[Feature: The Forefront of Brain Science Research] Kenji Tanaka: The Forefront of Approaches to Mental Disorders from the Perspective of Brain Science

2022/03/07

Do you think there is room for science to tackle mental illness? Suppose someone who has lost a spouse and is suffering from intense grief has lost their appetite and is unable to work. Most people would first stay close to them, remember the deceased together, and leave them be. It seems there is little room for science to intervene and solve this. Now, let me change the question. Do you think there is room for science to tackle brain diseases? Consider a mother whose forgetfulness is progressing and who complains that her money disappears every time a care manager visits. Since mental symptoms caused by dementia have a cause in the brain, intervening in the brain—the cause—should solve them. This can be said to be one approach to mental symptoms from the perspective of brain science.

One of the contrasts I made here is the question of stance: whether to view mental disorders as diseases of the mind or diseases of the brain. I would be happy if anyone noticed another subtle rephrasing: the question of whether to view mental disorders and mental symptoms as the same or different. Mental disorders fall into the category of diseases, such as depression or dementia. On the other hand, mental symptoms refer to a state at a specific moment—for example, feeling depressed right now, or being convinced right now that something is being stolen. In this article, I take the position of treating mental disorders as brain diseases. Furthermore, I will treat mental disorders and mental symptoms without distinguishing between them.

Brain science has developed primarily around academic systems previously treated as medical sciences, such as anatomy (what cells the brain is made of and how they are connected), physiology (what functions the brain has), and Pharmacology (Division of) (why drugs work for mental disorders). However, I believe many readers feel that these alone are not enough to understand the brain or the mind. That is correct; more humanistic and social science perspectives are needed, such as psychology (the study of how the mind works), sociology (the study of connections between people), and nursing (the study of supporting the sick). It is also a fact that the entry of science and technology fields such as artificial intelligence and computational science has led to dramatic progress in brain science over the past decade.

Currently, brain science can be described as a single academic system that integrates various academic fields. Each field has its own cutting edge, but I would like to describe the forefront from a medical perspective, which is my specialty.

Currently, national projects to dissect and thoroughly investigate the brain are underway in Europe, the United States, Japan, and China. It is said that the brain has tens of billions of cells, and one cell is said to have more than 10,000 inputs. Since "it is said" is not enough, ambitious projects are currently underway to clarify this using the best technology available to humanity.

You might be disappointed, but because the human brain is still too large and complex for us, we are thoroughly investigating the brains of mice, which are also mammals. In other words, to understand the human brain, we are thoroughly studying mouse brain anatomy. In the last 10 years, there have been several discoveries that have rewritten the knowledge in conventional textbooks.

Another breakthrough is the progress in functional analysis based on anatomy, so-called physiological analysis. Anatomy is like creating a precise map of the brain, while physiology clarifies how the roads are used (the flow of signals), such as which roads are empty and which are congested. Observing where signals are flowing in the brain at this very moment also requires advanced technology. There is a reason why signals flow to a certain brain region at that moment, and there have been technological innovations that can clarify the "why."

I also use mice as experimental animals and conduct thorough anatomical and physiological research every day. I am enhancing my own research while incorporating new findings revealed by domestic and international projects. Brain science researchers, including myself, have no intention of ending our research careers with mouse studies; we use them to help understand the human brain.

In fact, the mouse brain (about the size of a thumbnail) has the same basic structure and function as the human brain. Since mice and humans are completely different animals, you might think that's ridiculous, but both mice and humans move using limbs, eat using mouths, and sleep. They engage in sexual activity to produce offspring, and mothers lactate and raise their young. If an enemy approaches, they sense it and flee. The basic behaviors for survival are almost the same, and the basic functions of the brain that give commands for those behaviors are also almost the same.

Research dealing with the human mind, such as philosophy and theology, has a history of thousands of years. On the other hand, brain research has a history of only about 200 years. In the early days of brain research, to investigate what the brain was like, dissections were performed on the brains of deceased individuals. People who recovered from a stroke would experience various higher brain dysfunction, including paralysis. For example, by dissecting the brain after death, it was discovered that blindness occurred because a brain region called the visual cortex, located in the occipital lobe, was damaged.

