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

Do you think there is room for science to tackle illnesses of the heart? Suppose someone who has lost a spouse and is suffering from intense grief loses their appetite and becomes 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 things here. Now, let me change the question. Do you think there is room for science to tackle diseases of the brain? A mother whose forgetfulness is not only progressing but who also claims that her money disappears every time a care manager visits. Since mental symptoms caused by dementia have a cause in the brain, they should be resolved by intervening in the brain, which is the cause. This can be said to be one approach to mental symptoms from the perspective of brain science.

One of the contrasts I have made here is the question of stance: whether to view mental disorders as illnesses of the heart or illnesses of the brain. There is another question of stance that I hope some of you noticed I casually rephrased: whether to view mental disorders and mental symptoms as the same thing or as different things. 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, the state of feeling depressed right now, or the state of being convinced right now that things are 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 are effective for mental disorders). However, I believe many readers feel that these alone are far from enough to understand the brain and the heart. That is correct; more humanistic and social science perspectives are also necessary, such as psychology (the study of how the heart 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 rephrased as a single academic system that integrates various academic fields. While each field has its own cutting edge, I would like to describe the frontline from the medical sciences 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 each cell is said to have over 10,000 inputs. Since "it is said" is not enough, there are currently ambitious projects 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 the work of creating a precise map of the brain, but in physiology, we clarify 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 their limbs, eat using their 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 heart, 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 directly 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 they lost their sight because the 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. Progressive paralysis occurs some time after a syphilis infection—for example, 10 years later—and manifests as mental symptoms such as mania or violent behavior. Then, motor impairments 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 it was Hideyo Noguchi who discovered through a vast number of post-mortem brain dissections that the syphilis bacteria itself infects the brain.

However, because 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 infections themselves decreased after the war as its use spread, and progressive paralysis also plummeted. The discovery that the progressive brain disease accompanied by diverse 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 work was done 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 investigating post-mortem brains anatomically 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 mental disorder 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 brain from 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. I believe readers have 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 while the subject is alive.

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 piece of medical equipment 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 year by year, the analysis of large-scale data with a very high computational load has become possible on PCs owned by individual researchers. The entry of mathematical statisticians into brain science has also played a significant role in 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 and revealed that in schizophrenia patients, a brain region located in the center of the brain called the globus pallidus is slightly larger 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 become larger? Does one develop schizophrenia because the globus pallidus becomes larger? Or did the globus pallidus become larger because of the schizophrenia? These questions come to mind immediately, but confirming them in humans is not easy.

Therefore, our research group returned to mice. I will not go into details here, but we focused on other neurological disease models in mice where the globus pallidus becomes larger. When we analyzed the brain structure of those neurological disease models in the same way using MRI and thoroughly analyzed mouse post-mortem brains 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 one develop schizophrenia because the globus pallidus becomes larger?"

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 level: "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 I have shared this ongoing research with you as we are about to enter the main stage. What I wanted to convey here is the progress in brain research, where we were able to discover a brain structural abnormality—the completely unexpected enlargement of the globus pallidus—by imaging the structure of the brains of schizophrenia patients (where abnormalities could not be detected with conventional neuropathology) using MRI while they were alive, collecting that as data from thousands of people, and calculating it 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, mouse brain anatomy is being performed precisely at the micro level, and the results are freely available for researchers around the world to view, so functional clarification based on that anatomical data is being actively pursued. The central roles in that functional clarification are played by technology to observe the activity of specific neuronal populations and technology to manipulate that activity. This is a much more precise method of observing neural activity than MRI. With 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 to observe activity and the technology to manipulate 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 Keio Medical Science Prize recipient, 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 light-sensitive channels, and Dr. Karl Deisseroth, a 2014 Keio Medical Science Prize recipient, introduced neural activity manipulation technology using light-sensitive channels to the world as optogenetics.

Brain science researchers around the world, including myself, are using these two technologies to challenge the clarification of brain function. Since both are proteins that do not originally exist in the brain, gene transfer is a prerequisite. Since gene transfer 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 clarification of the neural basis governing motivation. Motivation can be evaluated through behavior in both humans and mice. I think you will agree that one can only be evaluated as having high motivation when they have both the initial enthusiasm of "Okay, let's do this!" and the power to sustain it and see it through. 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 the persistence can also be seen from the phrase "a three-day monk" (someone who gives up easily). A "three-day monk" can start motivated behavior but cannot sustain it. And that is controlled by different brain circuits. Now, the question is how to use this to understand mental disorders. In depression, motivation decreases. Motivation also decreases in mouse models of depression. Among the decreases in motivation, we focused on the inability to sustain motivated behavior. 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, though we do not know yet.

In this article, I have introduced the frontlines of approaches to mental disorders from human brain science and mouse brain science from my perspective. If the author were different, I believe the frontline would be discussed 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.