Respiratory Rhythm Research Articles

Relaxation Effect of Light-Emitting Chair in Synchronization with Heartbeat and Respiration Rhythms

Relaxation Effect of Light-Emitting Chair in Synchronization with Heartbeat and Respiration Rhythms

Current research in pathophysiology of opioid-induced respiratory depression, neonatal opioid withdrawal syndrome, and neonatal antidepressant exposure syndrome

Respiratory depression (RD) is the primary cause of death due to opioids. Opioids bind to mu (µ)-opioid receptors (MORs) encoded by the MOR gene Oprm1, widely expressed in the central and peripheral nervous systems including centers that modulate breathing. Respiratory centers are located throughout the brainstem. Experiments with Oprm1-deleted knockout (KO) mice undertaken to determine which sites are necessary for the induction of opioid-induced respiratory depression (OIRD) showed that the pre-Bötzinger complex (preBötC) and the pontine Kölliker-Fuse nucleus (KF) contribute equally to OIRD but RD was not totally eliminated. Morphine showed a differential influence on preBötC and KF neurons – low doses attenuated RD following deletion of MORs from preBötC neurons and an increase in apneas after high doses whereas deletion of MORs from KF neurons but not the preBötC attenuated RD at both high and low doses. In other KO mice studies, morphine administration after deletion of Oprm1 from both the preBötC and the KF/PBN neurons, led to the conclusion that both respiratory centres contribute to OIRD but the preBötC predominates. MOR-mediated post-synaptic activation of GIRK potassium channels has been implicated as a cause of OIRD. A complementary mechanism in the preBötC involving KCNQ potassium channels independent of MOR signaling has been described. Recent experiments in rats showing that morphine depresses normal, but not gasping breathing, cast doubt on the belief that eupnea, sighs, and gasps, are under the control of preBötC neurons. Methadone, administered to alleviate symptoms of neonatal opioid withdrawal syndrome (NOWS), desensitized rats to OIRD. Protection lost between postnatal days 1 and 2 coincides with the preBötC becoming the dominant generator of respiratory rhythm. Neonatal antidepressant exposure syndrome (NADES) and serotonin toxicity (ST) show similarities including RD. Enzyme CYP2D6 involved in opioid detoxification is polymorphic. Individuals of different CYP2D6 genotype may show increased, decreased, or no enzyme activity, contributing to the variability of patient responses to different opioids and OIRD.

Chapter 6 - Critical roles for breathing in the genesis and modulation of emotional states

Breathing can be classified into metabolic and behavioral categories. Metabolic breathing and voluntary behavioral breathing are controlled in the brainstem and in the cerebral motor cortex, respectively. This chapter places special emphasis on the reciprocal influences between breathing and emotional processes. As is the case with neural control of breathing, emotions are generated by multiple control networks, located primarily in the forebrain. For several decades, a respiratory rhythm generator has been investigated in the limbic system. The amygdala receives respiratory-related input from the piriform cortex. Excitatory recurrent branches are located in the piriform cortex and have tight reciprocal synaptic connections, which produce periodic oscillations, similar to those recorded in the hippocampus during slow-wave sleep. The relationship between olfactory breathing rhythm and emotion is seen as the gateway to interpreting the relationship between breathing and emotion. In this chapter, we describe roles of breathing in the genesis of emotion, neural structures common to breathing and emotion, and mutual importance of breathing and emotion. We also describe the central roles of conscious awareness and voluntary control of breathing, as effective methods for stabilizing attention and the contents in the stream of consciousness. Voluntary control of breathing is seen as an essential practice for achieving emotional well-being.

