Respiratory Oscillations Research Articles

Stabilizing Ventilation in OSAHS with CPAP Emergent Periodic Breathing Through the Use of Dead Space

Stabilizing Ventilation in OSAHS with CPAP Emergent Periodic Breathing Through the Use of Dead Space

Fourier Analysis of Human Finger Bioimpedance Variances

Fourier analysis was employed to determine the amplitudes of spectrum components of small variations of electrical resistance (bioimpedance) in human finger recorded using an original hardware-software complex. It revealed periodic bioimpedance oscillations at the frequencies of heartbeats, respiration, and Mayer wave (0.1 Hz). These periodic variations were observed under normal conditions and during circulation arrest in the arm. It is concluded that the spectrum peaks of bioimpedance variations in the phalanx of human finger reflect periodic blood pressure changes in the major vessels and rhythmic neural control of the regional vascular tone. During normal blood flow, the greatest amplitude of rhythmic changes in bioimpedance was observed at the heart rate; it surpassed by an order of magnitude the amplitudes of respiratory oscillations and Mayer wave. In contrast, the largest amplitude of rhythmical changes of the impedance during circulation arrest corresponded to the oscillations at respiration rate, while the amplitude of variations at the heart rate was the smallest. Under circulation arrest, the maximum frequency of bioimpedance variations was approximately 1.4 Hz (the third respiratory harmonic), which indicates the upper limit of frequency range of neural modulation of vascular tone in human finger. During normal respiration and circulation, two side cardiac peaks were revealed in bioimpedance amplitude spectrum, whose amplitude reflected the depth of the respiratory amplitude modulation of pumping action of the heart. During normal breathing, the second and the third harmonics of the cardiac bioimpedance variations were split reflecting respiratory frequency modulation of the heart rate.

Interacting oscillations in neural control of breathing: modeling and qualitative analysis

In mammalian respiration, late-expiratory (late-E, or pre-inspiratory) oscillations emerge in abdominal motor output with increasing metabolic demands (e.g., during hypercapnia, hypoxia, etc.). These oscillations originate in the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) and couple with the respiratory oscillations generated by the interacting neural populations of the Bötzinger (BötC) and pre-Bötzinger (pre-BötC) complexes, representing the kernel of the respiratory central pattern generator. Recently, we analyzed experimental data on the generation of late-E oscillations and proposed a large-scale computational model that simulates the possible interactions between the BötC/pre-BötC and RTN/pFRG oscillations under different conditions. Here we describe a reduced model that maintains the essential features and architecture of the large-scale model, but relies on simplified activity-based descriptions of neural populations. This simplification allowed us to use methods of dynamical systems theory, such as fast-slow decomposition, bifurcation analysis, and phase plane analysis, to elucidate the mechanisms and dynamics of synchronization between the RTN/pFRG and BötC/pre-BötC oscillations. Three physiologically relevant behaviors have been analyzed: emergence and quantal acceleration of late-E oscillations during hypercapnia, transformation of the late-E activity into a biphasic-E activity during hypercapnic hypoxia, and quantal slowing of BötC/pre-BötC oscillations with the reduction of pre-BötC excitability. Each behavior is elicited by gradual changes in excitatory drives or other model parameters, reflecting specific changes in metabolic and/or physiological conditions. Our results provide important theoretical insights into interactions between RTN/pFRG and BötC/pre-BötC oscillations and the role of these interactions in the control of breathing under different metabolic conditions.

How Global Are Olfactory Bulb Oscillations?

Previous studies in waking animals have shown that the frequency structure of olfactory bulb (OB) local field potential oscillations is very similar across the OB, but large low-impedance surface electrodes may have favored highly coherent events, averaging out local inhomogeneities. We tested the hypothesis that OB oscillations represent spatially homogeneous phenomena at all scales. We used pairs of concentric electrodes (200 μm outer shaft surrounding an inner 2-3 μm recording site) beginning on the dorsal OB at anterior and medial locations in urethane-anesthetized rats and measured local field potential responses at successive 200 μm depths before and during odor stimulation. Within locations (outer vs. inner lead on a single probe), on the time scale of 0.5 s, coherence in all frequency bands was significant, but on larger time scales (10 s), only respiratory (1-4 Hz) and beta (15-30 Hz) oscillations showed prominent peaks. Across locations, coherence in all frequency bands was significantly lower for both sizes of electrodes at all depths but the most superficial 600 μm. Near the pial surface, coherence across outer (larger) electrodes at different sites was equal to coherence across outer and inner (small) electrodes within a single site and larger than coherence across inner electrodes at different sites. Overall, the beta band showed the largest coherence across bulbar sites and electrodes. Therefore larger electrodes at the surface of the OB favor globally coherent events, and at all depths, coherence depends on the type of oscillation (beta or gamma) and duration of the analysis window.

