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京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第24543号 / 人健博第114号 / 新制||人健||8(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 黒木 裕士, 教授 稲富 宏之, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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The present study investigated the effects of meditative practices on the regulation of autonomic function. 74 subjects (38 women; 36 men) comprised from a range of experienced and non-experienced meditators, engaged in a series of psychophysiological tasks designed to generate specific autonomic states. Regression analyses revealed that experienced meditators, as predicted, displayed greater suppression of myocardial reactivity during a highly reflexive and stressful task. Meditative practice also predicted a rise in electrodermal activity during a relaxation task, contrary to expectations. These results support the concept that meditative practices may alter aspects of autonomic function. Further, these results inform an emerging mind-body paradigm and illustrate the potential consequences of meditative practices in specific disease states and prevention. / Ph. D.

The dynamic behaviors of a complex organism are explained via voluntary and involuntary action. One underpinning of this system is organized and facilitated by the autonomic nervous system, integrating information from conscious and non-conscious centers in a seemingly hierarchical fashion. As a result, voluntary actions have the ability to inhibit reflexive actions via an inhibitory circuit. 111 subjects performed four diverse autonomic tasks consisting of voluntary and involuntary combinations. Analysis supports the proposed hierarchical model. Each task evoked specific autonomic states. Voluntary tasks influenced autonomic actions more than involuntary tasks. And working memory capacity mediated voluntary control. / Master of Science

Heart rate variability (HRV) has been used to evaluate cardiac autonomic function by measuring variations in electrocardiographic R-R intervals between cardiac cycles. HRV was first used to associate decreases in autonomic nervous system (ANS) control with an increased risk of mortality in coronary heart disease and in the diagnosis of diabetes (1). Current clinical research interest has extended to investigate uses of HRV to evaluate changes in the cardiovascular system due to disease, aging, physical activity, and cardiac rehabilitation treatment (2, 5). HRV scores are derivatives of R-R intervals and these may be represented as a function of either time or frequency domain parameters. Time domain analysis is the simplest and includes: the standard deviation of R-R intervals and the number of adjacent RR intervals that differ by >50ms (dRR50). Frequency domain measures involve more elaborate calculation and have been applied in studies to evaluate sympathetic and parasympathetic autonomic balance. The latter include: Low Frequency Power (LF), High Frequency Power (HF), and LF/HF ratio. HRV has been measured in a variety of ways, the most common being a continuous 24-hour collection of R-R data. In recent years, several investigators have sought to assess HRV by utilizing brief collection periods. Controversy exists about the potential of these short-term sampling intervals to yield reproducible and meaningful measurements of HRV. Many confounders such as respiration, stress, and body positioning can influence HRV, which is why a longer collection period has been accepted as the standard for providing a stable index of ANS function. However, short sampling periods would be useful to evaluate HRV when faced with time constraints. The purpose of the current study was to evaluate the reproducibility of HRV using 8-hour daytime measures with the Polar R-R RecorderTM (Polar Electro Oy, Kempele, Finland) and with short sampling duration of 512 cardiac cycles, using the Schiller AT-10TM device (Schiller AG, Baar, Switzerland). Methods: 10 apparently healthy adult volunteers participated in the study, which was conducted at the Sleep Disorders Clinic in Christiansburg, VA. Each subject performed two HRV trials with the Cardiovit AT-10TM device using recordings of 512 cardiac cycles. Within one or two days following the Schiller, the same subjects wore a Polar R-R RecorderTM device to obtain an 8-hour recording of HRV during waking hours; 24-hour urine samples were collected on the same day. Urine was analyzed for catecholamine levels, including norepinephrine and epinephrine in order to evaluate sympathetic nervous system globally. Each subject recorded their personal impressions of unavoidable physical activity and daytime stress demands on the day of the 8-hour recording and urine collection. This entire protocol was repeated one week later. On one of the days of the short sampling recording, VO2pk also was evaluated for each subject using a ramp protocol on the cycle ergometer and a metabolic cart. Results: The correlation analysis for the HRV response variables using the Schiller method indicated a high-to-very high correlation between trials within a day for the time domain measures (r = 0.75-0.99). The frequency domain measures, however, were low-to-moderately correlated (r = 0.24-0.66) between trials within a day for the Schiller method. Correlations between days for HRV response variables using the Schiller method were similarly low for both time (r < 0.5) and (r < 0.4) frequency domain measures. Correlation coefficients between days for the HRV response variables using the Polar method were moderate (r = 0.59-0.67) for the time domain and only low-moderate for the frequency domain measures (r = 0.37-0.69). However, an important finding was that Polar R-R data for two of the subjects contained excessive signal artifact, which affected the fidelity of the HRV scores. When these two cases were excluded from the group analyses, the resulting correlations were high-very high for all time and frequency domain measures (r = 0.70-0.93). The means for each response HRV time and frequency domain variable between the Polar method and Schiller method were significantly different (P < 0.05). Additional correlational analyses did not reveal any systematic associations between HRV measures and simple markers of sympathetic activity (urinary NE or E) and aerobic fitness (VO2pk) in this small sample of subjects. Conclusions: Due to this important change in reproducibility with the Polar method, the consequence of artifact-free recordings is unmistakable. Within the limitations of this small study sample it is concluded that, while HRV in apparently healthy adults may not be measured reliably with brief data collection periods, longer daytime sampling periods of 8 hours (e.g. Polar device) yields acceptable reliability for both time and frequency domain parameters of HRV. / Master of Science

