Control Of Breathing Research Articles

Ventilatory limitations in patients with HFpEF and obesity

Heart failure with preserved ejection fraction (HFpEF) patients have an increased ventilatory demand. Whether their ventilatory capacity can meet this increased demand is unknown, especially in those with obesity. Body composition (DXA) and pulmonary function were measured in 20 patients with HFpEF (69 ± 6 yr;9 M/11 W). Cardiorespiratory responses, breathing mechanics, and ratings of perceived breathlessness (RPB, 0–10) were measured at rest, 20 W, and peak exercise. FVC correlated with %body fat (R2 =0.51,P = 0.0006), V̇O2peak (%predicted,R2 =0.32,P = 0.001), and RPB (R2 =0.58,P = 0.0004). %Body fat correlated with end-expiratory lung volume at rest (R2 =0.76,P < 0.001), 20 W (R2 =0.72,P < 0.001), and peak exercise (R2 =0.74,P < 0.001). Patients were then divided into two groups: those with lower ventilatory reserve (FVC<3 L,2 M/10 W) and those with higher ventilatory reserve (FVC>3.8 L,7 M/1 W). V̇O2peak was ∼22% less (p < 0.05) and RPB was twice as high at 20 W (p < 0.01) in patients with lower ventilatory reserve. Ventilatory reserves are limited in patients with HFpEF and obesity; indeed, the margin between ventilatory demand and capacity is so narrow that exercise capacity could be ventilatory limited in many patients.

Progressive tauopathy disrupts breathing stability and chemoreflexes during presumptive sleep in mice.

Rationale: Although sleep apnea occurs in over 50% of individuals with Alzheimer's Disease (AD) or related tauopathies, little is known concerning the potential role of tauopathy in the pathogenesis of sleep apnea. Here, we tested the hypotheses that, during presumptive sleep, a murine model of tauopathy (rTg4510) exhibits: 1) increased breathing instability; 2) impaired chemoreflex function; and 3) exacerbation of these effects with tauopathy progression. Methods: rTg4510 mice initially develop robust tauopathy in the hippocampus and cortex, and eventually progresses to the brainstem. Type I and II post-sigh apnea, Type III (spontaneous) apnea, sigh, and hypopnea incidence were measured in young adult (5-6months; n = 10-14/group) and aged (13-15months; n = 22-24/group) non-transgenic (nTg), monogenic control tetracycline transactivator, and bigenic rTg4510 mice using whole-body plethysmography during presumptive sleep (i.e., eyes closed, curled/laying posture, stable breathing for >200 breaths) while breathing room air (21% O2). Peripheral and central chemoreceptor sensitivity were assessed with transient exposures (5min) to hyperoxia (100% O2) or hypercapnia (3% and 5% CO2 in 21% O2), respectively. Results: We report significant increases in Type I, II, and III apneas (all p < 0.001), sighs (p = 0.002) and hypopneas (p < 0.001) in aged rTg4510 mice, but only Type III apneas in young adult rTg4510 mice (p < 0.001) versus age-matched nTg controls. Aged rTg4510 mice exhibited profound chemoreflex impairment versus age matched nTg and tTA mice. In rTg4510 mice, breathing frequency, tidal volume and minute ventilation were not affected by hyperoxic or hypercapnic challenges, in striking contrast to controls. Histological examination revealed hyperphosphorylated tau in brainstem regions involved in the control of breathing (e.g., pons, medullary respiratory column, retrotrapezoid nucleus) in aged rTg4510 mice. Neither breathing instability nor hyperphosphorylated tau in brainstem tissues were observed in young adult rTg4510 mice. Conclusion: Older rTg4510 mice exhibit profound impairment in the neural control of breathing, with greater breathing instability and near absence of oxygen and carbon-dioxide chemoreflexes. Breathing impairments paralleled tauopathy progression into brainstem regions that control breathing. These findings are consistent with the idea that tauopathy per se undermines chemoreflexes and promotes breathing instability during sleep.

Liver stereotactic body radiation therapy without fiducial or retained ethiodized oil guidance warrants greater than 5 mm planning target volumes.

