Increasing evidence suggests that respiratory rhythms are crucial for cognitive functions. Although recent findings suggest that respiratory activity may serve as an internal contextual framework during memory processes, the contribution of specific respiratory phases to encoding and retrieval remains unclear. Here, we investigated the breathing-dependent performance of 30 healthy volunteers during a visual delayed matching-to-sample recognition memory task while their nasal respiration was monitored. Reaction times (RTs) decreased when visual cues were both encoded and retrieved during the late phase of exhalation. In contrast, longer RTs were observed during late exhalation at retrieval when encoding occurred either (i) during a period that encompassed inspiratory onset (i.e., exhalation-to-inhalation transition or EI transition) or (ii) during the early phase of inhalation. These contrasting outcomes under identical retrieval conditions highlight the phase-dependent effects of respiration, specifically the alignment of respiratory timing between encoding and retrieval. Importantly, we found that the late phase of exhalation during both encoding and retrieval may represent a favorable temporal window for shaping memory performance. These findings suggest that respiratory phase alignment modulates memory processes by providing an interoceptive, phase-dependent context for cognition. ### Competing Interest Statement The authors have declared no competing interest. Hyogo Innovative Challenge, Hyogo Medical University Hyogo Medial University grant for the Research Promotion 2024 Academic Research grants, Hyogo Science and Technology Association Cooperative Study Program of National Institute for Physiological Sciences Grant-in-Aid for Scientific Research of the Japan Society for the Promotion of Science, 25K02551

Changes in reaction times (RTs) during attentional processing may be associated with the state of breathing. Although breathing and cardiac activity interact, the functional importance of the cardiorespiratory system for modulating attentional processing remains unclear. To determine the involvement of respiration and RR interval (RRI) variability in successful task performance, thirty-six healthy participants performed a short-term memory task. For RTs limited to correct responses, increases were observed under two conditions: i) when inspiratory onset (or exhalation-to-inhalation transition) occurred and ii) when RRI velocity increased during retrieval. Importantly, multilevel model analysis revealed that the timing of inspiratory onset and the increase in RRI velocity were temporally mismatched, suggesting that at least two independent mechanisms may prolong RT. These findings contribute to a better understanding of how respiration and RRI variability may be functionally differentiated and how each could be linked to attentional processes that influence performance.

Objective: Reproduce the antihypertensive effect of physical exercise by applying mechanical intervention. Design and method: We conducted animal experiments in which we reproduced mechanical accelerations generated in the head during treadmill running at a moderate velocity. We performed in vitro experiments using cultured cells to determine what type of mechanical force was responsible for the antihypertensive effect of mechanical intervention. We carried out clinical studies to validate the clinical relevance of our findings. Results: Passive head motion in hypertensive rats, which reproduced the mechanical accelerations generated in their heads during treadmill running at a moderate velocity, decreased the expression of angiotensin II type 1 receptor (AT1R) in astrocytes in the rostral ventrolateral medulla (RVLM). This decrease resulted in lowering their blood pressure. Passive head motion generated interstitial fluid movement, which was estimated to exert shearing forces with an average magnitude of < 1 Pa on the cells in the rat medulla. Application of fluid shear stress of relevant magnitudes decreased the AT1R expression in cultured astrocytes, but not in neuronal cells. Furthermore, interference with interstitial fluid movement by hydrogel introduction in the RVLM of hypertensive rats eliminated the ability of passive head motion and treadmill running to decrease their blood pressure and AT1R expression in the RVLM astrocytes. Consistent with these results from animal experiments, vertically oscillating chair riding by hypertensive adult humans, which reproduced the mechanical accelerations generated in their heads during light jogging, lowered their blood pressure. Conclusion: Brain-targeted mechanical intervention can be antihypertensive by modulating the function of RVLM astrocytes through interstitial fluid shear stress.

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.

Physical exercise is known to be beneficial for various brain functions. However, the mechanisms behind the positive effects of exercise on the brain remain to be elucidated. Here we show that passive head motion in hypertensive rats, which reproduces the mechanical accelerations generated in their heads during moderate-velocity treadmill running, decreases the expression of angiotensin II type 1 receptor (AT1R) in astrocytes in the rostral ventrolateral medulla (RVLM), thereby lowering blood pressure. Passive head motion generates interstitial fluid movement that is estimated to exert shear stress with an average magnitude of <1 Pa on the cells in the rat medulla. Fluid shear stress of a sub-Pa magnitude decreases AT1R expression in cultured astrocytes. In hypertensive rats, inhibition of interstitial fluid movement following hydrogel introduction to the RVLM eliminates the antihypertensive effects of passive head motion and treadmill running. Furthermore, vertically oscillating chair riding by hypertensive adult humans, which reproduces the mechanical accelerations generated in their heads during light jogging or fast walking, lowers their blood pressure. Our findings indicate that moderate mechanical intervention can have antihypertensive effects by modulating the function of RVLM astrocytes through interstitial fluid shear stress. We anticipate that mechanical regulation is responsible for a variety of the positive effects of physical exercise on human health, particularly those related to brain functions.