Nursing diagnoses of newborns in rooming-in care using ICNP®.

to create nursing diagnosis definitions for newborns in rooming-in care, using the International Classification for Nursing Practice (ICNP). methodological study following the steps for the identification and validation of relevant terms to care for clients; cross-mapping of the terms identified with the terms of the ICNP® 2019; elaboration and validation of the nursing diagnostic definitions of ICNP® and later classification according with the Basic Human Needs described by Wanda Horta. from the terms extracted, 168 were validated through specialist consensus, subsidizing the elaboration of 27 diagnosis definitions. the most common diagnoses for the clients studied were: "Effective Feeding Behaviour", "Effective Urination", "Normal Respiration Rhythm", "Effective Swallowing", "Effective Peripheral Intravenous Access", and "Effective Parent Child Attachment". It was confirmed that the records of psychobiological needs are mainly made by nurses, which were responsible for 23 of the diagnoses in this study.

Anatomopathological changes of the autonomic nervous system controlling the respiratory rhythm in sudden infant death: advances over the last 30 years

Sudden infant death syndrome (SIDS) is an irreparable loss for the parents and has life-long consequences for the grieved family Objective: This systematic review aims to compile all the researches conducted so far on the possible involvement of respiratory neuronal structures of brainstem in SIDS Methods: Studies were extracted by using MeSH words “Sudden infant death syndrome, neuropathology” on Pubmed database and also search through hand screening. Results: A total of 114 studies were identified which were later further screened for inclusion criteria such as SIDS cases, original articles and case reports and brain nuclei involved in SIDS, while review articles and editorials were excluded. After further screening 40 studies were shortlisted. All the data was analyzed through excel, yearwise, country wise comparison was also conducted. Maximum studies (24) were published from Italy, most publications were from 2010-2020 (27). Upon final screening according to the inclusion of neuronal brain nuclei studies in SIDS, 27 studies were finalized and used for analysis. Altogether there were 805 SIDS cases and 270 controls reported in these 27 studies. Alterations in the brain nuclei included arcuate nuclei, Dorsal raphe nuclei, preBötzinger complex, vagal nuclei, Kölliker-Fuse complex, Tractus solitarius, Parabrachial Kölliker-Fuse complex, Trigeminal nucleus, Parafacial/facial complex, Dentate gurus and others Conclusions: This study highlights the importance of further research in the underlying mechanisms of SIDS. It should be investigated at neuropathological as well as molecular level to understand the mechanisms. It may guide and help to identify the vulnerable infants and save their lives in future. Key words: Neuropathology, Sudden infant death syndrome, crib death, Cot death, brainstem, breathing

Perinatal inflammation and gestational intermittent hypoxia disturbs respiratory rhythm generation and long-term facilitation in vitro: Partial protection by acute minocycline

Perinatal inflammation triggers breathing disturbances early in life and affects the respiratory adaptations to challenging conditions, including the generation of amplitude long-term facilitation (LTF) by acute intermittent hypoxia (AIH). Some of these effects can be avoided by anti-inflammatory treatments like minocycline. Since little is known about the effects of perinatal inflammation on the inspiratory rhythm generator, located in the preBötzinger complex (preBötC), we tested the impact of acute lipopolysaccharide (LPS) systemic administration (sLPS), as well as gestational LPS (gLPS) and gestational chronic IH (gCIH), on respiratory rhythm generation and its long-term response to AIH in a brainstem slice preparation from neonatal mice. We also evaluated whether acute minocycline administration could influence these effects. We found that perinatal inflammation induced by sLPS or gLPS, as well as gCIH, modulate the frequency, signal-to-noise ratio and/or amplitude (and their regularity) of the respiratory rhythm recorded from the preBötC in the brainstem slice. Moreover, all these perinatal conditions inhibited frequency LTF and amplitude long-term depression (LTD); gCIH even induced frequency LTD of the respiratory rhythm after AIH. Some of these alterations were not observed in slices pre-treated in vitro with minocycline, when compared with slices obtained from naïve pups, suggesting that ongoing inflammatory conditions affect respiratory rhythm generation and its plasticity. Thus, it is likely that alterations in the inspiratory rhythm generator and its adaptive responses could contribute to the respiratory disturbances observed in neonates that suffered from perinatal inflammatory challenges.