Spontaneous variability and reactive postural beat-to-beat changes of integral ECG body surface potential maps.

There is virtually no information on spontaneous variability of ECG body surface potential maps (BSPMs) and on dynamics of their reactive changes in healthy subjects. This study evaluated quantitatively the depolarization (QRS) and repolarization (QRST) parameters derived from the respective integral BSPMs, constructed beat-to-beat, from continual body surface ECG records in 9 healthy men resting supine, during head-up tilting and sitting. Spontaneous variability of the BSPMs parameters, both at rest and during postural reactions, was characterized by significant respiratory and low frequency oscillations, more pronounced when related to repolarization. Head-up tilting and sitting-up evoked significant decrease in the QRST-BSPM amplitudes, widening of the angle alpha and reduction of nondipolarity indexes, compared to the respective supine values. All these changes were gradual, characterized by transition phenomena and prolonged after-effects. Tilting back to horizontal restored the resting supine values. The postural effects on depolarization were individually more variable and in the average showed a minimal QRS-BSPM amplitude increase. Beat-to-beat analysis of a train of ECG BSPMs provided the first evidence of spontaneous, non-random, respiratory and low frequency oscillations of the ventricular repolarization pattern, and the first insight into the dynamics of body posture associated changes in ventricular recovery.

Heart period sensitivity to forced oscillations in ventilatory pressure

Heart rate variability analysis is a dynamic method to estimate the autonomic control over the cardiac cycle. Although dysfunction in this control system may appear spontaneously, other deficits may require provocation of the system. In this article we describe a non-invasive method to perturb the autonomic influences on the cardiac cycle. We recorded the ECG and respiratory pressure of ten healthy volunteers while introducing a random forced oscillation pressure wave onto spontaneous respiration. The heart period time series was determined and the power spectra for the 0.05-0.15, 0.15-0.3 and 0.05-0.4 Hz bands were calculated. The random input did not alter mean heart rate. However, the segments with the forced oscillation input demonstrated, on average, a tenfold increase in spectral power averaged across all subjects, with a maximum observed effect of 100-fold increase in power. This increase in power correlated with the respiratory frequency. This study demonstrates that random noise ventilation, such as used in respiratory forced oscillation impedance estimates, significantly alters the autonomic input to cardiac cycle variability in wake subjects.

Fourier analysis of electrical impedance variations in urinary bladder during changes of intravesical pressure

Original hardware and software system was used to record and analyze the variations of electrical impedance of the urinary bladder in narcotized rats (n=7) at rest, during instillation of physiological saline into the bladder resulted in elevation of intravesical pressure, and during subsequent urination accompanied by intravesical pressure release. Fourier analysis of impedance variations revealed three periodic components with the frequencies of heartbeat, respiration, and the Mayer wave (~0.1 Hz). In resting bladder, the amplitude of Mayer and respiratory spectrum peaks were high, and they increased to a different extent during physiological elevation of intravesical pressure, while a small cardiac peak did not changed significantly and tended to decrease at high intravesical pressure. Urination released intravesical pressure and restored all the peaks to the resting level. It is hypothesized that Mayer and respiratory bioimpedance oscillations of urinary bladder are neural in origin, while the cardiac peak is mainly determined by hydrodynamic arterial pulsations. The novel method can assess vesical circulation and its neural control at various phases of bladder activity.

