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

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Scientists at the Human Brain Project (HBP) used a unique multiscale approach involving a variety of experimental techniques to study the complex organization of brain connectivity. They combined techniques such as anatomical and diffusion magnetic resonance imaging, two-photon fluorescence microscopy, and 3D polarized light imaging to visualize and understand nerve fibers at different spatial scales. Combined for reference in the Julich Brain Atlas, their findings reveal new insights into the connectivity and function of different brain regions.

Human Brain Project researchers used a multiscale approach combining different imaging techniques to understand the contextome, or interconnected structure, of the human brain from the molecular to the macrolevel. They used 3D polarized light imaging to visualize nerve fibers and placed their findings in the Julich Brain Atlas to spatially reference the data to reveal new insights into brain organization and function.

To understand how our brain works, it is impossible to study how different areas of the brain communicate with each other through nerve fibers. In the magazine ScienceHuman Brain Project (HBP) researchers review the current state of the field, provide insight into how the brain’s connectome is structured at different spatial scales, from the molecular and cellular to the macro level, and assess current methods and future requirements. understanding the complex organization of the connectome.

“It is not enough to study brain connectivity with one method, or even two methods,” says author and HBP Scientific Director Katrin Amunts, who heads the Forschungszentrum Jülich and the C. & O Institute for Neuroscience and Medicine (INM-1). Vogt Institute for Brain Research at University Hospital Dusseldorf. “Conntome is embedded on multiple levels. To understand its structure, it is necessary to look at several spatial scales at once by combining different experimental methods in a multiscale approach and combining the obtained data into multilevel atlases, such as the Julich Brain Atlas that we have created.”

Markus Axer is from the Forschungschentrum Jülich and the Faculty of Physics at the University of Wuppertal, first author. Science in the paper, together with the INM-1 group, developed a unique method called 3D polarized light imaging (3D-PLI) to visualize nerve fibers at microscopic resolution. Researchers trace the three-dimensional direction of fibers in serial brain sections to create a 3D fiber atlas of the entire human brain.

Fiber architecture of the human hippocampus

Detail of a human brain section showing the architecture of single axon fibers in the hippocampus revealed by 3D polarized light imaging. The colors represent the 3D fiber orientations showing the paths of individual fibers and strands. Credit: Markus Axer and Katrin Amunz, INM-1, Forschungzentrum Jülich

Together with other HBP researchers from Neurospin in France and the University of Florence in Italy, Axer and his team recently imaged the same tissue block from the human hippocampus using several different techniques: anatomical and diffusion-weighted magnetic resonance imaging (aMRI and dMRI), two-[{” attribute=””>photon fluorescence microscopy (TPFM) and 3D-PLI, respectively.

Microscopy methods like TPFM provide sub-micrometer resolution images of small brain volumes revealing microstructures of the brain’s cerebral cortex, but they have their limitations in disentangling fibers connecting distant brain regions, which build the deep white matter structures. This is even more true for electron microscopic measurements, which enable nanometre-resolved insights into a cubic millimeter of brain tissue. In contrast, dMRI can be used for tractography at the whole-brain level – visualizing white matter connections – but cannot resolve individual fibers or small tracts.

“3D-PLI serves as a bridge between micro and macro methods,” says Amunts. “This is because 3D-PLI resolves the fiber architecture at high resolution and, at the same time, allows imaging of whole-brain sections that we can then reconstruct in 3D to trace fiber connections.”

Combining dMRI, TPFM, and 3D-PLI enabled the researchers to superimpose the three modalities within the same reference space. “This integration of data was only made possible by imaging one and the same tissue sample,” explains Axer. The human hippocampus block traveled from Germany to France, back to Germany, and finally to Italy, being processed and imaged in different laboratories benefiting from the local, highly specialized equipment.

The researchers then used the Julich Brain Atlas to spatially anchor their data in an anatomical reference space. The three-dimensional atlas contains more than 250 cytoarchitectonic maps of brain areas and forms the centerpiece of the HBP’s Multilevel Human Brain Atlas. “Our brain atlas enables us to pinpoint exactly where in the brain we find these microstructures,” explains Amunts. The dataset is openly accessible via the HBP’s EBRAINS infrastructure and can be browsed in an interactive atlas viewer.

The researchers multi-scale approach combining multiple modalities at different spatial scales to unravel the human connectome is unique and provides exciting new insights into how the human brain works.

Even though the hippocampus reconstruction is a lighthouse project, there are several international efforts ongoing (or about to start) that need to be orchestrated at an open atlas level to enable the integration of multi-scale data. Amunts and Axer emphasize that this is a prerequisite for revealing the principles of connectivity within the experimentally accessible range of scales – from axons to pathways. In other words, an integrated multi-scale approach that combines micro and macro methods is necessary to describe and understand the nested organization of the human brain. This requires critical reassessment of current methodology, including tractography, the authors say.

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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