Negative respiratory sinus arrhythmia (nRSA) in the MRI-scanner - a physiologic phenomenon observed during elevated anxiety in healthy persons

Recently, we reported on a rare manifestation of respiratory sinus arrhythmia (RSA), namely the “switched-off” RSA (Rassler et al., 2018), also called negative RSA (nRSA). It was found in a minority of healthy persons during elevated fMRI-related anxiety characterized by slow spontaneous breathing and synchronous slow beat-to-beat interval (RRI) oscillations.From 23 healthy scanner naïve participants of an fMRI study consisting of 4 resting states, we selected resting states with highest state anxiety (AS) from 10 participants (AS=24.6±2.5) and compared them to those with lowest AS of the same participants (AS=15.1±3.8, p<0.001). During elevated anxiety, the percentage of nRSA (nRSA%) was more than twice of RSA (p=0.045), while RSA prevailed during low anxiety. This indicates that nRSA might be related to elevated anxiety.Interestingly, nRSA was not only associated with slow RRI and breathing oscillations, but also occurred at “normal” breathing rates in the 0.20-0.35 Hz range. We often observed coupled RRI oscillations at 0.1 or 0.15 Hz and respiration at 0.3 Hz (rate ratio 1:3 or 1:2) with respiration-synchronous 0.3 Hz-wavelets in the RRI rhythm (termed “superposition”) indicating a reduced dominance of the respiratory rhythm over the RRI rhythm. This novel finding is supported by the work of Perlitz et al., (2004) on a “0.15 Hz rhythm” in brainstem. The concept behind such a 1:n ratio is a pacemaker-like rhythm in the brainstem that “drives” the cardiac RRI signal and secondarily also respiration as reflected in the 1:n rate ratio.

Pertussis and pertussis-like syndrome in young children

The most common infectious diseases with a risk of severe, non-smooth course and unfavorable outcome in young children, including the first year of life, are pertussis and respiratory syncytial viral infection (RSV infection), often occurring with pertussis-like syndrome.Objective: to establish clinical and laboratory differential diagnostic criteria for pertussis and RSV infection in children of the first year of life.Materials and methods: A retrospective comparative study was conducted, which included patients of the first year of life (from 1 month to 11 months and 29 days), regardless of the duration of hospitalization and duration of the disease: 48 patients with pertussis and 26 with acute RSV infection.Results: The compared groups of patients were comparable in age, the number of severe forms (4.6 ± 0.5 months, 17% for pertussis and 4.0 ± 0.2 months, 16% for RS infection). The disease in both cases began subacute, however, with RSV infection 92% of children were hospitalized in the first 5 days from the onset of the disease, with pertussis — in the first week of the period of convulsive cough — 47.9%, in the second week — 41.7%, in the third week — 10.4%. 52% of patients with RSV infection had no fever or (in 32%) did not exceed 1—3 days. In 41.3% of patients it was subfebrile (37—38 °C), in 21.1% it was febrile (38—39 °C). In patients with pertussis the onset of the disease took place against the background of normal body temperature. In patients with RSV infection, bronchiolitis was recorded in 24% of cases, obstructive bronchitis — in 60%. Patients with pertussis, 89.6% of whom were not vaccinated and 10.4% did not complete the initial course of vaccination, had a typical paroxysmal cough with reprises. Complications in the form of respiratory rhythm disturbances were recorded in 14.6% of cases, pneumonia — in 6.3%. Comparison of hematological parameters revealed highly significant differences in the levels of leukocytosis and relative lymphocytosis (p &lt; 0.001), as well as thrombocytosis (p &lt; 0.01), with the predominance of all indicators in patients with pertussis.Conclusion. Differential diagnostic criteria for the similarity of the clinical picture may be established hematological differences: pronounced leukocytosis due to lymphocytosis, increasing in dynamics, and thrombocytosis in pertussis and normocytosis with moderate lymphocytosis, a possible tendency to thrombocytosis in severe RSV infection.

Release your inhibitions: The role of post-inhibitory rebound and synaptic inhibition in the generation of expiratory activity.

