Mixed predictability and cross-validation to assess non-linear Granger causality in short cardiovascular variability series.

A method to evaluate the direction and strength of causal interactions in bivariate cardiovascular and cardiorespiratory series is presented. The method is based on quantifying self and mixed predictability of the two series using nearest-neighbour local linear approximation. It returns two causal coupling indexes measuring the relative improvement in predictability along direct and reverse directions, and a directionality index indicating the preferential direction of interaction. The method was implemented through a cross-validation approach that allowed quantification of directionality without constraining the embedding of the series, and fully exploited the available data to maximise the prediction accuracy. Validation on short simulated bivariate time series demonstrated the ability of the method to capture different degrees of unidirectional and bidirectional interaction. Moreover, application to representative examples of heart rate, systolic arterial pressure and respiration series allowed the inference of causal relationships related to known physiological mechanisms and experimental conditions.     

Assessment of Interaction Between Cardio-Respiratory Signals Using Directed Coherence on Healthy Subjects During Postural Change

PurposeTo detect and quantify the directional interaction changes between cardio-respiratory system during postural change.MethodTraditional frequency domain analysis based on power spectrum and coherence are insufficient to quantify nonlinear structures and complexity of physiological subsystems. Recently, Granger causality is found as preferable method for evaluation of causality i.e., directional interaction. Frequency domain Granger causality based on directed coherence has been used in this study to identify directional interaction between cardiac and respiratory signal during postural change from supine to standing for healthy subjects.ResultECG and respiration signal are recorded for this study. The beat-to-beat variability series from ECG provides heart rate (RR) and the respiration amplitude corresponds to RESP time series. It was observed that respiration is responsible for the changes in ECG signal during supine position as compared to standing. The outflow of information from RESP to RR increases during supine results in stronger interaction but reduces during standing result in reduction of interaction. Similarly, the effect of RR on RESP is found significant only during standing.ConclusionThe proposed directed coherence approach detects the cardio-respiratory regulation during postural change and provide information about coupling changes during this transition.     

Cardiac and respiratory patterns synchronize between persons during choir singing

Dyadic and collective activities requiring temporally coordinated action are likely to be associated with cardiac and respiratory patterns that synchronize within and between people. However, the extent and functional significance of cardiac and respiratory between-person couplings have not been investigated thus far. Here, we report interpersonal oscillatory couplings among eleven singers and one conductor engaged in choir singing. We find that: (a) phase synchronization both in respiration and heart rate variability increase significantly during singing relative to a rest condition; (b) phase synchronization is higher when singing in unison than when singing pieces with multiple voice parts; (c) directed coupling measures are consistent with the presence of causal effects of the conductor on the singers at high modulation frequencies; (d) the different voices of the choir are reflected in network analyses of cardiac and respiratory activity based on graph theory. Our results suggest that oscillatory coupling of cardiac and respiratory patterns provide a physiological basis for interpersonal action coordination.     

Phasic coordination between locomotor and respiratory rhythms in Lymnaea. Real behavior and computer simulation

In the pond snail Lymnaea stagnalis, a firm phase-locked coupling of pneumostome movements to the locomotor cycle was observed during terrestrial locomotion, thus demonstrating that the coordination between locomotor and respiratory rhythms is a natural behavioral event in this animal. The results of computational modelling suggest a possible scheme of coordination between these motor rhythms which is based on inhibitory projection from the central pattern generator for locomotion to that for respiration. These findings allow the neuronal mechanisms underlying coordination of two rhythmic behaviors to be investigated.     

