Ischemic Stroke Risk Assessment by Multiscale Entropy Analysis of Heart Rate Variability in Patients with Persistent Atrial Fibrillation.

It has been recognized that heart rate variability (HRV), defined as the fluctuation of ventricular response intervals in atrial fibrillation (AFib) patients, is not completely random, and its nonlinear characteristics, such as multiscale entropy (MSE), contain clinically significant information. We investigated the relationship between ischemic stroke risk and HRV with a large number of stroke-naïve AFib patients (628 patients), focusing on those who had never developed an ischemic/hemorrhagic stroke before the heart rate measurement. The CHA2DS2-VASc score was calculated from the baseline clinical characteristics, while the HRV analysis was made from the recording of morning, afternoon, and evening. Subsequently, we performed Kaplan-Meier method and cumulative incidence function with mortality as a competing risk to estimate the survival time function. We found that patients with sample entropy (SE(s)) ≥ 0.68 at 210 s had a significantly higher risk of an ischemic stroke occurrence in the morning recording. Meanwhile, the afternoon recording showed that those with SE(s) ≥ 0.76 at 240 s and SE(s) ≥ 0.78 at 270 s had a significantly lower risk of ischemic stroke occurrence. Therefore, SE(s) at 210 s (morning) and 240 s ≤ s ≤ 270 s (afternoon) demonstrated a statistically significant predictive value for ischemic stroke in stroke-naïve AFib patients.

Early diagnosis of type 2 diabetes based on multiple biomarkers and non-invasive indices.

We previously reported that type 2 diabetes risk, early impaired glucose tolerance and insulin resistance can be predicted by measuring the fasting levels of certain biomarkers. Here we validated these findings in randomly recruited healthy volunteers (n = 101) based on biomarker expression as well as various non-invasive indices. Weight, body mass index, waist circumference and visceral fat differed between individuals with impaired fasting glucose and/or impaired glucose tolerance, and normal subjects. Fasting plasma levels of glycated hemoglobin, leptin, pro-insulin and retinol binding protein 4 differed between impaired fasting glucose/impaired glucose tolerance and normal subjects group and between newly detected diabetes and normal subjects group. Insulin resistance was correlated with fasting levels of insulin and leptin/adiponectin (r = 0.913); of insulin, retinol binding protein 4 and leptin/adiponectin (r = 0.903); and of insulin, glycated albumin, and leptin/adiponectin (r = 0.913). Type 2 diabetes risk, early impaired glucose tolerance and insulin resistance were predicted with >98% specificity and sensitivity by comparing fasting glucose levels to the estimated Matsuda Index based on fasting levels of insulin, adiponectin and leptin with or without oxidative lineolate metabolites. Non-invasive indices are slightly correlated with glucose tolerance and insulin resistance but do not increase the accuracy of predicting type 2 diabetes risk.

Interstitial-fluid shear stresses induced by vertically oscillating head motion lower blood pressure in hypertensive rats and humans.

The mechanisms by which physical exercise benefits brain functions are not fully understood. Here, we show that vertically oscillating head motions mimicking mechanical accelerations experienced during fast walking, light jogging or treadmill running at a moderate velocity reduce the blood pressure of rats and human adults with hypertension. In hypertensive rats, shear stresses of less than 1 Pa resulting from interstitial-fluid flow induced by such passive head motions reduced the expression of the angiotensin II type-1 receptor in astrocytes in the rostral ventrolateral medulla, and the resulting antihypertensive effects were abrogated by hydrogel introduction that inhibited interstitial-fluid movement in the medulla. Our findings suggest that oscillatory mechanical interventions could be used to elicit antihypertensive effects.

An algorithm for detecting startle state based on physiological signals.