Release your inhibitions: The role of post-inhibitory rebound and synaptic inhibition in the generation of expiratory activity.

Preoperative evaluation of pleural adhesion in patients with lung tumors using four-dimensional computed tomography performed during natural breathing.

The presence of pleural adhesions increases blood loss, occurrence of pulmonary fistulation due to lung injury, and operative time and may complicate thoracoscopic surgery. Recently, it has been reported that four-dimensional computed tomography (4D-CT) synchronized with breathing predicts pleural adhesion. These studies have been performed by asking the patients to maintain a constant respiratory rhythm at the time of scanning. However, many patients face difficulty in doing so, particularly elderly individuals and patients with respiratory dysfunction. We examined the utility of 4D-CT performed while maintaining a natural breathing pattern, which reduces patient burden, in detecting pleural adhesions.A total of 36 patients with a lung tumor near the pleura underwent 4D-CT during free breathing. The migration distance between the lesion and the nearest point on the chest wall on 4D-CT was measured. A sufficient distance indicated the absence of adhesion in that area. The presence of actual adhesions was evaluated and confirmed by intraoperative thoracoscopic findings.There were 7 cases determined to have adhesion by 4D-CT, and 4 of them had actual adhesions confirmed during surgery. The sensitivity and specificity were 80.0% and 90.3%, respectively. The mean migration distance of tumors was 0.8 ± 0.2 cm in the 5 cases with adhesion and 2.6 ± 1.8 cm in the 31 cases without adhesion (P = .01).These results suggest that 4D-CT is a convenient and useful technique for the preoperative assessment of pleural adhesion.

Cheyne–Stokes respiration in two sheep during recovery from general anaesthesia for experimental convection enhanced drug delivery

AbstractTwo 8‐month‐old Suffolk sheep, weighing 45 and 55 kg, respectively, were anaesthetised for an intrathalamic injection of an experimental drug. After an uneventful procedure and general anaesthesia using controlled mechanical ventilation, the sheep were weaned off the ventilator and allowed to breathe spontaneously with end‐tidal carbon dioxide (PE′CO2) levels remaining within normal limits. During recovery, intermittent apnoeic phases were observed with increasing PE′CO2 (&gt;70 mmHg) and decreasing oxygen saturation of haemoglobin (SpO2) levels (90%–91%). The sheep appeared unresponsive, and reflexes were absent. This alternated with phases of normal mentation, normal reflexes and regular spontaneous ventilation, where ventilatory parameters improved. Tentative treatment to reduce intracranial pressure and administration of the opioid receptor antagonist naloxone were unsuccessful. Definite diagnosis of Cheyne–Stokes respiration is difficult but was suspected in these two cases; cerebral cortex damage, intracranial haemorrhage or opioid mediated respiratory rhythm disturbances are possible causes.

Systemic 8-OH-DPAT challenge causes hyperventilation largely via activating pre-botzinger complex 5-HT1A receptors

Systemic 8-OH-DPAT (a 5-HT1A receptor agonist) challenge evokes hyperventilation independent of peripheral 5-HT1A receptors. Though the pre-Botzinger Complex (PBC) is critical in generating respiratory rhythm and activation of local 5-HT1A receptors induces tachypnea via disinhibition of local GABAA neurons, its role in the respiratory response to systemic 8-OH-DPAT challenge is still unclear. In anesthetized rats, 8-OH-DPAT (100 μg/kg, iv) was injected twice to confirm the reproducibility of the evoked responses. The same challenges were performed after bilateral microinjections of (S)-WAY-100135 (a 5-HT1A receptor antagonist) or gabazine (a GABAA receptor antagonist) into the PBC. Our results showed that: 1) 8-OH-DPAT caused reproducible hyperventilation associated with hypotension and bradycardia; 2) microinjections of (S)-WAY-100135 into the PBC attenuated the hyperventilation by ˜60 % without effect on the evoked hypotension and bradycardia; and 3) the same hyperventilatory attenuation was also observed after microinjections of gabazine into the PBC. Our data suggest that PBC 5-HT1A receptors play a key role in the respiratory response to systemic 8-OH-DPAT challenge likely via disinhibiting local GABAergic neurons.