Assessment of vasomotor oscillations with Fourier analysis of biological tissue impedance

Fourier analysis revealed a number of periodicities in small variations of bioimpedance of human finger including the major spectrum peaks at the frequencies of heart beats, respiration, and Mayer wave (0.1 Hz). These periodic variations of bioimpedance were detected under the normal conditions and during blood flow arrest in the hand by a pneumatic cuff placed on the arm. They are explained by periodic variations in systemic blood pressure and by oscillations of regional vascular tone resulted from neural vasomotor control. During normal blood flow, the greatest variations in bioimpedance were observed at the heart rate, and their amplitude surpassed by an order of magnitude the amplitudes of respiratory oscillations and Mayer wave. In contrast, during blood arrest, the largest amplitude of rhythmical changes of the impedance characterized the oscillations at respiration rate, while the amplitude of oscillations at the heart rate was the smallest. During normal respiration and circulation, two side cardiac peaks were revealed in bioimpedance amplitude spectrum which disappeared during respiration arrest and thought to reflect the amplitude respiratory modulation of the cardiac output via sympathetic influences. During normal breathing, the second and the third harmonics of the cardiac spectrum peak were split reflecting frequency respiratory modulation of the heart rate by parasympathetic influences. The results favour applicability of Fourier analysis of bioimpedance variations in assessment of regional neural influences and neurogenic modulation of cardiac activity.

Spontaneous variability and reactive postural beat-to-beat changes of integral ECG body surface potential maps

There is virtually no information on spontaneous variability of ECG body surface potential maps (BSPMs) and on dynamics of their reactive changes in healthy subjects. This study evaluated quantitatively the depolarization (QRS) and repolarization (QRST) parameters derived from the respective integral BSPMs, constructed beat-to-beat, from continual body surface ECG records in 9 healthy men resting supine, during head-up tilting and sitting. Spontaneous variability of the BSPMs parameters, both at rest and during postural reactions, was characterized by significant respiratory and low frequency oscillations, more pronounced when related to repolarization. Head-up tilting and sitting-up evoked significant decrease in the QRST-BSPM amplitudes, widening of the angle α and reduction of nondipolarity indexes, compared to the respective supine values. All these changes were gradual, characterized by transition phenomena and prolonged after-effects. Tilting back to horizontal restored the resting supine values. The postural effects on depolarization were individually more variable and in the average showed a minimal QRS-BSPM amplitude increase. Beat-to-beat analysis of a train of ECG BSPMs provided the first evidence of spontaneous, non-random, respiratory and low frequency oscillations of the ventricular repolarization pattern, and the first insight into the dynamics of body posture associated changes in ventricular recovery.

Do changes in the coupling between respiratory and sympathetic activities contribute to neurogenic hypertension?

1. It is well known that respiration markedly modulates the sympathetic nervous system. Interactions between pontine and medullary neurons involved in the control of sympathetic and respiratory functions are the main mechanism underlying the respiratory related oscillations in sympathetic nerve activity. 2. Recently, in rats treated with chronic intermittent hypoxia, we demonstrated that alterations in respiratory pattern may drive increased sympathetic outflow and hence the development of systemic hypertension. These experiments, performed in the in situ working heart-brain stem preparation, raise the possibility that enhanced central coupling between respiratory and sympathetic activities could be a potential mechanism underpinning the development and/or the maintenance of neurogenic hypertension. 3. In the present review, we discuss the neural basis of the enhanced entrainment between respiratory and sympathetic neurons in the brain stem that can be induced by chronic intermittent hypoxia and the possible implications of these mechanisms in the genesis of sympathetic overactivity and, consequently, hypertension.

Feasibility of NIRS in the Neurointensive Care Unit: A Pilot Study in Stroke Using Physiological Oscillations

Near-infrared spectroscopy (NIRS) is a non-invasive, real-time bedside modality sensitive to changes in cerebral perfusion and oxygenation and is highly sensitive to physiological oscillations at different frequencies. However, the clinical feasibility of NIRS remains limited, partly due to concerns regarding NIRS signal quantification, which relies on mostly arbitrary assumptions on hemoglobin concentrations and tissue layers. In this pilot study comparing stroke patients to healthy controls, we explored the utility of the interhemispheric correlation coefficient (IHCC) during physiological oscillations in detecting asymmetry in hemispheric microvascular hemodynamics. Using bi-hemispheric continuous-wave NIRS, 12 patients with hemispheric strokes and 9 controls were measured prospectively. NIRS signal was band-pass filtered to isolate cardiac (0.7-3 Hz) and respiratory (0.15-0.7 Hz) oscillations. IHCCs were calculated in both oscillation frequency bands. Using Fisher's Z-transform for non-Gaussian distributions, the IHCC during cardiac and respiratory oscillations were compared between both groups. Nine patients and nine controls had data of sufficient quality to be included in the analysis. The IHCCs during cardiac and respiratory oscillations were significantly different between patients versus controls (cardiac 0.79 +/- 0.18 vs. 0.94 +/- 0.07, P = 0.025; respiratory 0.24 +/- 0.28 vs. 0.59 +/- 0.3; P = 0.016). Computing the IHCC during physiological cardiac and respiratory oscillations may be a new NIRS analysis technique to quantify asymmetric microvascular hemodynamics in stroke patients in the neurocritical care unit. It allows each subject to serve as their own control obviating the need for arbitrary assumptions on absolute hemoglobin concentration. Future clinical applications may include rapid identification of patients with ischemic brain injury in the pre-hospital setting. This promising new analysis technique warrants further validation.

