A boy whose brain can help understand autism (part 2)

_{Richard Milnes}



At KDPV - the building of the Sydney Opera House, illuminated in blue in support of the World Autism Awareness Day. The article by Maya Salavits describes the theory of the intense world of Henry Markram.



Part 1

Part 3

* * *

He met his second wife, Camille Senderek, in 2000 at a conference on neurobiology. With Anat Markram was already divorced. “It was love at first sight,” says Camilla.



Her parents left communist Poland for western Germany when Camille was five. She met Markrama when she received a degree in neuroscience at the Max Planck Institute. Markram moved to Lausanne to work on the “Human Brain” project, she began her studies there.



High, like her husband, with straight blond hair and green eyes, she was wearing a dark blue jacket, jumper and jeans at an office meeting at Lake Geneva. Here, in addition to autism research, she manages the world's fourth largest open source research firm, Frontiers, with more than 35,000 scientists as editors and reviewers. She laughs when I notice a lizard tattoo on her ankle: a reminder of the teenage hobby of The Doors.



To the question of whether she was worried that she was marrying a man whose son had behavior problems, she responds as if such a question never arose: “I already knew about Kai’s problems,” she says, “to By that time, he was already quite impulsive and difficult to control. "



The first time they spent time together, Kai was seven or eight. “Maybe I had a couple of bruises and bites on my hands, it was something with something. I could suddenly break down and do something dangerous, so I had to be on the alert, ”she says, noting that Kai could run out onto the roadway. "It was very difficult with him," she shrugs, "but he usually responded to caressing the same."



“Camilla was wonderful,” says Markram. “More systematic and set clear rules. She really helped him. Not at all like a stepmother in a movie. ” Soon, the couple began a joint study on autism at the Swiss State Institute of Technology (EFPL). “We talked a lot with each other and both were disappointed that science could no longer help,” recalls Markkram. Their common interests as parents merged with their research enthusiasm.



They began to study the brain at the level of signals. Markram took a graduate student, Tanya Rinaldi Barkat, to find a better animal model, since such studies cannot be carried out in humans.



When I was there, Barkat looked into Camilla’s office, ten years ago she switched to other studies. She warmly welcomed former colleagues.



Barkat began research for final work with a literature search for an animal model. They concluded that the most similar to human autism in rats caused prenatal action of valproic acid (VPA, Depakote). Like other “autistic” rats, VPA rats showed abnormal social behavior, repetitive actions, such as over-cleaning.



But more importantly, in pregnant women who were prescribed VPA to control seizures, the risk of having a child with autism increased sevenfold. A 2005 study says that 9 percent of these children have autism.



Because of the association of VPA with autism, it seemed that its effect on animal cells would be similar. A neuroscientist who studied VPA in rats once told me: "I do not see this as a model, but as a repetition of the disease in other species."



Barkat set to work. Early studies have shown that time and dose effects are critical: different periods can lead to opposite symptoms, and large doses sometimes cause physical deformities. The “best” time to cause autistic symptoms in rats is the 12th embryonic day, so Barkat was giving the drug at this time.



At first the work was unbearable. For the first two years, Barkat studied inhibitory neurons from the cortex of rats with VPA, using the same patch-clamp method as Markram a few years earlier. If these cells were less active, it would confirm the imbalance that Merzenich suggested.



She repeated the experiment, making neat clips to study the braking distance. But after two years of this technically difficult, tedious and time-consuming work, she had nothing to show.



“I didn’t see any difference,” she says, “they looked perfectly normal.” She continued to make clamps, cell by cell, endlessly repeating the procedure, but again there were no deviations. As she herself says, at least she became a specialist in this technique.



Markram was ready to give up, but Barkat objected, saying that he wanted to switch from brake to VPA exciting networks. It was there that she found a solution.



“There was a difference in the excitability of the entire network,” she says enthusiastically. The cells in the VPA network responded twice as strongly as normal - and they had redundant connections. If a normal cell had connections to ten others, then the VPA cell was connected to twenty. In addition, they did not react less. On the contrary, they were hyperactive, which is not necessarily a defect: a network with a large number of connections is more flexible and learns faster.