Time of night effects on heart rate variation in normal neonates

Circadian patterns have been observed in infants as early as the first few postnatal days. We hypothesized that, in each sleep-waking state, heart rate variation in several distinct frequency bands would show consistent variations across a night in newborn infants. Twelve-hour night-time recordings of EEG, ECG, EOG, digastric EMG, respiratory movements, and CO2 were obtained from 25 normal full-term infants at 2-7 days postnatal age. The extents of three types of heart rate variation were determined for all epochs identified as quiet sleep, rapid eye movement (REM) sleep, and waking during each 4-hr period of the night. In particular states, the extent of all three types of heart rate variation decreased from the evening (7-11pm) to the late night (11pm-3am). Heart rate variation at the respiratory frequency showed such a time-of-night effect in quiet sleep only, resulting in a significant sleep state effect on respiratory sinus arrhythmia during the evening that disappeared later in the night. Previous studies have indicated that respiratory sinus arrhythmia is enhanced during quiet sleep, relative to other states, after 3 mo of age; the present findings suggest that the tendency for enhancement during quiet sleep is present even in the neonate, although this tendency is only expressed during the evening. Results indicate that time-of-night effects on heart rate variation are not constant across physiological states in neonates, and heart rate variation during the waking state is particularly unresponsive to these time-of-night influences.     

Breath-by-breath analysis of cardiorespiratory interaction for quantifying developmental maturity in premature infants

In healthy neonates, connections between the heart and lungs through brain stem chemosensory pathways and the autonomic nervous system result in cardiorespiratory synchronization. This interdependence between cardiac and respiratory dynamics can be difficult to measure because of intermittent signal quality in intensive care settings and variability of heart and breathing rates. We employed a phase-based measure suggested by Sch?fer and coworkers (Sch?fer C, Rosenblum MG, Kurths J, Abel HH. Nature 392: 239-240, 1998) to obtain a breath-by-breath analysis of cardiorespiratory interaction. This measure of cardiorespiratory interaction does not distinguish between cardiac control of respiration associated with cardioventilatory coupling and respiratory influences on the heart rate associated with respiratory sinus arrhythmia. We calculated, in sliding 4-min windows, the probability density of heartbeats as a function of the concurrent phase of the respiratory cycle. Probability density functions whose Shannon entropy had a <0.1% chance of occurring from random numbers were classified as exhibiting interaction. In this way, we analyzed 18 infant-years of data from 1,202 patients in the Neonatal Intensive Care Unit at University of Virginia. We found evidence of interaction in 3.3 patient-years of data (18%). Cardiorespiratory interaction increased several-fold with postnatal development, but, surprisingly, the rate of increase was not affected by gestational age at birth. We find evidence for moderate correspondence between this measure of cardiorespiratory interaction and cardioventilatory coupling and no evidence for respiratory sinus arrhythmia, leading to the need for further investigation of the underlying mechanism. Such continuous measures of physiological interaction may serve to gauge developmental maturity in neonatal intensive care patients and prove useful in decisions about incipient illness and about hospital discharge.     

Lung and buccal ventilation in the frog: uncoupling coupled oscillators

The frog, with two distinct ventilatory acts, provides a useful model to investigate the prospective interaction of two oscillators in generating the respiratory rhythm. Building on evidence supporting the existence of separate oscillators generating buccal and lung ventilation, we have attempted to uncouple the two rhythms in the isolated brain stem preparation. Opioid preferentially inhibits the lung rhythm, suggesting an uncoupling of the lung from the buccal oscillator. Reduction of the superfusate chloride concentration alters both the buccal and the lung rhythms. Joint application of opioid and reduced-chloride superfusate leads to an increase in the variability of the buccal burst-to-lung burst intervals. This increase in variability suggests that chloride-mediated mechanisms are involved in coupling the buccal oscillator to the lung oscillator. Given the results from these interventions, we propose a simple schematic model of the frog respiratory rhythm generator, outlining the coupling of the lung and buccal oscillators.     