Dynamic Rhythmogenic Network States Drive Differential Opioid Responses in the In Vitro Respiratory Network.

Death from opioid overdose is typically caused by opioid-induced respiratory depression (OIRD). A particularly dangerous characteristic of OIRD is its apparent unpredictability. The respiratory consequences of opioids can be surprisingly inconsistent, even within the same individual. Despite significant clinical implications, most studies have focused on average dose-r esponses rather than individual variation, and there remains little insight into the etiology of this apparent unpredictability. The preBötzinger complex (preBötC) in the ventral medulla is an important site for generating the respiratory rhythm and OIRD. Here, using male and female C57-Bl6 mice in vitro, we demonstrate that the preBötC can assume different network states depending on the excitability of the preBötC and the intrinsic membrane properties of preBötC neurons. These network states predict the functional consequences of opioids in the preBötC, and depending on network state, respiratory rhythmogenesis can be either stabilized or suppressed by opioids. We hypothesize that the dynamic nature of preBötC rhythmogenic properties, required to endow breathing with remarkable flexibility, also plays a key role in the dangerous unpredictability of OIRD.SIGNIFICANCE STATEMENT Opioids can cause unpredictable, life-threatening suppression of breathing. This apparent unpredictability makes clinical management of opioids difficult while also making it challenging to define the underlying mechanisms of OIRD. Here, we find in brainstem slices that the preBötC, an opioid-sensitive subregion of the brainstem, has an optimal configuration of cellular and network properties that results in a maximally stable breathing rhythm. These properties are dynamic, and the state of each individual preBötC network relative to the optimal configuration of the network predicts how vulnerable rhythmogenesis is to the effects of opioids. These insights establish a framework for understanding how endogenous and exogenous modulation of the rhythmogenic state of the preBötC can increase or decrease the risk of OIRD.

Extending the spectral decomposition of Granger causality to include instantaneous influences: application to the control mechanisms of heart rate variability

Assessing Granger causality (GC) intended as the influence, in terms of reduction of variance of surprise, that a driver variable exerts on a given target, requires a suitable treatment of ‘instantaneous’ effects, i.e. influences due to interactions whose time scale is much faster than the time resolution of the measurements, due to unobserved confounders or insufficient sampling rate that cannot be increased because the mechanism of generation of the variable is inherently slow (e.g. the heartbeat). We exploit a recently proposed framework for the estimation of causal influences in the spectral domain and include instantaneous interactions in the modelling, thus obtaining (i) a novel index of undirected instantaneous causality and (ii) a novel measure of GC including instantaneous effects. An effective procedure to speed up the optimization of parameters in this frame is also presented. After illustrating the proposed formalism in a theoretical example, we apply it to two datasets of cardiovascular and respiratory time series and compare the values obtained within the frequency bands of physiological interest by the proposed total measure of causality with those derived from the standard GC analysis. We find that the inclusion of instantaneous causality allows us to correctly disentangle the baroreflex mechanism from the effects related to cardiorespiratory interactions. Moreover, studying how controlling the respiratory rhythm acts on cardiovascular interactions, we document an increase of the direct (non-baroreflex mediated) influence of respiration on the heart rate in the respiratory frequency band when switching from spontaneous to paced breathing. This article is part of the theme issue ‘Advanced computation in cardiovascular physiology: new challenges and opportunities’.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Long-Range Respiratory and Theta Oscillation Networks Depend on Spatial Sensory Context.