Manzai, one of the most popular Japanese comedies, features conversations of multiple performers who make the audience laugh. The level of amusement of manzai is evaluated based on how the judges or the audience feel. However, there is a problem of subjective bias. This study aimed to identify a physiological index that can objectively evaluate the degree of amusement of manzai acts. Ten healthy women in their 20s participated in the experiment. The subjects were asked to watch five manzai acts in a random order. After watching, they were asked to subjectively evaluate the acts on a questionnaire, after which the scores, including the score for the level of amusement, were calculated. Electroencephalography (EEG), electrocardiography (ECG), respiration, electrooculogram, and physiological sounds of the throat were evaluated and analyzed before, during, and after the viewing. The results showed that the beta-band power of the temporal EEG tended to be higher when the subjects considered manzai amusing. In contrast, the alpha wave power of EEG, the average frequency, the heart rate, and the ratio of the low frequency band to the high frequency band of the heart rate variability (LF/HF) were insignificantly related to the level of amusement of manzai. The results suggest that the level of amusement of manzai may be related to the beta-wave power of temporal EEG rather than EEG indices that are related to relaxation and arousal or to the linear indices of heart rate variability that reflect autonomic nerve activity.

Introduction: Exercise is known to be effective as a therapeutic/preventative measure for numerous physical disorders and diseases including hypertension. However, the mechanisms underlying the antihypertensive effect of exercise remain to be elucidated. Hypothesis: The positive effects of exercise may be mediated by mechanical forces generated during exercise activities. Exercise-mimicking mechanical intervention may have an antihypertensive effect. Methods: We conducted animal experiments in which we reproduced mechanical accelerations generated in the head during moderate-velocity running. We performed in vitro experiments using cultured cells to determine what type of mechanical force was responsible for the antihypertensive effect of mechanical intervention. We carried out clinical studies to validate the clinical relevance of our findings. Results: Passive head motion (PHM) in hypertensive rats, which reproduced the mechanical accelerations generated in their heads during moderate-velocity treadmill running, decreased the expression of angiotensin II type 1 receptor (AT1R) in astrocytes in the rostral ventrolateral medulla (RVLM), thereby lowering their blood pressure. PHM generated interstitial fluid movement that was estimated to exert shear stress with an average magnitude of <1 Pa on the cells in the rat medulla. Fluid shear stress of a sub-Pa magnitude decreased the AT1R expression in cultured astrocytes. Inhibition of interstitial fluid movement following hydrogel introduction to the RVLM eliminated the antihypertensive effects of PHM and treadmill running. Vertically oscillating chair riding by hypertensive adult humans, which reproduced the mechanical accelerations generated in their heads during light jogging, lowered their blood pressure. Conclusion: Brain-targeted mechanical intervention can have an antihypertensive effect by modulating the function of RVLM astrocytes through interstitial fluid shear stress.

Detection of non-motor symptoms specific to patients with Parkinson's disease (PD) is an important area for investigation because it may lead to early PD diagnosis. The aim of this study is to (i) verify whether there were differences between patients with PD and concurrent relatively severe sleep apnea syndrome (SAS) and non-PD patients with relatively severe SAS in terms of heart rate response to obstructive apnea/hypopnea events during sleep and (ii) to clarify the correlation between the extent of the heart rate response and the level of cardiac sympathetic denervation measured by 123I-metaiodobenzylguanidine (MIBG) scintigraphy. We analyzed the heart rate response to obstructive apnea/hypopnea events during sleep in 23 patients with PD and concomitant relatively severe SAS as well as in 36 non-PD patients with relatively severe SAS. The amplitude of increase in the heart rate in response to apnea/hypopnea events was significantly lower for patients in the PD group with SAS than for those in the non-PD group with SAS. A relatively strong positive correlation was found between the amplitude of heart rate increase in response to apnea/hypopnea events and the H/M ratio on 123I-MIBG scintigraphy in the PD group with SAS. Our results suggest that the amplitude of heart rate increase in response to obstructive apnea/hypopnea events reflects cardiac sympathetic nerve activity, and that in patients with relatively severe SAS concomitant with PD, the reactive increase in heart rate is suppressed due to degeneration of the cardiac sympathetic nervous system.

