Recent research has revealed that mental wounds from stress and abuse physically affect gene expression and brain chemistry. If these invisible mental wounds could be visualized, new pathways for treating psychiatric disorders might open up. Professor Akitoyo Hishimoto of Kobe University's Graduate School of Medicine is conducting research from both clinical and research perspectives to eliminate child abuse, depression, and suicide among children and youth through the development of biomarkers and the study of biological mechanisms that encompass child abuse prevention, youth depression, and even suicide risk.
Growing interest in mental care following earthquake disaster — Early intervention to prevent suicide
Words describing mental wounds such as trauma and post-traumatic stress disorder (PTSD) became widely known in Japan following the Great Hanshin-Awaji Earthquake that occurred in January 1995. Interest in mental care grew among physicians, and this became the catalyst for Professor Akitoyo Hishimoto, then a medical student at Kobe University, to pursue the path of psychiatry. However, what he discovered was that the elucidation of disease causes had not advanced in this field.
Only recently has molecular-level elucidation of pathology begun to advance for some diseases such as Alzheimer's disease, but many mental illnesses such as schizophrenia, alcohol dependence, and depression are still diagnosed as "symptoms" with unclear causes. While neuroscience studying the brain itself as an organ has advanced, this has not yet led to elucidation of psychiatric diseases as of the present day.
Why is it important to scientifically visualize the mind? For example, when suicidal ideation is apparent in clinical settings, physicians can focus on that and provide treatment. On the other hand, there are cases where the patient's condition is not manifest and is difficult to judge even in interviews with physicians. Hishimoto explains that people who have decided to commit suicide often appear to have calm and stable minds, and how to interpret this state is difficult even for clinicians.
Generally, suicide attempts are thought to occur at least 10 times more often than completed suicides, affecting not only the individual but also family members, friends, and others surrounding them. "The mind has a breaking point, and sometimes that limit can be suddenly exceeded. If we could visualize dangerous states beforehand, early intervention and prevention would be possible." Working toward visualizing mental states, the stress check system established by the Ministry of Health, Labour and Welfare in 2015 under the Industrial Safety and Health Act requires companies to assess the degree of psychological burden on workers. However, Hishimoto states that visualizing other mental states and enabling people to objectively view their own condition is extremely important for treatment and support.
Applying epigenome-wide association analysis and focusing on acquired changes in genes
Hishimoto has been engaged in research on the mind since his residency period, receiving guidance from Visiting Professor Osamu Shirakawa, who was a lecturer at Kobe University at the time, and has worked on Japan's first genetic research on suicide. Overseas, there were reports that when "serotonin," a neurotransmitter that stabilizes the mind, is insufficient, the mind becomes unstable and makes suicide more likely, but there were few studies that actually examined the brain at that time. There was also strong resistance to using the brain as a specimen after death, and there was the challenge that the brain's condition changes over time.
This led Hishimoto and his team to devise a method of examining genetic information from blood rather than the brain itself. When he studied abroad in the United States, Hishimoto conducted research using a genome-wide association study (GWAS). GWAS is a method for investigating the genetic factors of diseases from the entire genome, which is the genetic information of organisms. By 2010, many candidate genes for physical diseases such as diabetes had been discovered using this method.
When he returned to Japan in 2008, he expanded his ongoing research to GWAS. Within a limited research budget, he conducted a GWAS on suicide completers over approximately 10 years, and in 2019 was the first in the world to experimentally prove the existence of genetic factors in suicide. Genomic research suggests that inherited genetic factors lead to suicidal behavior, which could potentially create discrimination and prejudice. This is why he focused on the "epigenome." The epigenome refers to gene expression control mechanisms that do not involve changes in DNA base sequences and is known to be subject to changes acquired through aging and environment, becoming involved in various diseases. In other words, he thought that by comprehensively examining the epigenome using an epigenome-wide association study (EWAS), it might be possible to understand how not only genetic factors but also environment and lifestyle affect diseases.
Epigenomic aging due to abuse: Rejuvenation possible through treatment and rest
The reason Hishimoto studies the epigenome is that it can be improved through intervention, while the genome never changes throughout life. The "epigenetic clock" proposed by Dr. Steve Horvath of the United States in 2013 is a method for evaluating epigenome age, i.e. biological age, separate from chronological age (how many years have passed since birth) by analyzing the state of the epigenome. Since it is known that when organisms experience stress or damage, aging proceeds faster than chronological age, this could become one method for visualizing mental states.
