US, WASHINGTON (ORDO NEWS) — There is an opinion that our brain is involved only 10 percent. In fact, this body works all and always, but how it all works, scientists are just beginning to understand.
Having smoothed a graying beard, Van Vedin leans towards the monitor screen, searching among hundreds of files he needs. We are sitting in a library with no windows among the boxes, brown with time, filled with old letters and long-standing issues of scientific journals with curled pages; right there is an ancient projector for slides – it’s a pity to throw it away. “It will take some time to find your brain,” Vedin says. Hundreds of monkey, rat and human brains are stored on the hard drive of this computer, that is, their most detailed three-dimensional images. Among them is mine. Wedin suggested that I take a trip on my head. “We will visit all the sights,” he smiles. This is my second visit to Van Vedin at the Martinos Center for Biomedical Imaging, located in the building of the former cable factory in the port of Boston. For the first time, a few weeks ago, I offered myself the role of an experimental guinea pig. I was taken to a tomography room, where I was sitting on a hard couch, resting my head in an open plastic box. The radiologist put a white plastic helmet on my face. Through the openings for the eyes, I watched him screw the helmet tighter so that the 96 miniature sensor antennas installed in it were as close to my brain as possible and could better catch the radio waves emitted by it. When the couch entered the cylindrical womb of the tomograph, I remembered the film based on the novel by Alexander Dumas “Iron Mask”. The magnets around me began to hum and squeak. For an hour I lay motionless, with my eyes closed, and tried to remain calm. It was not easy. To achieve the best resolution, Wedin and his colleagues made the tomograph so tight, that a man of my physique could barely squeeze in there. Suppressing a panic attack, I tried to breathe smoothly and mentally wandered through the back streets of my memory – for example, I suddenly remembered how I once led my daughter to school through a snowstorm.
Neuroscientists see not only the brain in action, but also violations in its work.
Lying in the tomograph, I reflected on the fact that the same one and a half kilogram piece of flesh that is being studied produces all these thoughts and feelings: and my fear, transmitted by electrical signals that converge in a piece of tissue called the amygdala, and a soothing answer to it, which occurs in the frontal lobe. The memory of how I drove my daughter to school was reproduced by another group of neurons, a shape resembling a seahorse (hence the name), the hippocampus. The hippocampus awakened an extensive network of connections in the brain that first appeared when I made my way through the snowdrifts, and evoked this memory. “Position in the tomography” was for me part of an editorial assignment related to one of the greatest scientific revolutions of our time, namely, a striking breakthrough in understanding how the brain works. Some neuroscientists are focused on studying the complex structure of individual nerve cells, or neurons. Others track the biochemical processes taking place in the brain, figuring out how 100 billion of our neurons produce and use thousands of different types of proteins. Still others, including Vedin, create surprisingly accurate and detailed maps of the network of approximately 160 kilometers of nerve fibers called white matter, which connect different parts of the brain, generating everything that we think, experience and feel. Neuroscientists see not only the brain in action, but also violations in its work. They begin to identify the differences between a healthy brain and the brain of people with ailments such as schizophrenia, autism, and Alzheimer’s. Compiling more and more detailed maps of the brain, they are trying to figure out exactly where these diseases are hidden, and maybe they will eventually understand what causes them. But back to Vedin’s lab. He finally finds an image of my brain, and it appears on the screen. Diffusion tensor imaging technology, better known as magnetic resonance imaging, or MRI, which Vedin uses, converts the radio signals emitted by white matter into a high-precision atlas of my neural Internet. The tomograph maps the bundles of nerve fibers, forming hundreds of thousands of ways along which a stream of information flows from one part of the brain to another, and the scientist paints each bundle with its own color, so that my brain looks like a multi-colored fur of a psychedelic Persian cat. Wedin shows me some of these pathways that are important for linguistic activity and other types of thinking. Then it removes most of them to make it easier to see, how separate “overpasses” are organized. He enlarges the picture, and something amazing appears before his eyes: despite the dizzying complexity of the neuropaths, they all intersect at right angles, like lines on a sheet of a notebook in a cell.
