In 1909, German Neurologist, Korbinian Brodmann created one of the earliest known maps of the surface of the human brain. Named after the neurologist himself, Brodmann’s areas were 52 identified regions of the cerebral cortex based on cytoarchitecture which refers to the cell sizes, spacing and organization of the cells. Based on the different regions of the brain, Brodmann assigned each a number together with its corresponding part of the cerebral cortex related to its function. Regions were identified through Nissl-staining section of the human brain.1
Stepping ahead, decades later scientists are still wrapping their heads around trying to understand how the human brain functions and explain the cause of many psychological disorders and neurological diseases. With an added advantage of technological advancements, researchers in the field can now leverage of these technologies in assisting them to produce a complete map of the human brain connectome.
Mapping of the entire human brain can help to uncover the intricacies and complex networks that make up the various functions of our brain. Findings from a clear map of the brain could also allow neurologists to gain insights to neurological diseases such as neurodegenerative diseases like Alzheimer’s Diseases and Parkinson’s Disease. Having a closer look at its molecular mechanisms that lead to these diseases or other psychological disorders could provide valuable information for potential therapeutic targets for effective treatment.
Connecting the Dots
Connectomes are comprehensive maps of all the neural connections in the organism’s brain and is also known as a “wiring diagram”. In 1986, biologist Sydney Brenner and his team successfully published a detailed nanoscale connectome of the nematode Caenorhabditis elegans.2 This study found a total of 302 neurons within the organism’s brain.
More recently, in 2018 a complete map of a Drosophila melanogaster (fruit fly) brain was release by a team of scientists at the Howard Hughes Medical Institute Janelia Research Campus. Using transmission electron microscopy, they were able to take detailed pictures if an adult female fruit fly. 7,062 brain slices and 21 million images were the produce of this research.3 These high-resolution images then allowed the researchers to have a nanoscale overview of all the neurons and follow each path within the whole fruit fly brain.
With improvements in laboratory techniques and new found collaborators, mapping of the fruit fly brain has reach new heights. As outlined by Xu, C. S. et al., 2020 the team built upon the FlyEM project initially at Janelia Research Campus and with Google collaborators to produce a complete map of a large portion of the fruit fly brain. 4
A study published in 2009 estimated that an average human brain contains approximately 86 billion neurons.5 Mapping of all the different permutations of neuronal connections and associating them with the different functions in the brain proves to be no easy feat. By contrast, mapping the human brain is indeed more complex than the brains of a Drosophila melanogaster and Caenorhabditis elegans.
In an effort to obtain crowdsourced data of a map of neurons, the Seung Lab, previously at the Massachusetts Institute of Technology is now located at Princeton University, created EyeWire. It reaches out to the public or anyone who has an eye for recognizing patterns to assist in mapping neurons in a mouse brain.6
The crowdsourcing brain mapping game, EyeWire was launched in 2012 which required the help of players to map the brain. Scientific background was not essential, the interdisciplinary team who designed this game made use of the ability to recognize patters to develop the gaming platform for mapping the human brain. The game required players to map branches of a neuron from one side of a cube to another. This allowed the researchers to identify new synapses and possible new cell types. In its last update, more than 200,000 people have participated over 150 countries across the world.
The game made use of artificial intelligence algorithms to reconstruct parts of the neuron and with the help of the players; make connections that were missed out by the algorithm. To date, players have contributed to charting cells in the mouse retina which led to the discovery of six types of neurons. In an update on February 2019, Amy Robinson Sterling shared that from the data gathered EyeWire will be moving on to a new game called Neo which might be launched in its alpha stage in time to come. Dataset used for Neo looks to be 150 times larger than what was used for EyeWire.7
Other efforts such as the large-scale Human Connectome Project which was a five-year project set out to collect data on the human brain. The project was announced by the National Institutes of Health, pumping a total of USD$ 30 million, brain imaging data was collected from a total of 1,200 participants which included 300 pairs of twins. This project was a first of its kind in gathering a large dataset to address questions of the connections within the human brain.8
Achieving Clarity
With the billions of neurons in the human brain, creating a map of all its connections would mean the generation of an extremely large dataset.