For liver stereotactic body radiation therapy (SBRT), the placement of fiducial markers or retained ethiodized oil by transarterial chemoembolisation (TACE) provides a landmark for consistent target localisation. TACE and fiducial markers are invasive procedures that harbour additional risks. We hypothesise that liver SBRT can be accurately delivered without the use of these invasive surrogate markers. We retrospectively identified 50 consecutive patients who underwent liver SBRT with respiratory motion management to a single lesion which exhibited retained ethiodized oil per prior TACE delivery. For each SBRT fraction, two manual rigid image registrations were performed by the treating physician. One using the liver contour as a surrogate for the target and second aligning only to the radio-opaque retained ethiodized oil of the treated lesion. The magnitude of the displacement vector between the two registration methods was used to assess the accuracy of target localisation if ethiodized oil was not present. For the 50 patients, a total of 244 analysable cone-beam CTs (CBCTs) were included (six CBCTs excluded due to poor ethiodized oil visualisation). Respiratory motion management techniques consisted of active breathing control for 13 and abdominal compression for 37 patients. Forty-two patients had peripheral lesions and eight had central lesions (<2 cm from left and right portal veins). The average target localisation offset between the two registration methods (i.e. liver contour vs. retained ethiodized oil alignment) for patients with a single peripheral or central liver lesion was 5.8 and 5.3 mm, respectively. Across all patients, the average change in target position exceeded 5 mm for image registration methods based on the liver contour alone versus the retained ethiodized oil region. This suggests that margins greater than 5 mm may be required for respiratory motion-managed liver SBRT treatments in patients who do not undergo prior TACE or fiducial placement.

The Constrained Disorder Principle Accounts for the Variability That Characterizes Breathing: A Method for Treating Chronic Respiratory Diseases and Improving Mechanical Ventilation.

Variability characterizes breathing, cellular respiration, and the underlying quantum effects. Variability serves as a mechanism for coping with changing environments; however, this hypothesis does not explain why many of the variable phenomena of respiration manifest randomness. According to the constrained disorder principle (CDP), living organisms are defined by their inherent disorder bounded by variable boundaries. The present paper describes the mechanisms of breathing and cellular respiration, focusing on their inherent variability. It defines how the CDP accounts for the variability and randomness in breathing and respiration. It also provides a scheme for the potential role of respiration variability in the energy balance in biological systems. The paper describes the option of using CDP-based artificial intelligence platforms to augment the respiratory process's efficiency, correct malfunctions, and treat disorders associated with the respiratory system.

뇌기능 조절의 관점에서 바라본 선도 수행 : 지감⋅조식⋅금촉을 중심으로

뇌기능 조절의 관점에서 바라본 선도 수행 : 지감⋅조식⋅금촉을 중심으로

Caffeine exacerbates seizure-induced death via postictal hypoxia

Sudden unexpected death in epilepsy (SUDEP) is the leading epilepsy-related cause of premature mortality in people with intractable epilepsy, who are 27 times more likely to die than the general population. Impairment of the central control of breathing following a seizure has been identified as a putative cause of death, but the mechanisms underlying this seizure-induced breathing failure are largely unknown. Our laboratory has advanced a vascular theory of postictal behavioural dysfunction, including SUDEP. We have recently reported that seizure-induced death occurs after seizures invade brainstem breathing centres which then leads to local hypoxia causing breathing failure and death. Here we investigated the effects of caffeine and two adenosine receptors in two models of seizure-induced death. We recorded local oxygen levels in brainstem breathing centres as well as time to cessation of breathing and cardiac activity relative to seizure activity. The administration of the non-selective A1/A2A antagonist caffeine or the selective A1 agonist N6-cyclopentyladenosine reveals a detrimental effect on postictal hypoxia, providing support for caffeine modulating cerebral vasculature leading to brainstem hypoxia and cessation of breathing. Conversely, A2A activation with CGS-21680 was found to increase the lifespan of mice in both our models of seizure-induced death.

An analysis of the impact of different levels of inspiratory volume using active breathing control on the intrafraction motion and dose coverage of target volumes in patients undergoing thoracic radiotherapy