“A solid grid,” Vedin says. In 2012, when he discovered the lattice structure of the brain, some scientists were skeptical, believing that this was only part of a much more complicated system. However, now Vedin is more than ever convinced that this structure is not accidental. Whatever brain he explores — human, monkey, avian — a grid is everywhere. The earliest nervous system in various creatures of the Cambrian period (who lived more than half a billion years ago), the scientist says, was a simple lattice: a pair of nerve strands going from head to tail, and similar to the jumpers of the rope ladder connections between them. In the course of evolution, which led to the appearance of man, the nerves of the head end multiplied to billions, but the lattice structure was preserved. May be, when nerve signals are transmitted from one part of the brain to another, our thoughts move like cars along city streets. “It is impossible to imagine that there were no patterns in this,” Vedin says, peering intently at the image of my brain. “We just have not yet reached the point where we can recognize their simplicity.” Today scientists learn about the braina lot of new things, and it’s very easy to forget that until recently we had no idea how this body works, and what it really is. Doctors of the ancient world believed that the brain consists of a cold mucous substance – phlegm. Aristotle considered him the coldest part of the body, moderating warmth and boiling in the heart. Prior to the Renaissance, inclusive, anatomists confidently stated that all our sensations, emotions, reasoning and actions are the result of “animal spirits” – mysterious and incomprehensible fumes that swirl in the cavities of the head and travel with blood throughout the body. These ideas began to change during the scientific revolution of the 17th century. The English doctor Thomas Willis realized that all of our spiritual activities take place mostly in the substance of the brain, similar to custard. Wanting to find out how everything works there, Willis dissected the brain of sheep, dogs and his deceased patients, making up the first accurate description of this organ. In order to understand that it’s not animal spirits at all, but electric impulses that rush through the brain and through the nervous system – throughout the body, researchers took another century. But even at the end of the 19th century, scientists knew little about where the paths along which impulses are transmitted lead. Italian doctor Camillo Golgi argued that the brain is one continuous network. Based on his research, the Spanish neuroanatomist Santiago Ramon y Cajal tried out new methods of staining individual neurons in order to trace their confused processes. He managed to notice that each neuron is an independent cell. The neuron sends its signals along the long processes – axons. There is a tiny gap between the ends of the axons and the receiving tips of neighboring neurons – dendrites. Later, scientists will discover that in order to transmit a signal to a neighboring neuron, axons fill this gap – the synaptic cleft – with a mixture of chemical compounds. The neuroscientist Jeff Liktman, who currently occupies the faculty of Ramon-i-Cajal at Harvard, continues the research initiated by the great Spaniard. Instead of sketching manually painted neurons with a pen, he and his colleagues create three-dimensional images of the highest accuracy. Getting to the smallest details of the structure of nerve cells, sooner or later they will receive answers to some most important questions about the nature of the brain. Each neuron has an average of 10 thousand synapses – contacts with other cells. Is there a certain order in how do some neurons come in contact with others, or does this happen by chance? To get the images, Liktman and his colleagues put pieces of the canned mouse brain into the neuroanatomical semblance of a slicer, which cuts the thinnest – less than one thousandth of the thickness of a human hair – tissue layers. Scientists take photographs of each slice using an electron microscope, and then “stitch” the photographs into a single unit on a computer. “Now everything is visible,” says Licktman.
A tiny piece of the brain looked like a barrel full of wriggling snakes.