Sleep-induced periodic breathing and apnea: a theoretical study

To elucidate the mechanisms that lead to sleep-disordered breathing, we have developed a mathematical model that allows for dynamic interactions among the chemical control of respiration, changes in sleep-waking state, and changes in upper airway patency. The increase in steady-state arterial PCO2 accompanying sleep is shown to be inversely related to the ventilatory response to CO2. Chemical control of respiration becomes less stable during the light stage of sleep, despite a reduction in chemoresponsiveness, due to a concomitant increase in "plant gain" (i.e., responsiveness of blood gases to ventilatory changes). The withdrawal of the "wakefulness drive" during sleep onset represents a strong perturbation to respiratory control: higher magnitudes and rates of withdrawal of this drive favor instability. These results may account for the higher incidence of periodic breathing observed during light sleep and sleep onset. Periodic ventilation can also result from repetitive alternations between sleep onset and arousal. The potential for instability is further compounded if the possibility of upper airway occlusion is also included. In systems with high controller gains, instability is mediated primarily through chemoreflex overcompensation. However, in systems with depressed chemoresponsiveness, rapid sleep onset and large blood gas fluctuations trigger repetitive episodes of arousal and hyperpnea alternating with apneas that may or may not be obstructive. Between these extremes, more complex patterns can arise from the interaction between chemoreflex-mediated oscillations of shorter-cycle-duration (approximately 36 s) and longer-wavelength (approximately 60-80 s) state-driven oscillations.     

Aerobic Exercise during Pregnancy and Presence of Fetal-Maternal Heart Rate Synchronization

It has been shown that short-term direct interaction between maternal and fetal heart rates may take place and that this interaction is affected by the rate of maternal respiration. The aim of this study was to determine the effect of maternal aerobic exercise during pregnancy on the occurrence of fetal-maternal heart rate synchronization.

Methods

In 40 pregnant women at the 36^th week of gestation, 21 of whom exercised regularly, we acquired 18 min. RR interval time series obtained simultaneously in the mothers and their fetuses from magnetocardiographic recordings. The time series of the two groups were examined with respect to their heart rate variability, the maternal respiratory rate and the presence of synchronization epochs as determined on the basis of synchrograms. Surrogate data were used to assess whether the occurrence of synchronization was due to chance.

Results

In the original data, we found synchronization occurred less often in pregnancies in which the mothers had exercised regularly. These subjects also displayed higher combined fetal-maternal heart rate variability and lower maternal respiratory rates. Analysis of the surrogate data showed shorter epochs of synchronization and a lack of the phase coordination found between maternal and fetal beat timing in the original data.

Conclusion

The results suggest that fetal-maternal heart rate coupling is present but generally weak. Maternal exercise has a damping effect on its occurrence, most likely due to an increase in beat-to-beat differences, higher vagal tone and slower breathing rates.     

Multivariate and multiorgan analysis of cardiorespiratory variability signals: the CAP sleep case.

Signals from different systems are analyzed during sleep on a beat-to-beat basis to provide a quantitative measure of synchronization with the heart rate variability (HRV) signal, oscillations of which reflect the action of the autonomic nervous system. Beat-to-beat variability signals synchronized to QRS occurrence on ECG signals were extracted from respiration, electroencephalogram (EEG) and electromyogram (EMG) traces. The analysis was restricted to sleep stage 2. Cyclic alternating pattern (CAP) periods were detected from EEG signals and the following conditions were identified: stage 2 non-CAP (2 NCAP), stage 2 CAP (2 CAP) and stage 2 CAP with myoclonus (2 CAP MC). The coupling relationships between pairs of variability signals were studied in both the time and frequency domains. Passing from 2 NCAP to 2 CAP, sympathetic activation is indicated by tachycardia and reduced respiratory arrhythmia in the heart rate signal. At the same time, we observed a marked link between EEG and HRV at the CAP frequency. During 2 CAP MC, the increased synchronization involved myoclonus and respiration. The underlying mechanism seems to be related to a global control system at the central level that involves the different systems.     