Kobe City maintains a medical examiner system, and when bodies with unknown causes of death are discovered, autopsies are performed at Kobe University. With this background, Kobe University possesses DNA samples from 1,600 suicide cases—the only collection of its kind in Japan and the largest in Asia. Hishimoto and his team verified these samples and revealed that the epigenomic age of young suicide completers in their teens to thirties was 10 years more than normal (Figure 1). Furthermore, analysis of blood samples from children in their teens with a history of abuse revealed that compared with the control group, children with a history of abuse showed epigenomic aging, with particularly pronounced aging in children with suicidal tendencies (Figure 2).
What is interesting is that even when aging has progressed, epigenomic age can be rejuvenated by resting the mind and body or receiving treatment. In young depression patients, epigenomic age can sometimes become about one year younger after receiving treatment for approximately three months (Figure 3). Hishimoto points out that being able to concretely show one's improved state as numerical values becomes a positive message for patients.
Furthermore, he states that genomic and epigenomic research may enable investigation of the causes of why people fall into emotionally unstable states such as depression and aggressive states. That suicide has become a major problem worldwide can be inferred from the fact that research has rapidly advanced in Europe and America, where such research had previously been taboo. The International Suicide Genetics Consortium, in which Hishimoto has participated from its establishment, was founded in 2020, and research results worthy of top journals are being published by global teams. Recently, it has become clear that there are not only risk genes that cause suicide, but also genes that suppress suicide. "Research is now in its burgeoning period. Over next 5-6 years, knowledge that seems to connect to drug discovery and the discovery of new treatment methods will be obtained, and major breakthroughs may emerge in about 10 years," Hishimoto says with gleaming eyes.
Comparing brain images to explore factors — AI application and ELSI considerations advance
Hishimoto has achieved many results so far, but as a Project Manager for Goal 9 of JST's Moonshot Research and Development Program, adopted in 2023, he is accelerating his research. The achievements of the exploratory research selected for the program have been recognized, and from April 2025, the project will transition to core research. The core research will newly address four research and development items: ① elucidation of the biological mechanisms underlying stress and resilience, ② development of indicators evaluating biological impacts of abuse, depression, and suicide, ③ designing implementation technologies considerate of sensitive issues, and ④ ELSI strategies for technology implementation and dissemination (Figure 4).
With regard to methods for visualizing biological impacts, in addition to epigenomics, research is also being conducted using positron emission tomography (PET) brain scans uniquely developed by Professor Tomoyuki Miyazaki's team at Yokohama City University. This involves comparing brain images of people with experiences of abuse or suicidal behavior with those without such tendencies, examining differences in the state of AMPA receptors that play a central role in information transmission, and identifying the factors involved.
These studies aim to develop biomarkers that predict abuse and suicide risk that children themselves find difficult to articulate or that are difficult to detect on the surface, and to elucidate epigenomic and gene expression that increases emotional instability. Additionally, consideration of neuromodulation therapy, which is a mechanism for adjusting neural function through various stimuli, is being advanced as a new treatment method. Instead of conventional physical stimulation, alternative stimulation through computer applications and utilization of cutting-edge technologies such as artificial intelligence (AI) are also within view. Furthermore, ethical, legal, and social issues (ELSI) for social implementation will also be considered together.
Increase in student suicides during COVID-19: Biological approaches also necessary
Hishimoto says that it is necessary to continue accumulating research in the future regarding the visualization of the mind. Neuroscience and psychiatry require listening to patients and incorporating that into research, and by conducting clinical work and research simultaneously, the research he wants to pursue becomes visible.
One reason Hishimoto continues his research is his desire to somehow address the ongoing effects of the COVID-19 pandemic. While the number of suicides in Japan had been decreasing until then, they are again showing an increasing trend. In the most recent 2024 fiscal year, the total number of suicides decreased from the previous fiscal year, but suicides among elementary, junior high, and high school students are on an increasing trend (Figure 5). With the advancement of the declining birthrate, this impact is significant, and while social measures including education and administration are important, he states that it is also necessary to approach this from biological perspectives.
In this context, Hishimoto's hope is that researchers from younger generations will solve mental health problems with their own hands. Children who spent three years of their important growth period in the COVID-19 pandemic will likely view society positively with a strength different from humanity thus far and build new interpersonal relationships. "With the advancement of information technology such as SNS and various changes occurring rapidly in modern society, I have expectations for the next generation of researchers regarding how they will survive in the future," Hishimoto concluded.
(Article: Yuko Nonoshita, Photography: Hiroshi Matsui)
