Interviews

First step towards the dream, being a brain scientist – Tohoku University, Kyoto University, Karolinska Institutet

- Electroencephalography is the first thing I recall learning about brain research. When you entered medical school, how far had brain imaging research progressed? Had imaging research just started, or it had not yet started and brain research was focused on electroencephalography research? Could you explain the situation at that time and what made you interested in research on functional brain imaging?

At that time, I learned electroencephalography in clinical medicine, but I honestly did not fully understand it. When I was in my fifth year at Tohoku University’s School of Medicine, the first positron emission tomography (PET) machine was introduced. This was the first PET machine at any of the National Universities. The machine was introduced for the early diagnosis of cancer. However, I attended a lecture by a professor who handled PET and suggested that it could be used to image human brain function and activities depending on how it was applied. Since my dream from junior high school was to transplant my brain function into a computer, I thought “this was it!” and joined a radiology laboratory in graduate school where I could handle the PET machine. I wanted to take a shortcut to analyze human brain function, instead of taking a long way by studying the mouse brain.

- In that sense, PET had been introduced in Tohoku University in a timely manner. Can we say that Tohoku University was the top runner in functional brain imaging research at that time?

No, that is not really true. The most difficult point at graduate school was that no one knew how to handle the machine. No one was sure how to apply PET to brain research, and the machine became a waste of talent. I found that the situation at Tohoku University was far from applied research and decided to transfer to Kyoto University to study the cerebral physiology of monkeys. Since there were no predecessors who studied human cerebral physiology there, I started by tracing the experiments in monkey cerebral physiology to humans.

- We could imagine that you had a great deal of problems bridging the research in monkeys to humans. If you could please elaborate on some of the problems you faced, particularly with ingenuity.

Basically, we conducted cerebral physiology research in which electrodes were inserted into the brain of a Japanese monkey and recorded the neuronal activity in a single unit while the Japanese monkey learned a particular behavior. When applying the method to humans, it was necessary to consider how to design the task and how to be aware of the problem. A human imaging experiment that was identical to the one conducted in monkeys was the go/no-go task experiment designed by Dr. Kubota of the Primate Research Institute of Kyoto University, under whom I studied. It was a simple task of either behaving or withholding and suppressing. In physiology, it was mainly carried out to analyze two different brain activities of “go = behaving” and “no-go = preparing to behave but did not actually behave”. We conducted this study in humans. In fact, we were successful in finding that both humans and monkeys took quite different processes in go and no-go. While there were no major problems; we did experience certain limitations. What we found difficult was that the monkey’s abilities were limited and most of the behavior were conditioned responses, even though they were called spontaneous behavior. Conversely, almost all human activities are voluntary movements and spontaneous behavior. I wanted to study physiology using functional brain imaging, such as PET, but I also felt that the result might be ignored if my study got out of the existing academic purview. Since the study on monkey’s cerebral physiology was also a state-of-the-art at that time, I took the strategy that first obtained the similar experimental results in the human brain, to prove there was no methodological mistake, and then got into the study of distinctive functions in the human brain.

- Could you tell us a little about your experience of studying abroad at Karolinska Institutet, and about your research and its outcomes during your study there?

While studying at the graduate school of Kyoto University, I was very frustrated to hear that researchers in the Karolinska Institutet in Sweden had used the same device and already completed a paper on the mapping of brain functions. Soon after I heard the news, I sent a letter to the professor who wrote the paper; I went to Karolinska University after I completed the graduate program at Kyoto University. I started the study of brain mapping there. I studied under a Danish professor, Per Roland, who conducted research on brain mapping using PET. His lab comprised one professor, international students mainly in charge of research, and graduate students. Therefore, I was able to conduct research using PET early on as a part of the main research force. Prof. Roland is a neurologist, a somatosensory/tactile expert. While helping Prof. Roland’s research on tactile sensations, I wondered every day if I could do my original research. There were two major studies that I was a part of at Prof. Roland’s lab: one was a study of spatial cognition during movement, and the other was a study where I found active involvement of inhibition of the sensory area, which prevents concentration when people focus on something to compensate for an activity of the area of concentration.

Activities of the Kawashima Lab

- We assume that the Kawashima Lab is currently carrying out research on three pillars: functional brain imaging, functional brain development, and dementia prevention. Could you introduce us to the latest research idea you are interested in?