The only problem is the vastness of this “everything.” The largest fragment of the mouse brain that Liktman’s group was able to recreate was a grain of salt. And the amount of information contained in this grain is already approaching a hundred terabytes. About the same place would be occupied by 25 thousand films in high resolution. After collecting the data, the most difficult work begins: scientists are trying to figure out by what rules the imaginary chaos of the brain is organized. Liktman’s pupil Narayanan Kashthuri recently decided to study every detail in a cylindrical fragment of a mouse brain the size of only a thousand cubic micrometers (this is one hundred thousandth of the same grain) and chose a site around a single axon. And this tiny piece of brain was like a barrel full of wriggling snakes. Kastkhuri found there a thousand axons and about 80 dendrites – branched processes, each of which formed about 600 synaptic connections with other neurons within the “cylinder”. “This example makes it clear how much more complex the brain is than we think,” Licktman explains. Yes, the brain is complex, but not chaotic: Liktman and Kasthuri found that each neuron is in contact with a single neighbor, carefully avoiding connections with almost all other neurons closely surrounding it. “It seems like they care about who to interact with,” says Licktman. While he cannot say, this intelligibility is a general rule or feature of a particular tiny area of the mouse brain. Even though he and his colleagues are improving their technology, they will need another two years to complete the scan of all 70 million mouse neurons. I ask how long it can take to scan a whole human brain, in which there are a thousand times more neurons than in a mouse. “Better not to think about it,” Licktman jokes. When (and if) Lictman will completehis work, a three-dimensional portrait of the brain will help to find answers to many questions, but still remain no more than a very accurate sculpture. Scanned neurons – blank mockups; real neurons are filled with living DNA, proteins, and other molecules. Each type of neuron uses a specific set of genes to build the molecular mechanism necessary to perform specific functions. For example, photosensitive eye neurons create proteins that capture photons, and neurons located in a site called the black substance produce dopamine, which affects a person’s sense of satisfaction. Knowing where certain proteins are formed is necessary to understand how the brain works – and how it begins to go astray. So, in Parkinson’s disease, neurons of the substantia nigra produce less dopamine;
A map of the molecular mechanisms of the brain, called the Allen Brain Atlas, was created at the Allen Brain Research Institute in Seattle, which was founded ten years ago with funds donated by Paul Allen, one of the co-founders of Microsoft. Scientists working at the institute examine the brains of recently deceased people (with the permission of their relatives). Using high-resolution MRI, an image of the brain is obtained and used as a three-dimensional plan on which the studied areas are applied. Then the brain is cut into microscopically thin layers, spread them on glass substrates, and then impregnated with chemicals that give out the presence of active genes located in neurons. To date, researchers have processed the brain of six people and recorded the activity of 20 thousand protein-coding genes in 700 areas of each brain. This is an enormous amount of data, and it is only just beginning to be comprehended. According to scientists, 84 percent of all the genes of our DNA are somehow involved in the work of various areas of the adult brain. (Simpler organs like the heart or pancreas need far fewer genes to work). In each of the 700 sites, neurons trigger a special group of genes. During a preliminary study of two parts of the brain, scientists compared a thousand genes, important, as established earlier, for the functioning of neurons. As it turned out, in all six people the areas of the brain in which each of these genes acted almost coincided. It seems like the brain has a thin and complex genetic structure, and special combinations of genes perform certain tasks in its various fields. And many brain diseases probably arise when certain genes “turn off” or begin to work incorrectly. All data contained in the Allen Brain Atlas is available online, and other scientists can familiarize themselves with it using a special program. It helps make new discoveries. So, a group of Brazilian researchers used this data to study Fahr’s syndrome, a destructive disease in which calcification occurs in areas located deep in the brain. Using the atlas, Brazilians found that the SLC20A2 gene is especially active in the areas of the brain that affects this disease. To rule out a mistake, they look for other genes that are active in the same parts of this organ. Maybe, the most amazing of the new ways to visualize the brain was invented by Stanford neuroscientist and psychiatrist Carl Disserot with colleagues. To see the brain, scientists first make it disappear. When I arrived at Disserot’s lab, student Janell Wallace led me to a lab table with a foam stand on which half a dozen Petri dishes were mounted. Wallace took one of them and showed me a pea-sized mouse brain lying at the bottom. But I looked not so much at the brain as through it: it was transparent like a glass ball. There is no need to clarify that the ordinary brain, both human and mouse, is opaque – its cells are shrouded in fat, glial (connective) and other tissues that do not allow light to pass through. That’s why Ramon-i-Cahal had to stain neurons to see them, and Licktman and his colleagues – cut the brain into thin layers. The advantage of a transparent brain is that we can look inside without destroying it. Karl Disserot and his student Kwanghun Chung have found a way to replace light-scattering compounds in the brain with transparent molecules. Having made the mouse brain transparent, they can then impregnate it with luminous chemical markers that attach only to given proteins and highlight a specific pathway connecting neurons in distant parts of the brain. After washing, add other chemicals that reveal the location and structure of the next type of neurons – so you can, without cutting, unravel the Gordian knot of the neural plexuses. It’s not easy for neuroscientists to surprise you with anything, but Dissert’s method, called CLARITY (from English “clarity”, “transparency”), literally shocked them. “This is fantastically cool!” – says Christophe Kock, scientific director of the Allen Institute.