To construct safe workspaces or daily life environments, it is important to develop a technology for automatically recording dangerous environmental situations. Based on increased finger skin conductance and decreased instantaneous heart (pulse) rate, we developed an algorithm for detecting the startle state of humans when encountering dangerous situations. The parameter values in the algorithm were optimized by tuning them with experimental results obtained in a virtual reality system, in which dangerous scenarios were presented to 21 subjects. The detection sensitivity of the optimized algorithm was 100% during a static standing condition and also while cycling. The detection specificity attained 90% and 87% for the static and exercising conditions, respectively. The optimized algorithm was applied to a real world situation such as car driving, and relatively high sensitivity of 87% and specificity of 80% were obtained.

Modeling effects of age and sex on cardiovascular variability responses to aerobic ergometer exercise.

After collecting data on the cardiovascular responses to ramp-type exercise tests on a cycle ergometer from 194 healthy male and female subjects aged from 20 to 69 years, we constructed a mathematical model that simulates typical patterns of the cardiovascular variability responses to ramp-type exercise loads below the anaerobic threshold. This was done by reflecting the following physiological mechanisms: (1) suppression of parasympathetic nerve activity, (2) reduction of total peripheral resistance, (3) resetting of the operating point in the baroreflex curve, (4) increase in stroke volume, and (5) increase in the coupling of stroke volume to pulse pressure. We estimated the values of model parameter that best fit the measured experimental data. The estimated steepness of the slope with which parasympathetic nerve activity decreased was lower in subjects with a higher anaerobic threshold, tended to increase with age, and in every age decade was higher for females than for males.

Causal coherence analysis of heart rate variability and systolic blood pressure variability under mental arithmetic task load.

Causal coherence analysis based on a closed-loop bivariate autoregressive model was applied to heart rate variability and systolic blood pressure (SBP) variability during mental arithmetic tasks to clarify how mental task load affects the linear closed loop interaction between cardiac and vascular systems. Thirteen normal male subjects performed a mental arithmetic task, button press task, and rest task while measuring their RR interval (RRI) and SBP. The mean value in the low frequency (LF) band (0.04-0.15Hz) of the squared causal coherence function from SBP to RRI during the mental arithmetic task was significantly higher than during the other two control tasks. Conversely, the LF band of the squared causal coherence function from RRI to SBP during the mental arithmetic task tended to be lower than during the rest task. These results suggest that mental arithmetic tasks enhance linear causal coupling from the vascular to cardiac system, and conversely weaken that from the cardiac to vascular system.

Closed-loop analysis of cardiovascular variability in rats under restraint stress.

Causal transfer function analysis was applied to the heart rate variability and blood pressure variability in normotensive male Sprague-Dawley rats those were measured before, during, and after acute restraint stress. The causal transfer gain (CTG) from systolic blood pressure (SBP) to RR interval (RRI) and CTG from RRI to SBP were estimated. The mean value of the CTG from SBP to RRI in the low-frequency (LF) band (0.27-0.74 Hz) was significantly lower during the restraint period than during the baseline period and remained significantly lower during the recovery period. The mean value of the CTG from RRI to SBP in the LF band, in contrast, was significantly higher during the restraint period than during the baseline period, and during the recovery period it tended to return relatively rapidly to the baseline level. Arterial pressure tended to increase only at the onset of the restraint stress and then to decline not only during the restraint period but also during the recovery period, finally leveling off significantly below the baseline level. These results suggest that restraint stress suppresses the baroreflex control gain not only during the restraint period but also during the recovery period and that this results in the arterial hypotension during the recovery period.

Multi-Biomarkers for Early Detection of Type 2 Diabetes, Including 10- and 12-(Z,E)-Hydroxyoctadecadienoic Acids, Insulin, Leptin, and Adiponectin.

