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Shin Fukudo (Psychosomatic Medicine)

Shin Fukudo (Psychosomatic Medicine)

Professor Fukudo graduated Tohoku University School of Medicine (MD) and was given PhD degree from the same university. He is a professor and director of Behavioral Medicine, Tohoku University since 1999 and has been recognized as one of the distinguished researchers of stress-related disorders and brain-gut interactions. His achievements include earlier conceptualization of disorders of brain-gut interactions and identifying key molecules of interoception. He uses many modalities to measure both the brain and the gut including positron emission tomography, functional magnetic resonance imaging, evoked potential, electroencephalogram, gastrointestinal manometry, barostat, electrical stimulation of the gut, and testing of autonomic function. He searches genes that regulate brain-gut function. He also developed several animal models of disordered brain-gut interactions. He is one of members of international Rome III committee for functional gastrointestinal disorders. He is known as a recipient of the Early Career Award of the American Psychosomatic Society in 1994 and Prize for Science and Technology, Research Category, the Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science, and Technology of Japan in 2006.

Introduction of Research

The great social benefit is expected if we can clarify the pathophysiology of stress-related disorders and coping program against it with brain science. The mission of the Department of Behavioral Medicine is to promote basic and clinical research on the relationships among health, illness, and behavior. Our research targets at any diseases that are influenced by psychosocial stress but mainly focuses on physiology of stress and pathophysiology of stress-related disorders.

Mind is results of brain function and development of the brain needs the peripheral organs both in the individual aspects and in the evolutional aspects. All environmental information is input to the peripheral organs at first, conducted to the brain as the sensory signal, and processed in the brain. The perception and emotion arise during this process. Emotion consists of changes in the function of the peripheral orgams via autonomic nervous system and endocrine as well as subjective feeling. Feedback or feedforward processing among the specific brain structures and between the brain and the peripheri forms further emotion. This response is considered to be partially determined with genes and epigenetic factors including combination and/or magnitude of the stimuli, developmental process, influence of pathogen, and so on. Individuals cope with environmental changes by behavior. The magnitude of the response is regulated in the normal range as the healthy condition. Deviated response out of the normal range is manifested as the stress-related disorder.

This concept is well applicable to irritable bowel syndrome (IBS), one of disorders of brain-gut interactions. We found stress-induced exaggeration of gastrointestinal motility and correlation between reduced alpha-power percentage in elecroencephalogram and indices of gastrointestinal motility under stress. Fear conditioning by combination of the sound and electrical stimulation induced fine movements of the colon simultaneously with increased regional cerebral blood flow in the anterior cingulate cortex, insula, and prefrontal cortex using positron emission tomography (PET). Conversely, the thalamus, anterior cingulate cortex, insula, and prefrontal cortex were activated by stimulation of the colon. Therefore, perception signal from the visceral organ or psychosolcial stressor activates the common limbic and paralimbic structures. Interestingly, patients with IBS show aberrant regional activation of the brain in response to the visceral stimulation. We tried to modify the visceral perception as the bottom-up processing with the top-down processing of the brain and succeeded to prove it using viscerosensory evoked potential and PET imaging. Subjective sensation and feeling were modified as well.

What kinds of substance regulate the brain-gut interactions is also one of the main interests of our group. We performed gene analysis and found that polymorphism of the serotonin transporter gene at least in part regulated negative emotion. Moreover, differential brain response was detected depending on the polymorphism of the serotonin transporter gene. Administration of corticotropin-releasing hormone (CRH) to IBS patients induces exaggerated secretion of adrenocorticotropic hormone and exaggerated motility of the colon. Administration of CRH antagonist improves exaggerated motility of the colon, visceral perception, anxiety, reduced alpha-power percentage in elecroencephalogram, and PET imaging in IBS patients. Increased input of the signal to the colon made rats have exaggerated colonic motility, increase noradrenaline release in the hippocampus, and be anxious. In this animal model of IBS, CRH antagonist was effective to alleviate the pathophysiology.