My main task is research on functional brain mapping. Our lab owns and utilizes all kinds of brain imaging equipment including functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). We are proud to have such a rich and unique research environment. We fully utilize the equipment to conduct research on brain activities and functional brain mapping.
In the late 1980s and early 1990s, when I brought this research (to Japan), the situation was vibrant, and the more I studied the newer knowledge I gained. However, since the 2000s, the equipment was started to be used by researchers who did not understand the basic principles, and the research direction was shifted to image the differences in very fine brain activities. We have been researching the area that we thought was most interesting in dynamism. Of course, as a team, we conduct research that depicts fine differences, but I do not find the recent trends interesting, and my interest has faded.
Another large team in the lab works on the Children’s Brain Development Research Project. This team is intended to fulfill a social mission. The goal of this team is to develop epidemiological studies based on the hypothesis that there may be hints for improving brain function in the lifestyles of healthy children and children with various cognitive dysfunctions. This research has yielded a number of outcomes and successfully returned the information to society. In addition, in elderly, we proved that their cognitive function could be improved by cognitive interventions, and it reached the point that a company in the United States started social implementation. In the future, we hope that it will become more sophisticated as it is applied in practice. The effectiveness of the interventions, other than that of the dual interventions, has not been confirmed, and I think this is the final step.
It is my practice to instruct graduate students and staff members to organize research in line with their own interests. Whenever we are asked about the overall direction of the lab, we say it is scattered (lol). If I force them to do what I want to do, the students will not grow as researchers. I wish that they grow with the motivation of “experimenting with their own interests, getting results, and publishing them.”

Starting with researchers’ self-reflection – NeU Corporation

- Could you tell us how you started at NeU Corporation and what kind of business NeU is developing?

The purpose for the establishment of NeU Corporation is to develop a simple device to measure daily brain function and provide a new brain training service while monitoring its activities. The origin of this company is based on our self-reflections as researchers.
Until now, functional brain mapping research has been conducted to examine human brain function only in a very specialized environment. Even with MRI and PET, the subject was lying in the gantry and given stimulus limited by the machine, and they showed extremely limited response. We could only know which part of the brain is activated. When I think of a living human, and when I think of my own dream of transplanting my brain into a computer, I experimented with a doubt whether the data are really valid. From such experiences, I wondered if I could properly decode brain activities in daily life. To realize this belief, I wanted to develop a simple device to measure daily brain function.
Another main aspect of NeU’s functioning is providing brain training services, which is also a reflection of the research conducted at the university lab. For example, suppose we obtained robust data supported by statistics, showing that cognitive interventions improved dementia symptoms in elderly people. As a scholar, this score is full. However, if we look at individual data, even if it is a statistically significant improvement, 10–15% of subjects are usually excluded from the study. Therefore, a statistically significant improvement merely means a statistically significant difference. As a group, we are fulfilling our mission, but when you think about the social implications for the 15% of people who dropped out of the study, they did not receive any training.
When I thought about providing it as a service, I had to eliminate the loss of 15% dropout; therefore, I developed “prediction research.” This is a new type of study. In this research, we longitudinally follow-up the training environment and identify the training methodologies that generate good results. Ultimately, the study elucidates the modifications required to the initial setting of the training to avoid dropouts. For example, one study revealed that training was more effective in right-handers who more frequently trained the dorsolateral prefrontal area of the left hemisphere. In contrast, those who do not use that area did not show much improvement. It is very simple to monitor the brain activity of the area during the training. If we can provide training that is focused on improving that particular area, all subjects can train their brain without dropping out. However, only with a large funding in university research, we can use MRI for monitoring, but this is not possible in everyday life outside of the lab. For practical implementation, it is necessary for everyone to measure their own brain activity. Then, a simple device to measure brain function is essential for this research, and we are starting to collaborate with Hitachi High-Tech for this indispensable device.

- Are the activities by NeU becoming the nucleus of the Kawashima Lab?

I keep laboratory staff away from activities related to social implementation. I am not sure if they can make a living with this work in the future, and I want my students to devote themselves to “academics.” I devote my efforts to NeU based on my personal interest in implementing the results of basic research for the welfare of the society.

- Will the data obtained by the brain function measuring device developed by NeU be used only for personalized data? Or do you use it as mass data for all subjects?

I take the data as big data and make it available to collect data from all subjects. By collecting mass data that should originally belong to individuals, including genetic information, I hope new information that is more useful to society comes out. The current market is mainly in Japan, but the market is expanding in China and other Asian countries. The main interest in Asian countries is the education of children. We are responding to their requests, such as wanting to know more efficient ways of studying or to have a more study-suitable brain. Japan, Taiwan, and mainland China will enter a super-aging society in about 20 years and have a sense of crisis. Therefore, we are also targeting measures for an aging society. For middle-aged white-collar workers, we are collecting data mainly in Japan.

- For example, how do you think it would be useful to evaluate brain function using currently developed devices for children with developmental disabilities?

