Dr. Seiji Ogawa and the Past, Present, and Future of Functional MRI Research.

Abstract

In basic brain science and clinical investigations of psychiatric/neurological diseases, it is very important to be able to measure the functional state of the brain noninvasively. Dr. Seiji Ogawa worked on this issue for many years and succeeded in developing a novel imaging method of brain function based on the vascular response to functional activation of the brain. Remarkably, in the early 1990s, he developed a technique for detecting magnetic resonance imaging (MRI) signals that depend on blood oxygenation levels in the brain. He named these signals BOLD (for blood oxygen level dependent) and showed that BOLD signals can be used for functional mapping of the human brain following sensory stimulation, thereby establishing the basic principles underlying functional MRI (fMRI).1,2 This method enabled the noninvasive mapping of human brain activity without the use of radioactive isotopes.3 Currently, various noninvasive methods for evaluating functional brain activities have been developed and applied, including electroencephalography (EEG) and magnetoencephalography (MEG). Although fMRI does not directly detect the electrophysiological or electrochemical activity of the brain, fMRI has the advantage of being able to localize the functioning site of the whole brain with high resolution, compared to other noninvasive methods including EEG and MEG.4 In fact, Dr. Ogawa’s pioneering work has inspired the widespread use of fMRI by researchers and physicians in the field of basic and clinical brain science. For example, fMRI techniques are applied to determine which part of the brain is activated when performing a task (task-based fMRI) and to investigate functional brain connectivity in the resting state [resting state fMRI (rsfMRI)]. fMRI is now combined with more recent technologies such as optogenetics. By taking advantage of this combined method [integrated optogenetics and BOLD-fMRI (ofMRI)], Drs. Jin Hyung Lee and Karl Deisseroth at Stanford University observed that BOLD signals are positively induced in the mouse brain on activating a specific subset of neurons (i.e., local CaMKIIα-expressing excitatory neurons) and clearly showed that widely applied fMRI BOLD signals could provide a suitable tool for functional circuit analysis as well as for the global phenotyping of dysfunctional circuitry.5 Dr. Kenji Tanaka and our collaborative team at Keio University recently took advantage of ofMRI and found that optogenetic astrocyte activation evokes BOLD fMRI responses that accompany oxygen consumption without the modulation of neuronal activity.6 Evidently, fMRI is an indispensable methodology for elucidating functional networks in the brain and for analyzing various brain functions and behavioral mechanisms of action in normal subjects and in patients with neurodevelopmental disorders and psychiatric disorders. Comprehensive brain mapping in humans and model animals is generating increasing interest worldwide.7,8 In world-class brain projects, including the BRAIN Initiative in the U.S., the Human Brain Project in Europe, and Brain/MINDS in Japan, rsfMRI-based functional brain mapping is one of the key technologies. From this point of view, Dr. Ogawa’s pioneering work on fMRI can be considered a monumental research achievement that will be forever acknowledged in the history of brain science. Based on his remarkable achievements and the application of fMRI technology in various fields of medicine and brain science, Dr. Ogawa has received many international academic awards, such as the Keio Medical Science Prize (2017), Thomson Reuters Citation Laureates (2009), the Gairdner Foundation International Award (2003), and the Japan Prize (2003). In commemoration of Dr. Ogawa’s receipt of the Keio Medical Science Prize, the Keio Journal of Medicine asked Dr. Ogawa to write a Review Article for publication in the journal. Dr. Ogawa was kind enough to write a wonderful and impressive review of fMRI, which appears in this issue of the Keio Journal of Medicine.4 In this article, Dr. Ogawa and his colleague Dr. Yul-Wan Sung describe the basic principles and current applications of fMRI. Further, the authors humbly point out the limitations of fMRI, such as low time resolution because of its slow response time; however, they then discuss the new wave of fMRI research techniques, such as the application of artificial intelligence (AI) to neural networks based on Deep Learning to improve the image quality obtained from fMRI data.9 Finally, they discuss the future prospects of fMRI research, such as information-contentreflecting fMRI and application of investigations relating to the efficient information processing of the human brain