The Monitoring of Vital Functions in Different Associations of General Injectable Anesthetics in Dogs

The discovery of new anesthetics, more effective and less toxic, gave veterinarians the possibility to successfully intervene in resolving the most different situations encountered in their activity. This study consisted in monitoring respiratory frequency, cardiac frequency and body temperature in patients anesthetized and then subdued to different surgical interventions. The researches were carried on 20 dogs of different breeds, ages and sexes, diagnosed with different types of diseases, which needed surgical treatment under the effect of anesthesia. There were selected patients in which pain intensity associated with surgical intervention was relatively equal. Anesthesia protocols consisted mainly in the association of two substances: xylazine + ketamine – in 5 cases; medetomidine + ketamine – in 5 cases; acepromazine + ketamine – in 5 cases; propofol – in 5 cases. In case of anesthesia induced by xylazine-ketamine combination, it was observed a slight tendency to bradycardia, respiratory frequency oscillations and the decrease of body temperature (tendency to hypothermia). Medetomidine-ketamine association determined cardiac frequency oscillations (without a particular tendency), an initial increase of respiratory frequency followed by come-back to normal and a slight decrease of body temperature. Using acepromazine-ketamine combination, the studied parameters varied under acceptable limits during anesthesia. Propofol ensured good conditions for surgical interventions, with the observations that the anesthetic effect is short and it requires supplementary safety measures in order to avoid the appearance of respiratory disorders. The selection of anesthetic substances must be done considering patient-related factors, the purpose of anesthesia and the available equipments.

Cardiorespiratory interactions in patients with atrial flutter

Respiratory sinus arrhythmia (RSA) is generally known as the autonomically mediated modulation of the sinus node pacemaker frequency in synchrony with respiration. Cardiorespiratory interactions have been largely investigated during sinus rhythm, whereas little is known about interactions during reentrant arrhythmias. In this study, cardiorespiratory interactions at the atrial and ventricular level were investigated during atrial flutter (AFL), a supraventricular arrhythmia based on a reentry, by using cross-spectral analysis and computer modeling. The coherence and phase between respiration and atrial (gamma(AA)(2), phi(AA)) and ventricular (gamma(RR)(2), phi(RR)) interval series were estimated in 20 patients with typical AFL (68.0 +/- 8.8 yr) and some degree of atrioventricular (AV) conduction block. In all patients, atrial intervals displayed oscillations strongly coupled and in phase with respiration (gamma(AA)(2)= 0.97 +/- 0.05, phi(AA) = 0.71 +/- 0.31 rad), corresponding to a paradoxical lengthening of intervals during inspiration. The modulation pattern was frequency independent, with in-phase oscillations and short time delays (0.40 +/- 0.15 s) for respiratory frequencies in the range 0.1-0.4 Hz. Ventricular patterns were affected by AV conduction type. In patients with fixed AV conduction, ventricular intervals displayed oscillations strongly coupled (gamma(RR)(2)= 0.97 +/- 0.03) and in phase with respiration (phi(RR) = 1.08 +/- 0.80 rad). Differently, in patients with variable AV conduction, respiratory oscillations were secondary to Wencheback rhythmicity, resulting in a decreased level of coupling (gamma(RR)(2)= 0.50 +/- 0.21). Simulations with a simplified model of AV conduction showed ventricular patterns to originate from the combination of a respiratory modulated atrial input with the functional properties of the AV node. The paradoxical frequency-independent modulation pattern of atrial interval, the short time delays, and the complexity of ventricular rhythm characterize respiratory arrhythmia during AFL and distinguish it from normal RSA. These peculiar features can be explained by assuming a direct mechanical action of respiration on AFL reentrant circuit.