One of Hideyo Noguchi's achievements was identifying the cause of progressive paralysis. In progressive paralysis, mental symptoms such as mania or brutality appear some time after syphilis infection, for example, 10 years later. Then, motor disorders appear, and the patient dies in a state of decay. It was greatly feared because it led to death within two or three years after neurological symptoms appeared, but Hideyo Noguchi was the one who discovered through a vast number of post-mortem brain dissections that the syphilis bacteria itself infects the brain.

However, since there was no way to eradicate the syphilis bacteria that had infected the brain, it was an incurable disease at the time even if the cause was known. Psychiatric hospitals were established in Japan from the Meiji era onwards, but before 1950, progressive paralysis accounted for half of the patients admitted to psychiatric hospitals. The discovery of the antibiotic penicillin was before World War II, and its widespread use was after the war. Since syphilis bacteria are highly sensitive to penicillin, syphilis infection itself decreased after the war as its use spread, and progressive paralysis also plummeted. The discovery that the progressive brain disease with various neurological symptoms called progressive paralysis is an infectious disease caused by syphilis bacteria and can be treated with penicillin can be called a brilliant achievement of brain research.

Thorough efforts were made to collect the brains of people who died with neurological symptoms (inability to move the body, loss of sensation) or mental symptoms and investigate abnormalities macroscopically and using microscopes. This research into the anatomical study of post-mortem brains is called neuropathology, and through neuropathology, the pathology of neurological diseases such as Alzheimer's disease and Parkinson's disease was clarified one after another.

On the other hand, regarding mental disorders, no matter how much the post-mortem brains of patients were examined under a microscope, no abnormalities could be found. There was almost no difference from the post-mortem brains of healthy individuals. For this reason, the approach of trying to find structural abnormalities in the brains of patients with mental disorders fell out of favor. In particular, after the Japanese Society of Psychiatry and Neurology issued a policy in 1975 not to perform any psychosurgery (brain surgery for the treatment of mental disorders) due to reflections on the expanded application of lobotomies, it became difficult to obtain even post-mortem brains.

What broke through this sense of stagnation was technological innovation that visualizes the structure and function of the human brain in a living state. Readers have likely undergone CT or MRI scans at least once. MRI, in particular, is an excellent tool that allows for the observation of brain structure and function in a living state.

In the 1980s, MRI began to be used in clinical practice. At that time, by looking at the structure of the brain, abnormalities in "shape" were detected, such as a thin cerebral cortex or damage to the occipital lobe. In 1990, Dr. Seiji Ogawa established an MRI method for investigating brain function, which made it possible to conduct research visualizing brain function with MRI (Dr. Seiji Ogawa is a 2017 recipient of the Keio Medical Science Prize).

MRI is a medical device that brings together the best of physics, and it requires many calculations to obtain image data for a single patient. As if that weren't enough, MRI data obtained from a single patient is collected and analyzed on a scale of thousands of people. Fortunately, because computer performance is improving every year, the analysis of large-scale data with a very high computational load has become possible on PCs owned by individual researchers. It cannot be ignored that the entry of mathematical statisticians into brain science is advancing this data analysis. Personally, I expect that the quantum computer that has begun operation at Keio's Faculty of Science and Technology will dramatically improve large-scale brain image data analysis and bring about further revolutionary discoveries.

In 2016, a group centered at Osaka University analyzed MRI brain images of approximately 1,600 healthy individuals and 900 patients with schizophrenia, revealing that a brain region located in the center of the brain called the globus pallidus is slightly larger in schizophrenia patients than in healthy individuals. This study has since been replicated by foreign research groups that analyzed data from thousands of people. It seems to be a fact that the globus pallidus becomes larger in schizophrenia. So, why does it get larger? Does the globus pallidus get larger, leading to schizophrenia? Or did the globus pallidus get larger because of schizophrenia? These questions come to mind immediately, but confirming them in humans is not easy.

Therefore, our research group returned to mice. I won't go into detail here, but we focused on another neurological disease model in mice where the globus pallidus becomes larger. When we analyzed the brain structure of that neurological disease model in the same way with MRI and thoroughly analyzed the mouse post-mortem brain neuropathologically, we found an increase in the volume of certain neurons. We then identified a change in Gene X that could explain that increase in cell volume.

