Oh, yes, you might be thinking of the “Imitation Game”, the famous movie by Benedict Cumberbatch who performed the role of Alan Turing. Turing was the real scientist who decoded the German Enigma code. Enigma is an encoding machine used to encrypt secret messages of the German Army during World War II. They replaced German letters that make sense with a different nonsense sequence of letters that gives no meaning. This is exactly the case with neuroscience breakthroughs, it is as complex as decoding the enigma machines.
“All human actions will, of course, be classified according to these laws- mathematically, like a Logarithm table, up to 108000- and entered in a special almanac. Or, still better, certain edifying volumes will be published, similar to our encyclopedic dictionaries, in which everything will be calculated and designated in such precision that there will no longer be any actions or adventures in the world.”
Those sentences are the words that Fyodor Dostoevsky wrote in his masterpiece Notes from Underground. He was philosophically discussing the human will and whim. Unintentionally, he mysteriously predicted that in the future some sort of pattern will be discovered. Such a pattern will control human behavior. Moreover, as he thought this idea was revolting due to meaning a total restriction of the human being like a machine, he seems aware that this idea would be under research and may fill volumes!
That’s what he thought in the 17th century and he was never mistaken! Neuroscience has a big issue to solve, of course out of millions of others issues. Neurons are not sitting there alone. They are actually in large groups in what I like to call “the brain jungle”. They attach by their synapses to share neurotransmitters. Well, it is a sin to even think they are not us stuck in an Egyptian bus after 2 p.m.! No, they are not haphazardly arranged. Neurons form organized patterns that enable them to do their functions. Well, these patterns are collectively called neuronal circuits. I think as a medical student, this term may seem familiar. However, the story is just like an enigma much more difficult than you may think.
In 1899, a Spanish neuroanatomist, Santiago Roman Cajal, wrote: “While there are remarkable differences of organization of certain cortical areas, these points of difference do not go so far as to make impossible the reduction of cortical structure to a general plan”. What he proposed challenged many neuroscientists since then; to find what that plan is. The plan refers to the pattern of neuronal arrangement. It may seem like an easy problem to solve. However, a cylinder sliced from a neocortical column- 2 mm high and 0.5 in diameter- contains on the order of 10,000 neurons and about 100 million synapses. Strikingly, scientists were passionate about understanding the detailed wiring diagram of how these neurons connect to one another: the connectome of the neocortex. To give you a glimpse of the difficulty; synapses can be identified with confidence using electron microscopy. Slices that fit there necessitate very thin sections of brain tissue (~50mm) which was not an easy task at that time.
Trials to solve that issue were shaped by the scientist and by the way the future Nobel Laureate, Sidney Brenner, and his colleagues. They conducted their research in the laboratory of Biology at the National Institute for Medical Research at Mill Hill, in North London, England. Brenner believed that to find a proper solution, they should simplify the complexity of the issue to the minimum level. Accordingly, for Brenner to analyze the human connectome and construct the entire neuron mapping, he was seduced to start by a smaller creature. He selected a 1-mm flatworm Caenorhabditis elegans as a simple organism to start with. Surprisingly, the worm’s brain only counts 302 neurons and about 7000 synapses. Thus, giving a state of overall hope for a successful project. As they started their work in the early 1970s- 1980s, they needed to perform much of the work manually because computer systems barely exceeded the Dos software at that time. This was a long and arduous process. Since the publication of their work in 1986, these technical obstacles were diminished by the yield of technological advances like automated sectioning of the brain tissue by electron microscope, and computer-aided reconstruction of volumes of tissues from very thin sections.
Nowadays, and within the walls of the Nobel-laureate factor; Bell Laboratories in New Jersey, a young scientist worked on the same problem. Sebastian Sung showed a fascination to study the interactions of artificial neural networks. He began inventing algorithms that enabled artificial neural networks to learn. He invented his theory of the possible existence of recurrent connections between integrator neurons which he called: the “Oculomotor Integrator”. Depressed by the fact that his theory might not work. His mentors suggested he shift his research focus.
In parallel, Winfried Denk, who worked in Bell labs with Sebastian, started a project to build an ingenious automated device that could image the face of a block of brain tissue, and then shave off one slice to expose a new face. The device could subsequently acquire a three-dimensional model of the brain. So, in theory, from such an image, it would become possible to reconstruct the “wiring diagram” of that particular brain tracing the paths of neural branches and locating the synapses.
Because an electron microscope gives a high-resolution picture, it may consume a Petabyte, the equivalent of a billion pictures in a digital album is needed for a single cubic millimeter. Manual handling of wiring diagrams may be for sure time-consuming. In 2006, Sebastian’s lab provided a methodological application of machine learning principles to improve 3D model reconstruction. Nonetheless, the method still made errors, hindering the complete replacement of human intelligence.
In 2014, Nature Magazine published a startling title. The first eye-wire-assisted discovery: a new wiring diagram for a neural circuit in the retina. It discussed a very challenging question of the ability of the retina to detect moving visual stimuli. Such an article highlights the scale of technological development of neuron mapping systems.
Nowadays, for science to make that complicated issue much more simplified, they study different aspects of neural circuits. For example, they separately studied the mapping of the auditory cortex and retina. Old machinery of tissue investigation has rapidly evolved. Scientists have used new revolutionary devices such as the micrometer resolution to picture the brain lobes with high resolution.
Research papers on specified problems are being published to decode the secrets of human brain mapping. Yet, uncertainty still wraps around the mysterious arrangement of neurons. Could we possibly come to a complete mapping of the human brain? Could we predict the future human thinking process as Dostoevsky believed? Is artificial intelligence capable of mitigating the complexity of the problem in an era of magnificent discoveries? Hundreds of questions are still unanswered and tomorrow may bring the answer.
References
1. Bear, M., Connors, B., & Paradiso, M. A. (2020). Neuroscience: exploring the brain, enhanced edition: exploring the brain. Jones & Bartlett Learning.
2. Hodges, A. (2014). Alan Turing: the enigma. In Alan Turing: The Enigma. Princeton University Press.
3. Dostoevsky, F. (2005). Notes from underground. Bantam Dell. Translated by: Mirra Ginsburg.
4. Falet, J. R., Côté, J., Tarka, V., Martínez-Moreno, Z. E., Voss, P., & de Villers-Sidani, E. (2021). Mapping the human auditory cortex using spectrotemporal receptive fields generated with magnetoencephalography. NeuroImage, 238, 118222. https://doi.org/10.1016/j.neuroimage.2021.118222
5. Chang, S., Varadarajan, D., Yang, J., Chen, I. A., Kura, S., Magnain, C., Augustinack, J. C., Fischl, B., Greve, D. N., Boas, D. A., & Wang, H. (2022). Scalable mapping of myelin and neuron density in the human brain with micrometer resolution. Scientific reports, 12(1), 363. https://doi.org/10.1038/s41598-021-04093-y
6. Tysoe O. (2021). Mapping neuron functions in the gut-brain axis. Nature reviews. Endocrinology, 17(8), 448. https://doi.org/10.1038/s41574-021-00519-9
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