Ego-resiliency (ER) is a trait that describes the ability to cope with stress, while effortful control (EC) is an individual difference related to the ability to optimally inhibit negative emotion through attentional mechanisms. ER has been linked to flexible cardiovascular responding without accounting for autonomic nervous system origins of physiological responses. Similarly, EC tends to be associated with increased cardiac vagal control. However, differences in the autonomic characteristics of these constructs remain unclear. In the current study, it was hypothesized that compared to low-scorers, individuals who score high on ER and EC will each have greater vagal control and less sympathetic control over interbeat intervals (IBI) changes during laboratory stressors. Subjects engaged in a mental arithmetic, speech preparation, and verbal fluency task to elicit cardiovascular activation along a continuum of threat. Electrocardiography and impedance cardiography were collected before, during, and after these tasks to assess changes in autonomic functioning. Results from multiple regression analyses indicated that high levels of EC predicted increased vagal control over IBI recovery and less sympathetic reactivity of IBI reactivity. Contrary to predictions, ER showed an opposite pattern of autonomic regulation across stressors. / Master of Science

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 5 uppsatser.

The autonomic nervous system (ANS) controls most involuntary functions of the body. Dysfunctions of the ANS can be life-threatening. However, several critical questions related to cardiovascular and breathing regulations remain unclear. One of the open questions is how the system lose control of the vascular tones under certain circumstances. Using the septic shock model induced by lipopolysaccharide (LPS) in isolated and perfused mesenteric arterial rings, we found the vascular hyporeactivity is attributed to the decreased vasoconstriction to α-adrenoceptor agonists. The endotoxin-induced vasodilation can be intervened with endothelin-1 (ET-1), serotonin (5-HT) or vasopressin, which have never been used in clinical treatment. It is unclear how the excitability of endothelium affects vascular tones. Using optogenetics and transgenic mice with channelrhodopsin expression in endothelial cells (ECs), we found selective activation of the ECs induces a fast, robust, reproducible and long-lasting vasoconstriction in isolated and perfused hearts and kidneys. Breathing control by the ANS within the brain becomes abnormal in certain genetic diseases, such as Rett syndrome with defected norepinephrine (NE) system in locus coeruleus (LC). The LC neurons are hyperexcitable while NE release is deficient. Using optogenetics and double transgenic mice with Mecp2 null and channelrhodopsin expression in LC neurons, we found the NE-ergic modulation of hypoglossal neurons was impaired in transgenic mice, which cannot be improved with optostimulation, suggesting that LC neuronal hyperexcitability may not benefit the NE modulation in Rett syndrome. Collectively, our results provide insight into the autonomic dysfunctions using experimental interventions that have barely been used before.

The enteric nervous system (ENS) is derived from neural crest cells (NCCs). Once these NCCs reach the foregut, they are recognized as enteric NCCs(ENCCs) which subsequently colonize the gastrointestinal track. The proliferation, migration and neuronal versusglial differentiation of ENCCs are tightly controlled by multiple signaling pathways and transcription factors. Impaired ENS development may result in various human congenital disorders such as Hirschsprung disease(HSCR). Hedgehog (Hh) signaling is a key element in ENS development. Patched-1 (Ptch1) is a negatively regulated receptor for Hh. Binding to Hh or deletion of Ptch1releases its inhibitory function and activates the Hh signaling cascade. Our group has previously revealedPTCH1as a susceptibility gene for HSCR. In particular, NCC-specific deletionofPtch1in mice led to premature glial differentiation and depletion of proliferative ENCC pool, but the molecular mechanisms are still not very clear. Sox10, a member of SRY-related HMG-box family transcription factor, is implicated in these two processes of ENS development. It prompted us to hypothesis that Ptch1 may interact with Sox10 to control ENCC proliferation and glial lineage differentiation. In this study, I generated compound mouse mutants to i) investigate the potential functional interaction between Ptch1 and Sox10 in ENCC differentiation and proliferation, and ii) examine the link between the perturbed NCC differentiation and aberrant proliferation of ENS progenitors, to determine how interruption of these processes may lead to intestinal hypoganglionosis of Ptch1mutants. I found that persistent Hh activation through deletionofPtch1causes a differentiation bias toward glial lineage. Ptch1mutants consistently contained more Sox10expressing glial committed ENCCs and exhibited premature gliogenesis. To test whether elevated Sox10expressing cells contribute in the ENS phenotypes of Ptch1 mutants, 〖Sox10〗^(NGFP/+); Ptch1 compound mutants were generated, where one copy of Sox10 was deleted. Immunohistochemical analysis revealed that 〖Sox10〗^(NGFP/+) mutants exhibitpremature neurogenesis as reported previously, while the proliferation and glial differentiation of ENCCs are not affected.On the other hand, in the compound mutants, heterozygous deletion of Sox10 markedly rescued premature gliogenesis caused by deletion of Ptch1. These data suggest that Ptch1 regulates gliogenesis of ENCCs through maintaining Sox10 expression. To delineate how premature glial differentiation of ENCCs leads to hypoganglionosis, I further investigated whether the differentiation defect perturbs the proliferation capacities of ENCCs. Correction of glial differentiation defect in Ptch1 mutant by heterogeneous deletion of Sox10 could significantly restore the pool size of the proliferative ENCCs of the compound mutant. This observation implies that proliferation defects in Ptch1 mutant represents a secondary consequence of premature gliogenesis, highlighting the close link between these two developmental processes. In summary, the current study provides evidence that Sox10 works coordinately with Ptch1 to mediate ENS development. Loss of Ptch1 favors glial differentiation and formation ofSox10 expressing glial progenitors, leading to intestinal hypoganglionosis as seen in Hirschsprung’s disease. / published_or_final_version / Surgery / Master / Master of Philosophy