Early detection of non-motor symptoms, such as sleep disorder, is recommended for those with Parkinson's disease (PD). It is important to understand the sleep patterns of patients with PD having concomitant sleep apnea syndrome (SAS). The effect of PD on static sleep variables has been investigated, but its effect on the dynamic transition process of sleep stage has not been fully clarified. The aim of this study was to analyze the dynamic transition process of sleep stages between patients with PD with concomitant SAS and non-PD patients with SAS and to clarify one aspect of the difference in sleep disorder pathology in both patient groups. Sleep stage data of 31 patients with PD and concomitant SAS and 31 propensity score matched non-PD patients with SAS were analyzed, and (i) normalized transition probability and transition rate between each sleep stage as well as (ii) cumulative probability density function of the duration of each sleep stage were calculated. It was found that normalized transition probability and transition rate from rapid eye movement (REM) to Wake and from Wake to REM in PD patients with concomitant SAS were significantly lower than those in the non-PD patients with SAS. In addition, the cumulative probability density function of the duration of sleep stages was compared, and Wake and REM of PD patients with concomitant SAS were significantly more likely to continue than those of the non-PD patients with SAS. These results suggest that both REM-to-Wake transition and Wake-to-REM transition are less likely to occur in PD patients with SAS and that the stage is more likely to continue once Wake and REM sleep occur.

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.

It has been reported that increased intermittent non-Gaussian fluctuations in the instantaneous amplitude of low-frequency heart rate variability (LF-HRV) are related to high mortality risk in cardiac patients. However, little is known about the physiological origin of the amplitude modulation of LF-HRV. The purpose of this study was to clarify the relationship between amplitude modulation of LF-HRV and that of low-frequency blood pressure variability (LF-BPV). Eight normal male subjects performed movie-watching and calculation tasks in a sitting position for 40 min each while electrocardiogram and continuous blood pressure waveforms were recorded. From these signals, we calculated the instantaneous amplitude of the LF-band RR interval (RRILFamp) signal and that of the LF-band systolic blood pressure (SBP) signal (SBPLFamp) via band-pass filter and Hilbert transform. All subjects exhibited significant and relatively high positive correlation coefficients between RRILFamp and SBPLFamp in both tasks (mean Pearson correlation coefficient > 0.45). Mean coherence in the 0.01-0.05 Hz band between RRILFamp and SBPLFamp was also significant in all but one subject (mean coherence > 0.42). These results indicate a relatively high positive correlation between the amplitude modulation of LF-HRV and that of LF-BPV. We calculated the peak time lags of the cross correlation between RRILFamp and SBPLFamp in the 0.01-0.05 Hz band. A negative peak time lag implies that the amplitude modulation of LF-HRV precedes that of LF-BPV. All subjects exhibited negative peak time lag in the movie-watching task. All but one subject exhibited negative or zero peak time lag in the calculation task. These results imply that the amplitude modulation of LF-HRV precedes that of LF-BPV in the frequency range of 0.01-0.05 Hz.

It has been reported that the complexity characteristics of heart rate variability (HRV) in patients with permanent atrial fibrillation (AFib) based on multiscale entropy (MSE) analysis are associated with ischemic stroke risk. However, the interpretation of HRV complexity is not clear and the mathematical and physical relationships between HRV and ischemic stroke have not been established. MSE is determined not only by the correlation characteristics but also by probability density function characteristics. The aim of this study was to clarify which characteristics were important for the association between MSE and ischemic stroke risk in patients with permanent AFib. We analyzed 24 hours of HRV data from 173 patients with permanent AFib. Results show that long-range correlations like 1/f fluctuations in a range greater than 90s were observed in HRV time series in patients with AFib, but that these values had no predictive power as an ischemic stroke risk factor. On the other hand, probability density functions of coarse-grained scales greater than 2s were significantly associated with ischemic stroke risk. These results suggest that probability density functions are a useful risk factor for improving ischemic stroke risk assessment. To investigate the probability density function characteristics more in detail, we analyzed the asymmetric non-Gaussian properties of the probability distribution of HRV data. Part of this study was published in the journal Entropy [1].