But what did all this mean for autistic people? While Barkat was investigating the bark, Camilla Markram observed the behavior of the rats, noting the elevated levels of anxiety compared to normal rats. “It was a goldmine. The difference was visible to the naked eye. VPA rats were different from normal and their behavior was different, ”says Markkram. They were faster scared and quickly learned what to fear, but more slowly they understood that a previously threatening situation was now safe.



Unlike ordinary rats, which were subjected to electric impulses with certain sounds, VPA rats were afraid not only of the sound, but also of the grille itself, and everything associated with them - colors, other distinct sounds, smells.



“Fear was multiplied,” says Markram. “Then we looked at the reaction of the cells in the amygdala, they were also hyperactive. Wonderful".

* * *

Markram understood the significance of these results. He realized that hypersensitivity, memory and emotional systems can explain both the talents and the difficulties of autists. In the end, the rat's VPA problem was not that they could not learn - they learned too quickly, with great fear and irreversible.



He remembered the problems of Kai - how he covered his ears with his hands and refused to go to the cinema, was afraid of loud noises, his limited diet and the horror of new dishes.



“He remembers the place where he sat in a restaurant, trying to force himself to eat salad for hours,” says Camilla, recalling that she promised him something for it. But he could not bring himself to eat even a piece. This was clearly an excessive increase in fear.



The Markramas recalled Kai's tantrums, wondering if they were caused by strong experiences. They realized that identifying Kai’s particular sensitivity to certain situations could prevent a tantrum, allowing him to avoid a stressful situation or reduce stress before it becomes unbearable. The idea of ​​an intense world had immediate practical consequences.



VPA data also showed that autism is not limited to a single brain network. In the rat VPA brain, both the amygdala and the cortex were hypersensitive to external stimuli. Markrams decided that perhaps behavioral difficulties were not a defect in social interaction; perhaps they are the result of complete information overload.

* * *

Imagine what it is like to be a baby in a world of endless and unpredictable sensations. It is not surprising that a stunned infant may try to escape. Camilla compares this to insomnia, jet lag and hangover at the same time. “If you do not sleep for a night or two, everything hurts. From the light. From the sound. You are hiding, "she says.



However, unlike adults, small children cannot run. All they can do is cry and rock, and then try to avoid touch, eye contact, and other strong experiences. Autistic children can revel in models and predictability, only to understand the meaning of chaos.



At the same time, if children do not make contact in order to try to cope with the overload, they will miss what is known as the “sensitive period” - the stage of development when the brain is especially susceptible and quickly assimilates certain types of external stimulation. This can leave problems for life.



Language learning is a classic example: if children do not encounter speech for the first three years, their verbal abilities will be limited. Historically, this created a false connection between deafness and mental disability: before deaf children began to learn sign language at an early age, they often had problems with speech. Their problem was not defective “language zones”, but that they were denied linguistic stimuli at a critical moment. (By the way, the same phenomenon explains why it is easy for young children to master a second language).



It is of great importance for autism. If autistic children stop reacting when overloaded, their social and linguistic difficulties may arise not because of damaged areas of the brain, but because critical data are muffled by noise or missed because of attempts to hide when the brain really needs similar stimulation.



The Intensive World Theory also explains the tragic similarity between autistic children and abused children. Abused children often swing, avoid eye contact, and have social problems — just like autistic children. These parallels led to the fact that for decades the parents of autistic children, including the notorious “mother-refrigerator” , were accused. But if this behavior is a coping mechanism for stress, autistic people may not manifest it because of ill-treatment, but because the usual experience is stunning or even traumatic for them.



Markram found out further consequences: social problems cannot be a determining or integral feature of autism. Early intervention to reduce or mitigate the intensity of the environment for an autistic child may help protect his talents, while autism-related disorders will soften or possibly disappear.