Real-time luminescence monitoring of cell-cycle and respiratory oscillations in yeast

The use of luciferase reporters has become a precise, noninvasive, high-throughput method for real-time monitoring of promoter activity in living cells, especially for rhythmic biological processes such as circadian rhythms. We developed a destabilized firefly luciferase as a reporter for rhythmic promoter activity in both the cell division and respiratory cycles of the budding yeast Saccharomyces cerevisiae in which real-time luminescence reporters have not been previously applied. The continuous output of light from luciferase reporters allowed us to explore the relationship between the cell division cycle and the yeast respiratory oscillation, including the observation of responses to chemicals that cause phase shifting of the respiratory oscillations. Destabilized firefly luciferase is a good reporter of cell cycle position in synchronized or partially synchronized yeast cultures, in both batch and continuous cultures. In addition, the oxygen dependence of luciferase can be used under certain conditions as a genetically encodable oxygen monitor. Finally, we use this reporter to show that there is a direct correlation between premature induction of cell division and phase resetting of the respiratory oscillation under the continuous culture conditions tested.

Induction of oscillatory ventilation pattern using dynamic modulation of heart rate through a pacemaker

For disease states characterized by oscillatory ventilation, an ideal dynamic therapy would apply a counteracting oscillation in ventilation. Modulating respiratory gas transport through the circulation might allow this. We explore the ability of repetitive alternations in heart rate, using a cardiac pacemaker, to elicit oscillations in respiratory variables and discuss the potential for therapeutic exploitation. By incorporating acute cardiac output manipulations into an integrated mathematical model, we observed that a rise in cardiac output should yield a gradual rise in end-tidal CO2 and, subsequently, ventilation. An alternating pattern of cardiac output might, therefore, create oscillations in CO2 and ventilation. We studied the effect of repeated alternations in heart rate of 30 beats/min with periodicity of 60 s, on cardiac output, respiratory gases, and ventilation in 22 subjects with implanted cardiac pacemakers and stable breathing patterns. End-tidal CO2 and ventilation developed consistent oscillations with a period of 60 s during the heart rate alternations, with mean peak-to-trough relative excursions of 8.4 ± 5.0% (P < 0.0001) and 24.4 ± 18.8% (P < 0.0001), respectively. Furthermore, we verified the mathematical prediction that the amplitude of these oscillations would depend on those in cardiac output (r = 0.59, P = 0.001). Repetitive alternations in heart rate can elicit reproducible oscillations in end-tidal CO2 and ventilation. The size of this effect depends on the magnitude of the cardiac output response. Harnessed and timed appropriately, this cardiorespiratory mechanism might be exploited to create an active dynamic responsive pacing algorithm to counteract spontaneous respiratory oscillations, such as those causing apneic breathing disorders.

Cardiac and respiratory oscillations of the blood flow in microvessels of the human skin

Laser Doppler flowmetry with wavelet analysis, spectrophotometry, computer-aided capillaroscopy, and thermometry were used to study cardiac and respiratory oscillations of the blood flow in the skin microvessels of 30 subjects. The amplitudes of the cardiac and respiratory rhythms (Ac and Ar, respectively) were found to be determined predominantly by the distribution of perfusion and pressure in larger vessels (arterioles and venules). The cardiorespiratory coupling is a regulatory factor in the microcirculatory system; at rest, the value of Ac/Ar reflects the capillary arteriovenous ratio. In the structure of the microcirculation index (MI) and Ac, the velocity-to-volume ratio depends on the perfusion of the corresponding skin region: at rest, the volume-related component is expressed only in the skin with arteriolovenular anastomoses, whereas, in the skin without these anastomoses, MI and Ac are predominantly correlated with the dynamic velocity-related component. Ac is inversely dependent on both stationary and oscillatory components of the microvascular tone. The nature of the respiratory wave depends not only on the respiratory modulation of the venous outflow, but also on the perfusion pressure in the microvessels and venular hematocrit. The correlation of Ar with the total blood flow in the skin microvessels and the individual contributions of velocity-and volume-related components to Ar were significant only in situations where the blood flow was above a certain threshold, below which the respiratory waves can penetrate into the microvessels but their correlation with the total perfusion is nonsignificant.