Next, we confirmed that the globus pallidus becomes larger in a state where this Gene X is artificially overexpressed (since only this Gene X is overexpressed, it does not reproduce the original neurological disease model). This finally makes it possible to indirectly answer the question, "Does the globus pallidus get larger, leading to schizophrenia?"

The next step is how to think about schizophrenia in mice. There is no way to know if a mouse has auditory hallucinations or delusions, but it is known that mice also have symptoms similar to the cognitive impairment characteristic of schizophrenia. Therefore, we can deepen the previous question by one step: "What must be added to the preparatory state of an enlarged globus pallidus for cognitive impairment to appear?"

Our mouse research has only reached this point, and we are in a situation where the real work is about to begin, so I have shared our ongoing research with you. What I wanted to convey here is the progress in brain research: the ability to image the structure of the brains of schizophrenia patients—where abnormalities could not be detected with conventional neuropathology—using MRI in a living state, collect that as data from thousands of people, and discover a completely unexpected brain structural abnormality, the enlargement of the globus pallidus, as a result of calculations using mathematical statistics. This stance of using mice to solve various questions based on the latest results obtained from human research can be said to be one approach to mental disorders from human brain science.

On the other hand, there is also a way to approach mental disorders from mouse brain research. As mentioned earlier, the anatomy of the mouse brain is being performed precisely at the micro level, and the results are freely available for researchers around the world to view, so functional elucidation based on that anatomical data is being actively conducted. The central role in that functional elucidation is played by technology for observing the activity of specific neuronal populations and technology for manipulating that activity. This is a much more precise method of observing neural activity than MRI. In an MRI, one must not move a muscle inside the scanner, but this new neural activity observation method can accurately acquire signals even while the mouse is moving around freely. Both the technology for observing activity and the technology for manipulating it are characterized by the use of light.

The core of the technology for observing activity is fluorescent proteins, and the contribution of Dr. Atsushi Miyawaki (Keio University alumni), a 2020 recipient of the Keio Medical Science Prize, is outstanding. Dr. Miyawaki modified fluorescent proteins to develop proteins that can monitor the strength of neural activity through the intensity of the fluorescence emitted. The core of the technology for manipulating activity is photosensitive channels, and Dr. Karl Deisseroth, a 2014 recipient of the Keio Medical Science Prize, introduced neural activity manipulation technology using photosensitive channels to the world as optogenetics.

Brain science researchers around the world, including myself, are using these two technologies to challenge the elucidation of brain function. Since both are proteins that do not originally exist in the brain, gene introduction is a prerequisite. Since gene introduction into the human brain is not performed even as a treatment, these are research techniques possible only in model animals.

In my laboratory, we challenged the elucidation of the neural basis governing motivation. Motivation can be evaluated by behavior in both humans and mice. The enthusiasm at the start, saying "Let's do it!" and the power to sustain and finish it—I think you would agree that a high evaluation of motivation is only obtained when both are present. Through research using mice, we clarified that the start of motivated behavior is controlled by the insular cortex-striatum pathway, and the persistence of motivated behavior is controlled by the hippocampus-striatum pathway.

The fact that different brain circuits control the start and persistence can be seen from the phrase "a three-day monk" (quitting after three days). A three-day monk can start motivated behavior but cannot sustain it. And that is controlled by different brain circuits. So, how can this be used to understand mental disorders? In depression, motivation decreases. Motivation also decreases in mouse models of depression. We focused on the inability to sustain motivated behavior among the decreases in motivation. At this time, we clarified that hippocampal activity increases in a depressed state, which makes it impossible to sustain motivated behavior, and that the administration of antidepressants normalizes hippocampal activity and restores the persistence of motivated behavior. Through this kind of approach, we will be able to propose treatment methods focused on hippocampal function from mouse research, whether that approach is psychotherapy or getting a good night's sleep, which we don't know yet.

In this article, I have introduced the forefront of approaches to mental disorders from human brain science and mouse brain science from my perspective. If the author were different, the forefront would likely be told from a different angle. I believe this is proof that brain science is an academic system that spans other fields and that the results from brain science are expected by many people.