Since we had common ancestors with mice, a transparent mouse brain can tell a lot about how the human brain works. But Disserot sets his team a more ambitious goal – to make the human brain transparent. This is much more complicated, not least because our brain is three thousand times larger than the mouse. The CLARITY picture, showing the location of just one type of protein in the brain of one person, will “weigh” about two petabytes, that is, as much as several hundred thousand high-resolution films. Disserot hopes that someday CLARITY will help people like his current patients identify the underlying causes of illnesses such as autism and depression. But Karl does not allow himself to be too carried away by this dream. “We have a long way to go, “I don’t advise people to even think about it,” he says. “This is only intelligence.” No matter how much information the transparent brain once gives us, it will still be dead. Scientists need other tools in order to explore the living brain. The tomographs of Van Vedin can help in this if they are reprogrammed. Functional magnetic resonance imaging (fMRI) identifies areas of the brain involved in the performance of certain mental tasks. Over the past two decades, with the help of fMRI, chains have been found involved in the mental processes of all types, from face recognition and enjoying a cup of coffee to memories of mental trauma. FMRI images in which the brain is colored with all the colors of the rainbow certainly make an impression, but you need to remember that these are pretty crude images. The most powerful tomographs can detect activity only at the level of cubic millimeters, that is, pieces of tissue the size of sesame seeds. Inside these seeds, hundreds of thousands of neurons exchange signals harmoniously. How these signals interact with each other, causing larger processes – those that detect fMRI – remains a mystery. “There are simply ridiculously simple questions about the cerebral cortex that we still cannot answer,” says Clay Reid of the Allen Institute. Reid came to Seattle, hoping to find answers to some of these questions through a series of experiments that he and his colleagues called the “MindScope”. Their goal is to understand how a large number of neurons performs a complex task. that is, pieces of fabric the size of sesame seeds. Inside these seeds, hundreds of thousands of neurons exchange signals harmoniously. How these signals interact with each other, causing larger processes – those that detect fMRI – remains a mystery. “There are simply ridiculously simple questions about the cerebral cortex that we still cannot answer,” says Clay Reid of the Allen Institute. Reid came to Seattle, hoping to find answers to some of these questions through a series of experiments that he and his colleagues called the “MindScope”. Their goal is to understand how a large number of neurons performs a complex task. that is, pieces of fabric the size of sesame seeds. Inside these seeds, hundreds of thousands of neurons exchange signals harmoniously. How these signals interact with each other, causing larger processes – those that detect fMRI – remains a mystery. “There are simply ridiculously simple questions about the cerebral cortex that we still cannot answer,” says Clay Reid of the Allen Institute. Reid came to Seattle, hoping to find answers to some of these questions through a series of experiments that he and his colleagues called the “MindScope”. Their goal is to understand how a large number of neurons performs a complex task. – remains a mystery. “There are simply ridiculously simple questions about the cerebral cortex that we still cannot answer,” says Clay Reid of the Allen Institute. Reid came to Seattle, hoping to find answers to some of these questions through a series of experiments that he and his colleagues called the “MindScope”. Their goal is to understand how a large number of neurons performs a complex task. – remains a mystery. “There are simply ridiculously simple questions about the cerebral cortex that we still cannot answer,” says Clay Reid of the Allen Institute. Reid came to Seattle, hoping to find answers to some of these questions through a series of experiments that he and his colleagues called the “MindScope”. Their goal is to understand how a large number of neurons performs a complex task.