Developmental disabilities are quite diverse, sometimes 100 people have 100 different symptoms. Therefore, it is difficult to say whether we can write a common “equation” for all children. However, the results of this study indicate that cognitive training can not only increase cognitive function but also improve sociability. Particularly, attention-deficit hyperactivity disorder (ADHD) children like to use gadgets like smartphones and games, so I think cognitive interventions using these gadgets are effective. However, we think it is too early to provide training as a service. Parents and guardians of children with developmental disabilities are desperate and tend to believe everything. We know that if we provide the training that we have developed without sufficient evidence, they will rush out to obtain it. However, that is a bit different from the social implementation I want to achieve. We want to accumulate solid evidence and refine it to a point where we can provide personalized information before we provide the training.

- Could you explain near-infrared spectroscopy (NIRS) developed by Hitachi High Tech? How precisely can this optical topography detect blood flow fluctuations in the skull? From your perspective, how does it technically mature?

NIRS is an original Japanese technology, and Shimadzu and Hitachi High Tech have competed with each other to develop this device. At first, I was skeptical about the device and its original principles. The principle of NIRS is to deliver near-infrared light at the surface of the head and detect reflecting light in the brain. However, it is difficult to determine what the light is passing through. NIRS uses near-infrared light, and it uses the principle that if we deliver lights with wavelengths that are easily absorbed by lights of different wavelengths of oxyhemoglobin and deoxyhemoglobin, we can measure the hemoglobin concentration in the area where the light passed. However, I have greatly questioned its’ relation to brain activity. Therefore, prior to the formal adoption of NIRS for research, we conducted the same experiment with the same subjects using fMRI and verified whether we could obtain the matched data, at least for the brain surface. Surprisingly, the results showed no significant differences. Before proceeding with NIRS studies, we decide the target by mapping using fMRI and other methods. In other words, although we use NIRS as a decoding tool, it has been developed under the rule that focus areas will always be determined using refined imaging techniques.

- Having such a verification system in your own lab means that you have an excellent system that does not allow other followers.

Going slightly off topic, I think that research that is based only on NIRS is a little unreliable. A well-known error with this technique is that even tilting your head forward changes the NIRS signal. The point is that the neck becomes squeezed and the face becomes congested, making it look like the blood flow has increased. When a person does something, his/her neck is upright when he/she is relaxed, but when he/she is concentrated, his/her neck bends forward. It is obvious that is not it (lol). In addition, I laughed a lot when reading research results announced by a team that cerebral blood flow decreased when the patient was in a cold environment. When it is cold, the capillaries shrink, resulting in reduced blood flow to the skin. If the cerebral blood flow falls in a cold place, that is it.

The mission of the Institute for Development, Aging and Cancer

The Mycobacterial Disease Research Institute, the predecessor of the Institute of Development, Aging and Cancer, was founded in 1941 to develop treatment for tuberculosis and leprosy. Later, once the effectiveness of penicillin was confirmed and a public health prospect was established, the research ideology of the institute shifted to cancer- and aging-related issues.
According to the definitions used in aging research, “geriatrics” is not equal to “ageing.” Aging is a phenomenon along the time axis from the birth of life to development, maturation, senescence, and death. When I assumed the position of director, I thought I had to do my best to learn and properly support healthy longevity as we enter a super-aging society. Focusing on dementia, I have organized the personnel in the center with the aim of conducting research on dementia prevention in a consistent manner, from the field of molecular biology to the clinical practice. We still have two or three cancer research teams, but most of their research relates to dementia prevention. There is a team conducting research on antioxidation in basic molecular biology systems. They conduct research leading to clinical research by developing antioxidant research that suppresses fine inflammation in the brain. Another team studied cellular senescence. Their research topic is how to control senescence rather than simply viewing the aging process. As a derivation of the research, my team, which contains four members including me, is planning social implementation with the cooperation of doctors from various fields within the university while conducting cognitive science and psychological research with two other researchers.

- With an aging society, research on dementia is progressing. Conversely, it is very important to study the motor system, such as the skeletal muscle and skeleton, when people become bedridden. In this context, I felt it is important to develop and integrate research on the central nervous system and aging on the motor function in the future.

I agree with you. The mainstay of the final phase of such research is said to be multidomain interventions. Research is progressing towards supporting healthy longevity as a whole by combining not only exercise and cognition but also interventions related to daily life and sleep technology, which have recently begun. We have also started research on multiple domains while confirming cognitive brain function.

- You just mentioned the relationship between cellular senescence and the subtle inflammatory response of the brain and research on antioxidation. Alzheimer’s disease was once treated as a neurological disease. This notion has been changing, and Alzheimer’s disease is regarded as a cardiovascular disease, and research focusing on microcirculatory disorders has been increasing.