Degeneration of the autonomic nervous system is observed in the early stage of Parkinson’s Disease (PD). Because of this, early detection of PD may be possible by detecting abnormalities in autonomic nervous system activity. Although 27-60% of patients with PD have sleep apnea syndrome (SAS), sympathetic cardiac overdrive is observed in SAS patients, while degeneration of the sympathetic nervous system is observed in PD. These findings suggest it may be possible to differentiate patients with PD from patients with SAS using their autonomic nervous response. In this study, we analyzed and compared the heart rate response pattern to sleep apnea events in SAS patients to patterns in PD patients with SAS (PD + SAS). Twenty patients with SAS and 15 patients with PD + SAS underwent overnight polysomnography (PSG) at Toneyama National Hospital. Electrocardiography (ECG), SpO2, and airflow data were measured and used for analysis. Time series of participant’s instantaneous heart rate were calculated from ECG signals. The timing of sleep apnea events was calculated from airflow data. In addition, the (1) latency and (2) amplitude of participant’s heart rate response, area of (3) increasing and (4) decreasing heart rate responses, and (5) participant’s heart rate response during the early phase of SpO2 reduction were calculated for each heart rate response to sleep apnea events. Sleep apnea events were divided into two categories based on whether they were the first event in the consecutive series or not. Results found no statistically significant difference in heart rate response indices between patients with PD and PD + SAS for the first apnea event in a consecutive series. On the contrary, the amplitude and area of increasing heart rate responses as well as heart rate response during the early phase of SpO2 reduction were all statistically significantly lower in patients with PD + SAS than in patients with SAS for all the apnea events except the first one in the consecutive series. These results indicate the attenuation of the autonomic nervous system response to sleep apnea events in patients with PD.

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.

Multiscale entropy (MSE) profiles of heart rate variability (HRV) in patients with atrial fibrillation (AFib) provides clinically useful information for ischemic stroke risk assessment, suggesting that the complex properties characterized by MSE profiles are associated with ischemic stroke risk. However, the meaning of HRV complexity in patients with AFib has not been clearly interpreted, and the physical and mathematical understanding of the relation between HRV dynamics and the ischemic stroke risk is not well established. To gain a deeper insight into HRV dynamics in patients with AFib, and to improve ischemic stroke risk assessment using HRV analysis, we study the HRV characteristics related to MSE profiles, such as the long-range correlation and probability density function. In this study, we analyze the HRV time series of 173 patients with permanent AFib. Our results show that, although HRV time series in patients with AFib exhibit long-range correlation (1/f fluctuations)—as observed in healthy subjects—in a range longer than 90 s, these autocorrelation properties have no significant predictive power for ischemic stroke occurrence. Further, the probability density function structure of the coarse-grained times series at scales greater than 2 s is dominantly associated with ischemic stroke risk. This observation could provide valuable information for improving ischemic stroke risk assessment using HRV analysis.

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).

Atonia during rapid eye movement (REM) sleep is absent in patients with REM sleep behavior disorder (RBD), a phenomenon called REM sleep without atonia (RWA). RBD patients have symptoms in common with neurodegenerative diseases, and data from follow-up studies on idiopathic RBD patient indicate that RBD predicts development of neurodegenerative diseases, particularly Parkinson's disease (PD). Therefore, early diagnosis of RWA can help identify and possibly prevent neurodegenerative diseases. Currently, RWA assessment by visual analysis of polysomnogram (PSG) is only moderately reliable and extremely time-consuming, making it difficult to obtain objective, quantifiable results. We developed an algorithm to automatically quantify tonic and phasic electromyographic (EMG) activities of the musculus mentalis during REM sleep using the scoring manual proposed by the American Academy of Sleep Medicine. Hilbert transform and average rectification were used to calculate the amplitudes of phasic and tonic muscular activities, respectively. Parameter values in the algorithm were optimized by cross-referencing the classification result obtained from the algorithm with the result from epoch-by-epoch visual inspection by a neurologist. A total of 2315 REM epochs from 24 PD patients were analyzed. We calculated the optimal parameter set, at which the sum of sensitivity and specificity was the highest, as well as the area under the receiver operating characteristic (ROC) curve (AUC). Verification tests showed good detection accuracy (phasic: sensitivity = 88%, specificity = 82%, AUC = 0.92; tonic: sensitivity = 88%, specificity = 85%, AUC = 0.93). Thus, this automated RWA detection algorithm is potentially useful for rapid and accurate diagnosis of RBD.

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.