We are also exporing psychological trauma, maternal deprivation, alexithymia, and mucosal sensitization on the pathophysiology of the stress-related disorders. Moreover, we are developing applicable program for clinical practice; psychotherapy including cognitive behavioral therapy, hypnotherapy, etc, based on the evidence. We plan to proceed to further clarification of the pathophysiology of stress-related disorders, finding way of regulation of key molecule of stress response, and developing coping program against it with brain science.

Figure 1. Brain-Gut Interactions-1
(Upper Left) Viscerosensory evoked potential (VSEP) by summation of electroencephalogram under the electrical stimulation of the esophagus. Late component of VSEP N2 in FGID patients showed shorter than that in controls. N2 negatively correlated with somatization (Kanazawa M, et al. JAMA 286: 1974-5, 2001). (Upper Right) Regional cerebral blood flow measured with PET during the stimulation of the descending colon. Anterior cingulate cortex and thalamus were activated with abdominal pain and anxiety (Hamaguchi T, et al. Neurogastroenterol Motil 16: 299-309, 2004). (Lower Middle) Analysis of serotonin transporter gene polymorphism. Electrophoresis showed bands of l/extra-l, l/l, l/s, and s/s. This polymorphism relates to the negative emotion of stress-related disorders including IBS patients (Mizuno T, et al. J Psychosom Res 60: 91-7, 2006).

Figure 2. Brain-Gut Interactions-2 (Left) Corticotropin-releasig hormone (CRH) is a brain-gut peptide derived from the paraventricular nucleus of the hypothalamus. Administration of CRH to IBS patients induces robust activation of the motility of the small intestine and the colon (Fukudo S, et al. Gut 42: 845-849, 1998). (Right) Stimulation of the colon makes rats less spent time in the open arm of the elevate plus maze, indicating anxiety-like behaviors, compared with controls. Administration of specific CRH-R1 antagonist reverses visceral stimulation-dericed anxiety (Saito K, et al. Gastroenterology 129: 1533-43, 2005).

Video

Movie: Visual Brain-Gut Interactions Functional connection between the brain and the gut is called as "brain-gut interactions". which are altered by psychosocial stress and have great impact on the society. Function of the gut is mainly regulated by enteric nervous system (ENS) but is also influenced by autonomic nervous system (ANS) and central nervous system (CNS). Corticotropin-releasing hormone (CRH) is one of major mediators of stress-induced changes in brain-gut interactions. Brain-gut connection is reciprocal and visceral perception can be precisely analyzed with advanced technique of gastrointestinal physiology and brain imaging. Irritable bowel syndrome is disorder of brain-gut interactions with co-morbidity of many psychological/psychiatric disorders. Research on how interoception especially visceral perception derives emotion in human is in progress.

(Copyright: Japan Medical Association, Video Lecture of Irritable Bowel Syndrome, 2001)

  1. Fukudo S, Saito K, Sagami Y, Kanazawa M. (2006) Can modulating corticotropin-releasing hormone receptors alter visceral sensitivity ? Gut 55: 146-148.
  2. Chang L, Toner BB, Fukudo S, Guthrie E, Locke GR, Norton NJ, Sperber AD. (2006) Gender, age, society, culture, and the patient's perspective in the functional gastrointestinal disorders. Gastroenterology 130: 1435-1446.
  3. Saito K, Kasai T, Nagura Y, Ito H, Kanazawa M, Fukudo S. (2005) Corticotropin-releasing hormone receptor 1 antagonist blocks brain-gut activation induced by colonic distention in rats. Gastroenterology 129:1533-43.
  4. Kano M, Fukudo S, Gyoba J, Kamachi M, Tagawa M, Mochizuki H, Itoh M, Hongo M, Yanai K. (2003) Specific brain processing of emotion by facial expressions in alexithymia: a H215O-PET study. Brain 126: 1474-1484.
  5. Kanazawa M, Fukudo S, Nomura T, Hongo M. (2001) Electrophysiological correlates of personality influences in visceal perception. JAMA 286: 1974-1975.

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