In the past, neuroimaging methods have only provided a macro view of the brain which is no enough to determine the intimate cognitive and behavioural functions of the brain. The discovery and advancements in magnetic resonance imaging (MRI) later made it possible for more in-dept analysis of the human brain connectome.9
Advancements in microscopy techniques have also helped scientists in their quest to obtain clearer, detailed images of the brain. The development of Transmission Electron Microscopy (TEM) for imaging a fruit fly brain has shown to be a game changer in the field of brain mapping. A high-throughput system developed by Zheng et. al., 2018, enabled the sectional imaging of an entire fruit fly brain at the nanoscale.10
To solve the challenge of the massive amount of data that would be generated by mapping of the billions of neurons within the human brain, scientists have looked to using supercomputers. Neuroscience researcher at Argonne National Laboratory, Narayanan “Bobby” Kasthuri tapped on the computing power of “Theta”, a supercomputer at the Argonne National Laboratory to comprehensively map the structure of mouse brains. The end result will produce a predicted million terabytes, which is a monstrosity of raw information.
Looking closer to home, scientists from the National University of Singapore (NUS) announced on 15 January 2020 that it would be working together with an international team to create an ultra-high-resolution 3D comprehensive map of the neural network in the human brain. The team looks to make use of an extremely powerful X-ray technology known as synchrotrons to create a structural map with each image on the scale of 0.3 micro-metres taken at a speed of 1 cubic millimetre per minute. The project looks to be completed within the next four years. These images produced by the synchrotron will be complemented by both subcellular and molecular information from other imaging techniques such as infrared spectromicroscopy, super-resolution visible-light 3D microscopy and crytoelectron tomography.
Producing large amounts of data from the many brain mapping projects would indeed provide great insight to the workings of various neural connections and broaden the understanding of cognitive and behavioural functions in the brain. Amalgamating all the information generated and linking each neuronal connection at the molecular level would be the next challenge to overcome. [APBN]
References
- Jacobs K.M. (2011) Brodmann’s Areas of the Cortex. In: Kreutzer J.S., DeLuca J., Caplan B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, New York, NY
- White John Graham, Southgate Eileen, Thomson J. N. and Brenner Sydney 1997 The structure of the nervous system of the nematode Caenorhabditis elegansPhil. Trans. R. Soc. Lond. B3141–340. http://doi.org/10.1098/rstb.1986.0056
- Xu, C. S. et al. (2020) ‘A Connectome of the Adult Drosophila; Central Brain’, bioRxiv, p. 2020.01.21.911859. doi: 10.1101/2020.01.21.911859.
- Howard Hughes Medical Institute, (July 19, 2018) Complete Fly Brain Imaged at Nanoscale Resolution. Retrieved from: https://www.hhmi.org/news/complete-fly-brain-imaged-at-nanoscale-resolution
- Azevedo, F. A., Carvalho, L. R., Grinberg, L. T., Farfel, J. M., Ferretti, R. E., Leite, R. E., Jacob Filho, W., Lent, R., & Herculano-Houzel, S. (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. The Journal of comparative neurology, 513(5), 532–541. https://doi.org/10.1002/cne.21974
- Citizenscience, (n.d) EyeWire | A Game to Crowdsource Brain Mapping. Retrieved from: https://www.citizenscience.gov/eyewire-brain-mapping/#
- Amy Sterling, (February 4, 2019). 2019 Neo Update. Retrieved from: https://blog.eyewire.org/2019-neo-update/
- Human Connectome Project, (n.d.). Retrieved from: http://www.humanconnectomeproject.org/about/
- Toga, A. W., Clark, K. A., Thompson, P. M., Shattuck, D. W., & Van Horn, J. D. (2012). Mapping the human connectome. Neurosurgery, 71(1), 1–5. https://doi.org/10.1227/NEU.0b013e318258e9ff
- Zheng Z, Lauritzen JS, Perlman E, et al. A Complete Electron Microscopy Volume of the Brain of Adult Drosophila melanogaster. Cell. 2018;174(3):730-743.e22. doi:10.1016/j.cell.2018.06.019