PurposeTo determine whether the level of inspiratory volume affect the extent to which active breathing control (ABC) reduces intrafraction motion and the dose coverage of target volumes in patients receiving external beam radiation therapy (EBRT) to the thoracic region Materials/methods20 patients undergoing thoracic radiotherapy enrolled in a prospective study using ABC for respiratory motion management and volumetric-modulated arc therapy (VMAT) as the treatment technique. They were randomized to one of two groups, the control group of 80% inspiratory volume and the other test group of 70%. At least one set of repeated CBCTs was done weekly. All images including CBCTs and Planning CTs were sent to MIM softwareTM for analysis of intrafraction motion using Dice Similarity Coefficient (DSC). The target dose conformality was assessed using conformation number (CN). Intention-to-treat analysis was employed for statistical purpose. ResultsThe DSC for the 70% and 80% inspiratory volume group were 0.93 and 0.92, respectively. For the 70% group, there was a significant negative correlation (p < 0.05) between DSC and time between two CBCTs, but not for the 80% group. The average percentage change in CN for the 70% and 80% group was 10.91% and 8.14%, respectively, and their difference was significant (p < 0.05). Furthermore, the actual change in volume had a significant positive correlation (p < 0.05) with the percentage change in CN for the 70% inspiratory volume group but not the 80% group. ConclusionMore evidence suggests that the target volumes from the 80% inspiratory volume group have less intrafraction motion compared to the 70% group. The findings from the percentage change in CN suggest that there could potentially be less tumor motion for higher levels of inspiratory volume and this could possibly contribute to why intrafraction motion is less for the 80% inspiratory volume group.

Slow Breathing Reduces Biomarkers of Stress in Response to a Virtual Reality Active Shooter Training Drill.

Tactical occupations regularly encounter life-threatening situations while on duty. Although these occupations are often trained to utilize slow breathing (SB) during intense stress, there is no evidence supporting the effects on markers of stress in response to a virtual reality active shooter training drill (VR-ASD). The purpose of the study was to determine the impact of acute SB on biomarkers of stress in response to a VR-ASD. Seventy-nine (n = 79) subjects performed either slow breathing method 1 (SB1), slow breathing method 2 (SB2), or normal breathing (control) for five minutes, both pre- and post-VR-ASD. Saliva samples were analyzed for stress markers, including α-amylase (sAA) and secretory immunoglobulin-A (SIgA). Both methods of SB resulted in significantly lower sAA concentrations at 5 (p < 0.001) and 30 min post-VR-ASD (SB1: p = 0.008; SB2: p < 0.001) compared to the control. In the control condition, the sAA concentrations were significantly elevated 5 min post-VR-ASD (p < 0.001) but did not change across time in SB1 or SB2 (p > 0.05). Thus, both SB1 and SB2 reduced the sAA response and resulted in lower concentrations post-VR-ASD. This study was pre-registered as a clinical trial ("Impact of Breathing Interventions on Stress Markers"; NCT05825846).

Role of high flow nasal therapy in Intensive Care Units

Introduction and purpose: High Flow Nasal Therapy is quite new respiratory support method, although recently it became more popular – especially during COVID-19 pandemic. Physiological mechanisms as well as main applications were observed and described in several randomized controlled trias and metaanalisys. The purpose of this review is to present fundamental studies and indicate applications of this method.&#x0D; Brief description of the state of knowladge: Breathing mixture with a maximum flow 60l/min needs to be heated and humidified to protect the airways from dryness. Optimal humidity improves mucocilary clearance, reduces inflammation of the airways and energy expenditure, especially in acute respiratory failure. High flow nasal therapy may imrpove the mechanics of breathing also by washout of nasopharyngeal dead space and generating positive airway pressure during exhalation, which keeps airways open and prevents the alveoli from collapsing. High flow therapy can be use in many different applications but at Intensive Care Unit the most important are: acute hypoxemia, during extubation or rest breaks from NIV. It is important to monitor the patient and predict the need for intubation on time. There are physiological states that we shoud focus on: respiratory rate, dyspnea or work of breathing, but it is good to know ROX index which can be helpful to assess the success of the therapy.&#x0D; Summary (conlcusions): High flow nasal therapy is a simple and safety respiratory support method that can be applicable at Intensive Care Units. It can lower the intubation numbers and help during NIV rest breaks. High flow nasal therapy is a very promising method for all patients with respiratory failure but it is important to monitor the patient and not delay the intubation.

Modulating Hyperpolarization-Activated Cation Currents through Small Molecule Perturbations: Magnitude and Gating Control.