Yes. We are focusing on chronic inflammation as a cause of microcirculatory disorders. Based on the idea that one of the main causes of chronic inflammation is antioxidant activity, we proceeded with this research. I think that the effects of chronic inflammation may also affect the vascular system.

- Which area or what function of the brain would you like to investigate by utilizing the brain mapping analysis that you have developed so far? Mainly for the hippocampus?

Classical research targets the hippocampus, but we are also interested in cerebral cortex research. However, it is difficult to understand using human brain mapping. Therefore, using MRI for animals, we designed an experimental environment for mice and rats where we can obtain imaging results similar to those of human subjects. Predicting research that makes us understand what happens in the human brain is conducted at the same time.

- Creating model animals

That is correct. Model animals and human subjects use the same MRI to measure brain activity during similar tasks, and we even generated a similar aging hypothesis. My rats undergo brain training and muscle training. In our experiment, we make the rats do what we intend to make human subjects do and predict the results of human subjects from rat data.

- This is a very interesting experiment, especially for veterinarians specializing in animal science like us. I wish we could do some dream-inspiring research with you someday.
We have to adapt to new lifestyles with COVID-19 in the future. Do you have any thoughts on how you can utilize the research you have conducted so far with/after COVID-19, or starting research on new topics related to coronavirus? If communication is not successful, it will not be synchronized.

I have already started some research. For example, we have started research on how real face-to-face communication and web-based communication, like this interview, relate to the human brain. This study showed that the blood flow of the dorsomedial prefrontal cortex, the central part of the forehead, where the area of compassion for others is located, is synchronized with the state of good communication. If communication is not successful, it will not be synchronized. We measured brain activity during classes at school. When the class goes well, brain activity between students and teachers, and between students and students, are synchronized. Currently, I am writing an article on how the synchronization of brain activity appears in real-time and online communication.

- You can use your approach not only to improve individual brain function, but also to provide scientific insight into the quality of communication with others. In addition, it gives us a hint of how to build a good relationship with others.

Yes, I think the research in that area is very interesting. I think that brain science will be able to provide the world the extent that human brain is deceived and recognize web-based communication as real communication. Epidemiological research has already begun to find out what lifestyle habits are effective in improving depressive symptoms. Imaging research on the state of brain condition of people who feel lonely was also conducted, and results have already been obtained. We now consider the possibility of interventions for social implementation. In that sense, we can say that our laboratory is actively conducting research with/after COVID-19.

- I think that AI will become the mainstream of society in the future, and there might be a part where everything is left to machinery. From a layperson’s point of view, I have a dreaded imagination that the development of AI and brain function may conflict with each other. Is there a way to make good use of AI in order not to reduce the remarkable human brain function? How do you think of the danger to brain function due to the development of AI?

I always think about such issues. Our institute has a collection of data which includes information on academic records and lifestyle habits of all children who attend public elementary, junior high, and high schools in Sendai City. Using the data, we conduct research on how the use of smartphones and IT devices affects children’s behavior. As a result, data showed that children who use such digital devices more frequently have lost various things in the process of growth. For example, if they tend to depend on smartphones, they have a clear sign of aging in the cerebral white matter. In other words, we can say that “brain degeneration” has occurred.

- I would like researchers who specialize in AI to announce not only good points but also risks of AI scientifically by collaborating with brain function researchers like you.

I agree with you. I would definitely like to ask AI researchers what kind of future compositions their research is based on. If people stop thinking, what is all this for? If growth engineering develops further, there will be no need to have real children, is that not true? The point is that if our bodies are no longer necessary to leave genes, our existence becomes meaningless. It is up to us to decide which direction our civilization will be going forward from now on. Our basic physical fitness has been declining as we pay money for transportation methods instead of using our own body. To compensate for this situation, we pay money for the gym. I think the same is true for the brain. In the future, people will think less and train cognitive function in the same way as we go to the gym to keep ourselves human.

- At the end of this interview, could you please tell us what you expect on younger researchers?

I think the dynamism of research is lost. Many researchers might think they research only a part of a large stream. I understand that it will happen as research progresses, but I believe that we can always find areas where we can feel great dynamism. I want younger researchers to have a broader view and to study with a spirit of making their own wheel rather than being a cog in a wheel.

 

*1: In August 2017, NeU Corporation was established by fusing the “cognitive brain science discoveries” of Tohoku University’s Institute of Development, Aging and Cancer (IDAC), together with the “portable brain measurement technology” of Hitachi’s High Tech. With the mission of “contributing to improved quality of life in brain science,” NeU is developing a wide range of brain science solutions from brain fitness programs to simple devices that measure brain activity.

November 2020