Neural oscillations can couple networks of brain regions, especially at lower frequencies. The nasal respiratory rhythm, which elicits robust olfactory bulb oscillations, has been linked to episodic memory, locomotion, and exploration, along with widespread oscillatory coherence. The piriform cortex is implicated in propagating the olfactory-bulb-driven respiratory rhythm, but this has not been tested explicitly in the context of both hippocampal theta and nasal respiratory rhythm during exploratory behaviors. We investigated systemwide interactions during foraging behavior, which engages respiratory and theta rhythms. Local field potentials from the olfactory bulb, piriform cortex, dentate gyrus, and CA1 of hippocampus, primary visual cortex, and nasal respiration were recorded simultaneously from male rats. We compared interactions among these areas while rats foraged using either visual or olfactory spatial cues. We found high coherence during foraging compared with home cage activity in two frequency bands that matched slow and fast respiratory rates. Piriform cortex and hippocampus maintained strong coupling at theta frequency during periods of slow respiration, whereas other pairs showed coupling only at the fast respiratory frequency. Directional analysis shows that the modality of spatial cues was matched to larger influences in the network by the respective primary sensory area. Respiratory and theta rhythms also coupled to faster oscillations in primary sensory and hippocampal areas. These data provide the first evidence of widespread interactions among nasal respiration, olfactory bulb, piriform cortex, and hippocampus in awake freely moving rats, and support the piriform cortex as an integrator of respiratory and theta activity.SIGNIFICANCE STATEMENT Recent studies have shown widespread interactions between the nasally driven respiratory rhythm and neural oscillations in hippocampus and neocortex. With this study, we address how the respiratory rhythm interacts with ongoing slow brain rhythms across olfactory, hippocampal, and visual systems in freely moving rats. Patterns of network connectivity change with behavioral state, with stronger interactions at fast and slow respiratory frequencies during foraging as compared with home cage activity. Routing of interactions between sensory cortices depends on the modality of spatial cues present during foraging. Functional connectivity and cross-frequency coupling analyses suggest strong bidirectional interactions between olfactory and hippocampal systems related to respiration and point to the piriform cortex as a key area for mediating respiratory and theta rhythms.

The effect of lamotrigine and other antiepileptic drugs on respiratory rhythm generation in the pre-Bötzinger complex.

Lamotrigine and other sodium-channel blocking agents are among the most commonly used antiepileptic drugs (AEDs). Because other sodium channel blockers, such as riluzole, can severely alter respiratory rhythm generation during hypoxia, we wanted to investigate if AEDs can have similar effects. This is especially important in the context of sudden unexpected death in epilepsy (SUDEP), the major cause of death in patients suffering from therapy-resistant epilepsy. Although the mechanism of action is not entirely understood, respiratory dysfunction after generalized tonic-clonic seizures seems to play a major role. We used transverse brainstem slice preparations from neonatal and juvenile mice containing the pre-Bötzinger complex (PreBötC) and measured population as well as intracellular activity of the rhythm-generating network under normoxia and hypoxia in the presence or absence of AEDs. We found a substantial inhibition of the gasping response induced by the application of sodium channel blockers (lamotrigine and carbamazepine). In contrast, levetiracetam, an AED-modulating synaptic function, had a much smaller effect. The inhibition of gasping by lamotrigine was accompanied by a significant reduction of the persistent sodium current (INap) in PreBötC neurons. Surprisingly, the suppression of persistent sodium currents by lamotrigine did not affect the voltage-dependent bursting activity in PreBötC pacemaker neurons, but led to a hypoxia-dependent shift of the action potential rheobase in all measured PreBötC neurons. Our results contribute to the understanding of the effects of AEDs on the vital respiratory functions of the central nervous system. Moreover, our study adds further insight into sodium-dependent changes occurring during hypoxia and the contribution of cellular properties to the respiratory rhythm generation in the pre-Bötzinger complex. It raises the question of whether sodium channel blocking AEDs could, in conditions of extreme hypoxia, contribute to SUDEP, an important issue that warrants further studies.