We have previously found that fasting plasma levels of totally assessed 10- and 12-(Z,E)-hydroxyoctadecadienoic acid (HODE) correlated well with levels of glycated hemoglobin (HbA1c) and glucose during oral glucose tolerance tests (OGTT); these levels were determined via liquid chromatography-mass spectrometry after reduction and saponification. However, 10- and 12-(Z,E)-HODE alone cannot perfectly detect early impaired glucose tolerance (IGT) and/or insulin resistance, which ultimately lead to diabetes. In this study, we randomly recruited healthy volunteers (n = 57) who had no known history of any diseases, and who were evaluated using the OGTT, the HODE biomarkers, and several additional proposed biomarkers, including retinol binding protein 4 (RBP4), adiponectin, leptin, insulin, glycoalbumin, and high sensitivity-C-reactive protein. The OGTT revealed that our volunteers included normal individuals (n = 44; Group N), "high-normal" individuals (fasting plasma glucose 100-109 mg/dL) with IGT (n = 11; Group HN+IGT), and diabetic individuals (n = 2; Group D). We then used these groups to evaluate the potential biomarkers for the early detection of type 2 diabetes. Plasma levels of RBP4 and glycoalbumin were higher in Group HN+IGT, compared to those in Group N, and fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids were significantly correlated with levels of RBP4 (p = 0.003, r = 0.380) and glycoalbumin (p = 0.006, r = 0.316). Furthermore, we developed a stepwise multiple linear regression models to predict the individuals' insulin resistance index (the Matsuda Index 3). Fasting plasma levels of 10- and 12-(Z,E)-HODE/linoleic acids, glucose, insulin, and leptin/adiponectin were selected as the explanatory variables for the models. The risks of type 2 diabetes, early IGT, and insulin resistance were perfectly predicted by comparing fasting glucose levels to the estimated Matsuda Index 3 (fasting levels of 10- and 12-(Z,E)-HODE/linoleic acids, insulin, and leptin/adiponectin).

Effect of prolonged free-walking fatigue on gait and physiological rhythm.

This study examined the ways in which gait patterns and physiological rhythms such as those of muscle activity (tibialis anterior (TA) and biceps femoris (BF)) and cardiac activity are affected by the fatigue induced by prolonged free walking. Twelve normal subjects who walked for 3 h at their preferred pace were divided into two groups according to whether their mean gait cycle time (reciprocal of stride rate) during the second 90 min was higher (Group A: n=8) or lower (Group B: n=4) than that during the first 90 min. For Group A, the level of subjective fatigue during the walking task was significantly higher and the heart rate at rest was significantly lower than Group B. In Group A, prolonged walking significantly decreased the mean power frequency of the electromyography from TA, increased the variability of gait rhythm, decreased the largest Lyapunov exponent of the vertical component of back-waist acceleration, and decreased the amplitude of the vertical component of back-waist acceleration. Taking the onset timings of these changes into account, we propose that subjects who tire easily during prolonged walking first show local muscle fatigue at TA followed by instability of gait rhythm and then they slow their gait rhythm to enhance local dynamic stability. For both groups we constructed a physical fatigue index described by linear regression of gait and physiological variables. When we compared the subjective fatigue level with the fatigue level predicted using the index, we obtained a relatively high correlation coefficient for both groups (r=0.77).

Basic study on the most relaxing respiration period in children to aid the development of a respiration-leading stuffed toy.

Following natural disasters, accidents, and shocking incidents, some children experience post-traumatic stress disorder (PTSD). The respiration control method, which relaxes the body and mind, may efficiently prevent PTSD. Therefore, we developed a stuffed toy that leads children's respiration using the up-and-down movement of the abdomen to help them relax. We investigated the most appropriate respiration period for children's relaxation. Data from studies on heart rate variability (HRV) biofeedback training suggest that breathing at the respiration period at which HRV is the highest is effective for improving chronic diseases. Therefore, we measured the relationship between the respiration period and physiological indices, including HRV. The participants were 10 children aged 5-12 years. HRV was the highest at a 10-12-s respiration period in all 10 children. However, the most suitable respiration period for smooth breathing and relaxation was different from that at which HRV is the highest. Therefore, the most relaxing respiration periods for children need to be determined by indices other than HRV.

Singlet oxygen induced products of linoleates, 10- and 12-(Z,E)-hydroxyoctadecadienoic acids (HODE), can be potential biomarkers for early detection of type 2 diabetes.