Quantifying the strength of the linear causal coupling in closed loop interacting cardiovascular variability signals

 The coherence function measures the amount of correlation between two signals x and y as a function of the frequency, independently of their causal relationships. Therefore, the coherence function is not useful in deciding whether an open-loop relationship between x and y is set (x acts on y, but the reverse relationship is prevented) or x and y interact in a closed loop (x affects y, and vice versa). This study proposes a method based on a bivariate autoregressive model to derive the strength of the causal coupling on both arms of a closed loop. The method exploits the definition of causal coherence. After the closed-loop identification of the model coefficients, the causal coherence is calculated by switching off separately the feedback or the feedforward path, thus opening the closed loop and fixing causality. The method was tested in simulations and applied to evaluate the degree of the causal coupling between two variables known to interact in a closed loop mainly at a low frequency (LF, around 0.1 Hz) and at a high frequency (HF, at the respiratory rate): the heart period (RR interval) and systolic arterial pressure (SAP). In dogs at control, the RR interval and the SAP are highly correlated at HF. This coupling occurs in the causal direction from the RR interval to the SAP (the mechanical path), while the coupling on the reverse causal direction (the baroreflex path) is not significant, thus pointing out the importance of the direct effects of respiration on the RR interval. Total baroreceptive denervation, by opening the closed loop at the level of the influences of SAP on RR interval, does not change these results. In elderly healthy men at rest, the RR interval and SAP are highly correlated at the LF and the HF. At the HF, a significant coupling in both causal directions is found, even though closed-loop interactions are detected in few cases. At the LF, the link on the baroreflex pathway is negligible with respect to that on the reverse mechanical one. In heart transplant recipients, in which SAP variations do not cause RR interval changes as a result of the cardiac denervation, the method correctly detects a significant coupling only on the pathway from the RR interval to the SAP. Received: 28 June 2001 / Accepted in revised form: 23 October 2001     

Cardio-Respiratory Coordination Increases during Sleep Apnea

Cardiovascular diseases are the main source of morbidity and mortality in the United States with costs of more than $170 billion. Repetitive respiratory disorders during sleep are assumed to be a major cause of these diseases. Therefore, the understanding of the cardio-respiratory regulation during these events is of high public interest. One of the governing mechanisms is the mutual influence of the cardiac and respiratory oscillations on their respective onsets, the cardio-respiratory coordination (CRC). We analyze this mechanism based on nocturnal measurements of 27 males suffering from obstructive sleep apnea syndrome. Here we find, by using an advanced analysis technique, the coordigram, not only that the occurrence of CRC is significantly more frequent during respiratory sleep disturbances than in normal respiration (p-value<10⁻⁵¹) but also more frequent after these events (p-value<10⁻¹⁵). Especially, the latter finding contradicts the common assumption that spontaneous CRC can only be observed in epochs of relaxed conditions, while our newly discovered epochs of CRC after disturbances are characterized by high autonomic stress. Our findings on the connection between CRC and the appearance of sleep-disordered events require a substantial extension of the current understanding of obstructive sleep apneas and hypopneas.     

Effects of increase in body temperature on the breathing pattern in premature infants

This study was designed to determine the effects of a mild increase in body temperature within the physiological range (0.8 degrees C) in healthy premature infants. Seven unsedated premature infants (38.4 wk +/- 1.5 postconceptional age) were monitored polygraphically during "morning naps" in an incubator under two different environmental temperatures: (1) normothermia with the incubator temperature set at 25 degrees C and the rectal temperature equal to 36.9 degrees C +/- 0.1; (2) hyperthermia with the incubator temperature set at 35 degrees C and the rectal temperature equal to 37.7 degrees C +/- 0.15. Respiratory frequency and heart rate, respiratory events, i.e., central and obstructive apnea, and periodic breathing with and without apneic oscillations were tabulated. Results for respiratory events were expressed as (1) indices of the total number of respiratory events, and of specific respiratory events per hour of total, quiet and active sleep times; (2) duration of total and specific respiratory events expressed as a percentage of total sleep, quiet and active sleep times. Respiratory frequency and heart rate were significantly increased by hyperthermia (P less than 0.05). Hyperthermia did not significantly modify the indices or the duration of central and obstructive apnea. But the indices and the duration of periodic breathing with and without apneic oscillations were significantly increased by hyperthermia during active sleep (P less than 0.05) but not during quiet sleep. The present study shows that a mild increase in body temperature within the physiological range in premature infants enhances the instability of the breathing pattern during active sleep.     