Alveolar Pco2 oscillations and ventilation at sea level and at high altitude

This study examines the potential for a ventilatory drive, independent of mean PCO2, but depending instead on changes in PCO2 that occur during the respiratory cycle. This responsiveness is referred to here as "dynamic ventilatory sensitivity." The normal, spontaneous, respiratory oscillations in alveolar PCO2 have been modified with inspiratory pulses approximating alveolar PCO2 concentrations, both at sea level and at high altitude (5,000 m, 16,400 ft.). All tests were conducted with subjects exercising on a cycle ergometer at 60 W. The pulses last about half the inspiratory duration and are timed to arrive in the alveoli during early or late inspiration. Differences in ventilation, which then occur in the face of similar end-tidal PCO2 values, are taken to result from dynamic ventilatory sensitivity. Highly significant ventilatory responses (early pulse response greater than late) occurred in hypoxia and normoxia at sea level and after more than 4 days at 5,000 m. The response at high altitude was eliminated by normalizing PO2 and was reduced or eliminated with acetazolamide. No response was present soon after arrival (<4 days) at base camp, 5,000 m, on either of two high-altitude expeditions (BMEME, 1994, and Kanchenjunga, 1998). The largest responses at 5,000 m were obtained in subjects returning from very high altitude (7,100-8,848 m). The present study confirms and extends previous investigations that suggest that alveolar PCO2 oscillations provide a feedback signal for respiratory control, independent of changes in mean PCO2, suggesting that natural PCO2 oscillations drive breathing in exercise.

Respiratory rhythm and EEG oscillations in the olfactory system: a study using a biologically detailed model

EEG oscillations are found in several structures of the olfactory system, like the olfactory epithelium (OE), olfactory bulb (OB) and pyriform cortex (PC). From the theoretical side a possible way to study mechanisms responsible for the origin of these oscillations is the construction of biologically detailed computational models, which can exhibit oscillatory neural activity and allow simulations of EEG measurements which can be compared with real data. In this work we present a large-scale biologically detailed model of the olfactory system consisting of models of OE, OB and PC and use it to study relationships between EEG oscillations in these three areas and the respiratory rhythm. The OE model contains 2500 olfactory sensory neuron models (OSNMs) distributed in a 50 × 50 square grid. The OB model has two cell layers, a 8 × 8 grid of mitral cell models and a 10 × 10 grid of granule cell models. The PC model has 96 pyramidal cell models distributed in a 16 × 6 grid and 225 interneuron models arranged in three layers with 75 model cells in each one of them. These three layers are called, respectively, multipolar cell layer, horizontal cell layer and globular cell layer. We developed a function that generates a receptor current in the OSNM based on a respiratory frequency and odor concentration. This receptor current is injected directly at the soma of an OSNM, simulating the effect of a stimulus. The responses of the OE, OB and PC were measured in terms of raster plots and simulated EEG records. In OE and OB, EEG records were made by single point electrodes placed at the centers of both the OE and OB models. In PC, the EEG was calculated as the average of the extracellular field potentials measured by a simulated grid of 8 × 5 point electrodes placed at the surface of the PC model. The results show that the slow components of the electrical oscillations produced in OB and PC are directly associated with the respiratory frequencies and odor concentrations at the receptor layer while the fast components are related with the intrinsic synaptic activity at each neural layer.

Separating T-wave alternans from respiratory oscillations

Separating T-wave alternans from respiratory oscillations

Regulation of yeast oscillatory dynamics.

When yeast cells are grown continuously at high cell density, a respiratory oscillation percolates throughout the population. Many essential cellular functions have been shown to be separated temporally during each cycle; however, the regulatory mechanisms involved in oscillatory dynamics remain to be elucidated. Through GC-MS analysis we found that the majority of metabolites show oscillatory dynamics, with 70% of the identified metabolite concentrations peaking in conjunction with NAD(P)H. Through statistical analyses of microarray data, we identified that biosynthetic events have a defined order, and this program is initiated when respiration rates are increasing. We then combined metabolic, transcriptional data and statistical analyses of transcription factor activity, identified the top oscillatory parameters, and filtered a large-scale yeast interaction network according to these parameters. The analyses and controlled experimental perturbation provided evidence that a transcriptional complex formed part of the timing circuit for biosynthetic, reductive, and cell cycle programs in the cell. This circuitry does not act in isolation because both have strong translational, proteomic, and metabolic regulatory mechanisms. Our data lead us to conclude that the regulation of the respiratory oscillation revolves around coupled subgraphs containing large numbers of proteins and metabolites, with a potential to oscillate, and no definable hierarchy, i.e., heterarchical control.