Current diagnostic tests such as glycemic indicators have limitations for early detection of impaired glucose tolerance (IGT), which leads to diabetes. Oxidative stress induced by various oxidants in a random and destructive manner is considered to play an important role in the pathophysiology of a number of human disorders and diseases such as impaired glucose tolerance. We have developed an improved method for the measurement of in vivo lipid peroxidation, where the presence of 8-iso-prostaglandin F2α (8-iso-PGF2α), hydroxyoctadecadienoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs), and 7-hydroxycholesterol (7-OHCh), as well as their parent molecules, linoleic acid (LA) and cholesterol (Ch), was determined by performing LC-MS/MS (for 8-iso-PGF2α, HODE, and HETE) and GC-MS (for 7-OHCh, LA, and Ch) after reduction with triphenyl phosphine and saponification by potassium hydroxide. We then applied this method to volunteers (n = 57), including normal type (n = 43), "high-normal" (fasting plasma glucose, 100-109 mg/dL, n = 7), pre-diabetic type (IGT, n = 5), and diabetic type (n = 2) subjects who are diagnosed by performing oral glucose tolerance tests (OGTTs). Several biomarkers in plasma, such as insulin, leptin, adiponectin, interleukin-6, tumor necrosis factor-α, high sensitivity-C-reactive protein, HbA1c, and glucose levels were measured during OGTT. We found that the fasting levels of (10- and 12-(Z,E)- HODE)/LA increased significantly with increasing levels of HbA1c and glucose during OGTT and with insulin secretion and resistance index. In conclusion, 10- and 12-(Z,E)-HODE may be prominent biomarkers for the early detection of IGT and "high-normal" type without OGTT.

Effect of mood during daily life on autonomic nervous activity balance during subsequent sleep.

RR-interval and eight types of mood level were recorded for 48 h from 40 normal male subjects. Sympathovagal balance was evaluated by calculating the normalized high-frequency power (HFnu) of RR-interval variability. The mean mood levels during 6 h before bedtime and the mean HFnu during 3 h after bedtime were compared. The data were normalized individually and the differences from the first night (Deltamood and DeltaHFnu) were taken. The correlation coefficient between Deltadepression and DeltaHFnu was -0.53, and that between Deltaworry and DeltaHFnu was -0.44. This implies that both daily depression and worry shift toward sympathetic dominance during subsequent sleep.

MEG responses during rhythmic finger tapping in humans to phasic stimulation and their interpretation based on neural mechanisms.

The phase-resetting experiment was applied to human periodic finger tapping to understand how its rhythm is controlled by the internal neural clock that is assumed to exist. In the experiment, the right periodic tapping movement was disturbed transiently by a series of left finger taps in response to impulsive auditory cues presented randomly at various phases within the tapping cycle. After each left finger tap, the original periodic tapping was reestablished within several tapping cycles. Influences of the disturbance on the periodic right finger tapping varied depending on the phase of the periodic right finger tapping at which each left finger tap was made. It was confirmed that the periodic tapping was disturbed not by the auditory cues but by the left finger taps. Based on this fact, in this paper each single left tap was considered as the stimulus, and the phase of the periodic tapping of the right index finger when the left tap was executed as the phase of the stimulus. Responses of the neural activities (magnetoencephalography, MEG), the tapping movement, and the corresponding muscle activities (electromyography) were simultaneously measured. Phase-resetting curves (PRCs) representing the degree of phase reset as a function of the phase of the stimulus were obtained both for the left sensorimotor cortex MEG response and for the right index finger tapping response. The shapes of both PRCs were similar, suggesting that the phase reset of the left sensorimotor cortex activities and that of the finger tapping rhythm were the same. Four out of eight subjects showed type-0 reset in Winfree's definition, and the others showed type-1 reset. For general limit-cycle oscillators, type-0 reset is obtained for relatively strong perturbations and type 1 for weak perturbations. It was shown that the transient response of MEG to the single left tap stimuli in type-0 subjects, where the phase was progressively reset, were different from those in type-1 subjects. Based on detailed analysis of the differences, a neural network model for the phase reset of the tapping rhythm is proposed.