Respiratory ultradian rhythms of mean and low frequencies: a comparative physiological approach

Recent developments in human rhythmic respiratory pathology lead to this review of the literature for ultradian rhythms of middle and low frequencies, that is having periods longer than the usual respiratory rates, whose periods are seconds or fractions of seconds. Ultradian respiratory movements for respiratory periods (5 less than tau less than 50 min) have been reported in many species of small laboratory animals (mice, rats, guinea-pigs, rabbits, quails). Long-period respiratory rates (20 less than tau less than 90 min) have been found in human fetuses and infants. But they are more difficult to detect in human adults, except during sleep where they have been related to REM and NONREM activities. These respiratory rhythms of middle and low frequencies are supposed to result from dissipative energy structures related to surface-volume relationships, with interlocking chemical clocks, and to be relevant to a basic rest-activity cycle.     

Reduced creatine-stimulated respiration in doxorubicin challenged mitochondria: particular sensitivity of the heart

Doxorubicin (DXR) belongs to the most efficient anticancer drugs. However, its use is limited by a risk of cardiotoxicity, which is not completely understood. Recently, we have shown that DXR impairs essential properties of purified mitochondrial creatine kinase (MtCK), with cardiac isoenzyme (sMtCK) being particularly sensitive. In this study we assessed the effects of DXR on respiration of isolated structurally and functionally intact heart mitochondria, containing sMtCK, in the presence and absence of externally added creatine (Cr), and compared these effects with the response of brain mitochondria expressing uMtCK, the ubiquitous, non-muscle MtCK isoenzyme. DXR impaired respiration of isolated heart mitochondria already after short-term exposure (minutes), affecting both ADP- and Cr-stimulated respiration. During a first short time span (minutes to 1 h), detachment of MtCK from membranes occurred, while a decrease of MtCK activity related to oxidative damage was only observed after longer exposure (several hours). The early inhibition of Cr-stimulated respiration, in addition to impairment of components of the respiratory chain involves a partial disturbance of functional coupling between MtCK and ANT, likely due to interaction of DXR with cardiolipin leading to competitive inhibition of MtCK/membrane binding. The relevance of these findings for the regulation of mitochondrial energy production in the heart, as well as the obvious differences of DXR action in the heart as compared to brain tissue, is discussed.     

Reduced creatine-stimulated respiration in doxorubicin challenged mitochondria: Particular sensitivity of the heart

Doxorubicin (DXR) belongs to the most efficient anticancer drugs. However, its use is limited by a risk of cardiotoxicity, which is not completely understood. Recently, we have shown that DXR impairs essential properties of purified mitochondrial creatine kinase (MtCK), with cardiac isoenzyme (sMtCK) being particularly sensitive. In this study we assessed the effects of DXR on respiration of isolated structurally and functionally intact heart mitochondria, containing sMtCK, in the presence and absence of externally added creatine (Cr), and compared these effects with the response of brain mitochondria expressing uMtCK, the ubiquitous, non-muscle MtCK isoenzyme. DXR impaired respiration of isolated heart mitochondria already after short-term exposure (minutes), affecting both ADP- and Cr-stimulated respiration. During a first short time span (minutes to 1 h), detachment of MtCK from membranes occurred, while a decrease of MtCK activity related to oxidative damage was only observed after longer exposure (several hours). The early inhibition of Cr-stimulated respiration, in addition to impairment of components of the respiratory chain involves a partial disturbance of functional coupling between MtCK and ANT, likely due to interaction of DXR with cardiolipin leading to competitive inhibition of MtCK/membrane binding. The relevance of these findings for the regulation of mitochondrial energy production in the heart, as well as the obvious differences of DXR action in the heart as compared to brain tissue, is discussed.     