The VPA model also reflects other paradoxical signs of autism. Excessive sensitivity is most common, but autistic people are also often less sensitive to pain. The same applies to VPA rats. In addition, due to autism, abnormal growth of the brain, especially the cortex, occurs. There, research reveals an excess of links, called minicolumns, which can be considered microprocessors in the brain. VPA rats also exhibit this excess.



Moreover, redundant minicolumns were discovered at the autopsy of the bodies of scientists who were not autistic, so such an organization of the brain can appear without social problems and with exceptional intelligence.



As a high-performance engine, the autistic brain can only work in certain conditions. But in these conditions, these machines can significantly surpass others - like a Ferrari compared to Ford.

* * *

The first publication of the Markrams research appeared in 2007: a document on VPA rats in the works of the National Academy of Sciences. This was followed by a review in Frontiers in Neuroscience. The following year, a symposium on this topic was held at the Society for Neurology (SFN). In 2010, they updated and expanded their ideas in the second publication of Frontiers.



Since then, other groups have published more than 30 articles on VPA rats, extending the results of the Markrams. This year (2013), at least five new studies on VPA autism models were presented at SFN. The sensory aspects of autism have long been ignored, but the theory of the intense world and the VPA rats bring them to the fore.



Nevertheless, the reaction from colleagues was cautious. With the exception of Laurent Mottron, professor of psychiatry and director of autism research at the University of Montreal. He was the first to identify perceptual differences as critical for autism - even before the Markrams. Few researchers have studied sensory problems before him. Almost everyone else focused on social issues.



When Mottron first suggested that autism is related to what he calls “enhanced perceptual functioning,” he, like most experts, saw it as a consequence of a deficit. The idea was that, apparently, the excellent perception shown by some autistic people was caused by problems with the functioning of the brain, and historically it was rejected as simply “side skills” and not a sign of genuine intelligence. Savants used to be called idiots; as was considered, unlike the "real" geniuses, they had no creative control over their exceptional minds. Mottron described it in this way in a review document: “[A] dull people did not demonstrate atypical strengths of perception, but showed an inability to form representations at a general or high level”.



However, Mottron's research led him to believe that this opinion was erroneous. His own and other studies have shown the excellent abilities of autistic people not only in “low-level” sensory tasks, such as better defining musical tone and a greater ability to perceive certain visual information, but also in cognitive tasks, such as searching patterns in visual IQ tests.



It has long been known that the detection and manipulation of complex systems is the strength of autists, so much so that Savant has become a stereotype of Silicon Valley. In May, for example, SAP announced plans to hire 650 autistic people because of their exceptional abilities. Mathematics, music, and scientific achievement require understanding and interaction with systems, patterns, and structure. Both autistic people and their family members are over-represented in these areas, which suggests the influence of genetics.



“Our points of view are in different areas [of research], but we come to ideas that really touch each other,” says Mottron about the Markrachs and their intensive theory of the world. (He also notes that they are studying cellular physiology, and he is the whole human brain).



Since Henry Markram came to this area from the outside and has an autistic son, Mottron adds: “He may have an original point of view and no cliché can affect him,” especially those who took talents for shortcomings. “I like what they do,” he says, although he is not convinced that they have covered all the details.



Of course, Mottron’s support is not surprising, because the theory of the intense world is consistent with his own results. But even one of the creators of the concept of "theory of mind" finds most of the plausible.



Simon Baron-Cohen, who runs the Autism Research Center at Cambridge University, told me: “I’m open to the idea that the social deficit in autism, along with the cognitive aspects of empathy, that is, the“ theory of mind ”can come from sensory disorders.” , the Markrams physiological model can be the cause, and the social deficit that he studies has an effect. He adds that the model with VPA-rats is “curious.” However, he also notes that autism most often is not caused by VPA and it is possible that sensory and with socio defects occur together, rather than one causes another.



His colleague, Uta Frith, a professor of cognitive development at University College London, is not so sure. “They did not solve the problem,” she says of the theory of the intense world. “I don’t want to say that this is nonsense,” she says, “but I think they are trying to explain too much.”