level for multi-scale data integration. Amunts and Axer stress that this is crucial for unveiling the principles of connectivity within the experimentally accessible range of scales – from axons to pathways. In other words, an integrated multi-tiered strategy, combining minute and macroscopic techniques, is necessary to depict and understand the nested organization of the human brain. The authors suggest this requires a critical reevaluation of the current methodology, including tractography.

Reference: “Scale matters: The nested human connectome” by Markus Axer and Katrin Amunts, 3 November 2022, Science. DOI: 10.1126/science.abq2599

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More about Human Brain Project

• The Human Brain Project Official Website
• EBRAINS Infrastructure
• Science Journal
• 3D Polarized Light Imaging
• The Julich-Brain Atlas
• Connectome
• Diffusion MRI