The brain function that Reed and his colleagues chose was vision. A neuroscientist can place an electrode on the area of the mouse brain involved in the process of visual perception, and then monitor whether nearby neurons begin to emit electrical signals when the animal sees a particular object. This approach made it possible to find out which parts of the brain related to vision specialize in certain tasks – for example, determining the contours of objects or perceiving brightness. However, scientists could not consider how these sites interact, and therefore could not find out how a million or so neurons in the visual structures of the mouse brain instantly collect information that develops into the image of a cat. Reed’s group sets about solving this problem by breeding mice whose visual neurons will emit flashes of light at that moment when they get excited, say, at the sight of a cat or a delicious crust of cheese. Then scientists will try, by combining the data, to build mathematical models of vision. If the models turn out to be accurate, you can literally read what is on the mouse in your mind. Mouse Vision Studiesconducted by Reed is another step towards the ultimate goal of all neurobiology: to create a comprehensive idea of how a complex organ actually works, that is, create a theory of the brain. This is still a long way off, but there is one area of research – the neurocomputer interface – the successes in which have already begun to change people’s lives. At 43, Katie Hutchinson suffered a massive stroke and lost her ability to move and speak. Lying on a bed in the Massachusetts Central Hospital, she gradually realized that the doctors did not know if her brain was alive or not. Sister Hutchinson asked her if she understood her words, and Katie managed to answer with a look up. “It was such a great relief for me! – Hutchinson shares with me 17 years later. “After all, everyone spoke of me as if I were dying.” It’s a frosty winter day in Massachusetts. Hutchinson sits in a wheelchair in the middle of his living room, dressed in a dark green tracksuit and sneakers. Katie is still almost completely paralyzed and unable to speak, but can communicate: she looks at the letters on a computer monitor screwed to her chair, and the video camera monitors the movement of a tiny metal disk mounted in the center of her glasses. There is an area in the brain called the motor cortex where muscle commands arise. Each section of this cortex is responsible for the movement of certain parts of the body. In paralyzed people, the motor cortex often remains intact, but cannot command the body, since the connection between neurons and muscle cells is lost. John Donoghue, a neuroscientist at Brown University, decided to help paralyzed people by gaining access to signals from their motor cortex. Maybe, such patients can be taught to type on a computer or control mechanisms exclusively by the power of thought. Donoghue has perfected the implant for years and tested it on monkeys. When he and his colleagues were convinced that it was safe, they began to work with people. One of the patients became Katie Hutchinson. In 2005, surgeons from the Rhode Island Clinic at Brown University drilled a hole in her skull about two and a half centimeters in diameter and inserted a sensor into the brain of a device created by Donoghue. A sensor the size of a ladybug was equipped with a hundred miniature needles, which, piercing the tissue of the motor cortex, pick up signals from nearby neurons. A bundle of wires extending from the sensor through a hole in the skull leads to a metal connector mounted on the top of the Hutchinson. When the postoperative wound has healed, researchers from Brown University connected the implant with a cable that transmitted signals from the brain to a cart with computers. To begin with, the researchers taught these computers to recognize signals emanating from the patient’s motor cortex and to move the cursor around the screen in accordance with them. This happened on the first try, because scientists already knew how to convert signals of brain activity into movement. Two years later, they connected a mechanical arm to the computers, which, obeying the signals from Hutchinson’s brain, moved back and forth, rose and fell, squeezed and unclenched fingers. After several workouts, Hutchinson, the computer and the arm became one team. “The feeling was completely natural,” Katie admits. So natural that one day she reached for a cup of coffee, took it, brought it to her lips and took a sip. “Katie’s smile when she drank coffee … This is most important to me,” says Donoghue.
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