Evolution of vertebrate respiratory central rhythm generators

Tracing the evolution of the central rhythm generators associated with ventilation in vertebrates is hindered by a lack of information surrounding key transitions. To begin with, central rhythm generation has been studied in detail in only a few species from four vertebrate groups, lamprey, anuran amphibians, turtles, and mammals (primarily rodents). Secondly, there is a lack of information regarding the transition from water breathing fish to air breathing amniotes (reptiles, birds, and mammals). Specifically, the respiratory rhythm generators of fish appear to be single oscillators capable of generating both phases of the respiratory cycle (expansion and compression) and projecting to motoneurons in cranial nerves innervating bucco-pharyngeal muscles. In the amniotes we find oscillators capable of independently generating separate phases of the respiratory cycle (expiration and inspiration) and projecting to pre-motoneurons in the ventrolateral medulla that in turn project to spinal motoneurons innervating thoracic and abdominal muscles (reptiles, birds, and mammals). Studies of the one group of amphibians that lie at this transition (the anurans), raise intriguing possibilities but, for a variety of reasons that we explore, also raise unanswered questions. In this review we summarize what is known about the rhythm generating circuits associated with breathing that arise from the different rhombomeric segments in each of the different vertebrate classes. Assuming oscillating circuits form in every pair of rhombomeres in every vertebrate during development, we trace what appears to be the evolutionary fate of each and highlight the questions that remain to be answered to properly understand the evolutionary transitions in vertebrate central respiratory rhythm generation.

Effects of Cardiac Resynchronization Therapy on Cardio-Respiratory Coupling.

In this study, the effect of cardiac resynchronization therapy (CRT) on the relationship between the cardiovascular and respiratory systems in heart failure subjects was examined for the first time. We hypothesized that alterations in cardio-respiratory interactions, after CRT implantation, quantified by signal complexity, could be a marker of a favorable CRT response. Sample entropy and scaling exponents were calculated from synchronously recorded cardiac and respiratory signals 20 min in duration, collected in 47 heart failure patients at rest, before and 9 months after CRT implantation. Further, cross-sample entropy between these signals was calculated. After CRT, all patients had lower heart rate and CRT responders had reduced breathing frequency. Results revealed that higher cardiac rhythm complexity in CRT non-responders was associated with weak correlations of cardiac rhythm at baseline measurement over long scales and over short scales at follow-up recording. Unlike CRT responders, in non-responders, a significant difference in respiratory rhythm complexity between measurements could be consequence of divergent changes in correlation properties of the respiratory signal over short and long scales. Asynchrony between cardiac and respiratory rhythm increased significantly in CRT non-responders during follow-up. Quantification of complexity and synchrony between cardiac and respiratory signals shows significant associations between CRT success and stability of cardio-respiratory coupling.

ACE2 expression in rat brain: Implications for COVID-19 associated neurological manifestations

We examined cell type-specific expression and distribution of rat brain angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, in the rodent brain. ACE2 is ubiquitously present in brain vasculature, with the highest density of ACE2 expressing capillaries found in the olfactory bulb, the hypothalamic paraventricular, supraoptic, and mammillary nuclei, the midbrain substantia nigra and ventral tegmental area, and the hindbrain pontine nucleus, the pre-Bötzinger complex, and nucleus of tractus solitarius. ACE2 was expressed in astrocytes and astrocytic foot processes, pericytes and endothelial cells, key components of the blood-brain barrier. We found discrete neuronal groups immunopositive for ACE2 in brainstem respiratory rhythm generating centers, including the pontine nucleus, the parafascicular/retrotrapezoid nucleus, the parabrachial nucleus, the Bötzinger, and pre-Bötzinger complexes and the nucleus of tractus solitarius; in the arousal-related pontine reticular nucleus and gigantocellular reticular nuclei; in brainstem aminergic nuclei, including substantia nigra, ventral tegmental area, dorsal raphe, and locus coeruleus; in the epithalamic habenula, hypothalamic paraventricular and supramammillary nuclei; and in the hippocampus. Identification of ACE2-expressing neurons in rat brain within well-established functional circuits facilitates prediction of possible neurological manifestations of brain ACE2 dysregulation during and after COVID-19 infection.