Revisiting spontaneous internal desynchrony using a quantitative model of sleep physiology

Early attempts to characterize free-running human circadian rhythms generated three notable results: 1) observed circadian periods of 25 hours (considerably longer than the now established 24.1- to 24.2-hour average intrinsic circadian period) with sleep delayed to later circadian phases than during entrainment; 2) spontaneous internal desynchrony of circadian rhythms and sleep/wake cycles--the former with an approximately 24.9-hour period, and the latter with a longer (28-68 hour) or shorter (12-20 hour) period; and 3) bicircadian (48-50 hour) sleep/wake cycles. All three results are reproduced by Kronauer et al.'s (1982) coupled oscillator model, but the physiological basis for that phenomenological model is unclear. We use a physiologically based model of hypothalamic and brain stem nuclei to investigate alternative physiological mechanisms that could underlie internal desynchrony. We demonstrate that experimental observations can be reproduced by changes in two pathways: promotion of orexinergic (Orx) wake signals, and attenuation of the circadian signal reaching hypothalamic nuclei. We reason that delayed sleep is indicative of an additional wake-promoting drive, which may be of behavioral origin, associated with removal of daily schedules and instructions given to participants. We model this by increasing Orx tone during wake, which reproduces the observed period lengthening and delayed sleep. Weakening circadian input to the ventrolateral preoptic nucleus (possibly mediated by the dorsomedial hypothalamus) causes desynchrony, with observed sleep/wake cycle period determined by degree of Orx up-regulation. During desynchrony, sleep/wake cycles are driven by sleep homeostasis, yet sleep bout length maintains circadian phase dependence. The model predicts sleep episodes are shortest when started near the temperature minimum, consistent with experimental findings. The model also correctly predicts that it is possible to transition to bicircadian rhythms from either a synchronized or desynchronized state. Our findings suggest that feedback from behavioral choices to physiology could play an important role in spontaneous internal desynchrony.     

Causal relationships between frequency bands of extracellular signals in visual cortex revealed by an information theoretic analysis

Characterizing how different cortical rhythms interact and how their interaction changes with sensory stimulation is important to gather insights into how these rhythms are generated and what sensory function they may play. Concepts from information theory, such as Transfer Entropy (TE), offer principled ways to quantify the amount of causation between different frequency bands of the signal recorded from extracellular electrodes; yet these techniques are hard to apply to real data. To address the above issues, in this study we develop a method to compute fast and reliably the amount of TE from experimental time series of extracellular potentials. The method consisted in adapting efficiently the calculation of TE to analog signals and in providing appropriate sampling bias corrections. We then used this method to quantify the strength and significance of causal interaction between frequency bands of field potentials and spikes recorded from primary visual cortex of anaesthetized macaques, both during spontaneous activity and during binocular presentation of naturalistic color movies. Causal interactions between different frequency bands were prominent when considering the signals at a fine (ms) temporal resolution, and happened with a very short (ms-scale) delay. The interactions were much less prominent and significant at coarser temporal resolutions. At high temporal resolution, we found strong bidirectional causal interactions between gamma-band (40–100 Hz) and slower field potentials when considering signals recorded within a distance of 2 mm. The interactions involving gamma bands signals were stronger during movie presentation than in absence of stimuli, suggesting a strong role of the gamma cycle in processing naturalistic stimuli. Moreover, the phase of gamma oscillations was playing a stronger role than their amplitude in increasing causations with slower field potentials and spikes during stimulation. The dominant direction of causality was mainly found in the direction from MUA or gamma frequency band signals to lower frequency signals, suggesting that hierarchical correlations between lower and higher frequency cortical rhythms are originated by the faster rhythms.