The hyperpolarization-activated cation current (Ih) exhibits a slowly activating time course of the current (Ih) when the cell membrane is hyperpolarized for an extended duration. It is involved in generating electrical activity in various excitable cells. Numerous structurally distinct compounds or herbal drugs have the potential to impact both the magnitude and gating kinetics of this current. Brivaracetam, a chemical analog of levetiracetam known to be a ligand for synaptic vesicle protein 2A, could directly suppress the Ih magnitude. Carisbamate, an anticonvulsant agent, not only inhibited the Ih amplitude but also reduced the strength of voltage-dependent hysteresis (Hys(V)) associated with Ih. Cilobradine, similar to ivabradine, inhibited the amplitude of Ih; however, it also suppressed the amplitude of delayed-rectifier K+ currents. Dexmedetomidine, an agonist of α2-adrenergic receptor, exerted a depressant action on Ih in a concentration-dependent fashion. Suppression of Ih amplitude was observed when GAL-021, a breathing control modulator, was present at a concentration exceeding 30 μM. Lutein, one of the few xanthophyll carotenoids, was able to suppress the Ih amplitude as well as to depress Hys(V)'s strength of Ih. Pirfenidone, a pyridine derivative known to be an anti-fibrotic agent, depressed the Ih magnitude in a concentration- and voltage-dependent fashion. Tramadol, a synthetic centrally active analgesic, was shown to reduce the Ih magnitude, independent of its interaction with opioid receptors. Various herbal drugs, including ent-kaurane-type diterpenoids from Croton tonkinensis, Ganoderma triterpenoids, honokiol, and pterostilbene, demonstrated efficacy in reducing the magnitude of Ih. Conversely, oxaliplatin, a platinum-based chemotherapeutic compound, was observed to effectively increase the Ih amplitude. Collectively, the regulatory effects of these compounds or herbal drugs on cellular function can be partly attributed to their perturbations on Ih.

Artificial Airway Suctioning: A Systematic Review.

Airway suctioning is routinely performed in the majority of care circumstances, including acute care, subacute care, home-based settings, and long-term care. Using an artificial airway to suction the patient allows for the mobilization and evacuation of secretions. When a patient can't independently remove all of the secretions from their respiratory tract, suction is used. This can occur when the body produces excessive secretion or it is not eliminated quickly enough, causing the respiratory system's upper and lower respiratory secretions to accumulate. Airway blockage and inadequate breathing may result from this. Ultimately, this leads to a shortage of oxygen and carbon dioxide from the air, both of which are necessary for ideal cellular activity. Artificial airway suctioning is one of the most crucial components of airway care and a core competency for medical professionals trying to ensure airway patency. Artificial airway suctioning is a standard treatment carried out every day globally and is frequently done in both outpatient and inpatient patients. Therefore, specialists must know the safest and most efficient ways to perform surgery and any potential side effects. In ventilated infants and children, the removal of obstructive secretions by endotracheal suctioning is frequently done. It is unknown how suctioning affects the mechanics of breathing. This study used a prospective observational clinical design to examine the immediate impact of airway resistance in endotracheal suctioning, tidal volume, and dynamic lung regulation in mechanically ventilated adult patients and mechanically ventilated pediatric patients. The preparation, process, and indications for intraoperative fusion treatment in various circumstances are covered in this systematic review.

Aesthetic and physiological effects of naturalistic multimodal music listening

Compared to audio only (AO) conditions, audiovisual (AV) information can enhance the aesthetic experience of a music performance. However, such beneficial multimodal effects have yet to be studied in naturalistic music performance settings. Further, peripheral physiological correlates of aesthetic experiences are not well-understood. Here, participants were invited to a concert hall for piano performances of Bach, Messiaen, and Beethoven, which were presented in two conditions: AV and AO. They rated their aesthetic experience (AE) after each piece (Experiment 1 and 2), while peripheral signals (cardiorespiratory measures, skin conductance, and facial muscle activity) were continuously measured (Experiment 2). Factor scores of AE were significantly higher in the AV condition in both experiments. LF/HF ratio, a heart rhythm that represents activation of the sympathetic nervous system, was higher in the AO condition, suggesting increased arousal, likely caused by less predictable sound onsets in the AO condition. We present partial evidence that breathing was faster and facial muscle activity was higher in the AV condition, suggesting that observing a performer's movements likely enhances motor mimicry in these more voluntary peripheral measures. Further, zygomaticus (‘smiling’) muscle activity was a significant predictor of AE. Thus, we suggest physiological measures are related to AE, but at different levels: the more involuntary measures (i.e., heart rhythms) may reflect more sensory aspects, while the more voluntary measures (i.e., muscular control of breathing and facial responses) may reflect the liking aspect of an AE. In summary, we replicate and extend previous findings that AV information enhances AE in a naturalistic music performance setting. We further show that a combination of self-report and peripheral measures benefit a meaningful assessment of AE in naturalistic music performance settings.

Curiosity, Opportunity, and Luck: Were the 1970s Different?

Control of Breathing Using an Extracorporeal Membrane Lung. By T Kolobow, L Gattinoni, TA Tomlinson, JE Pierce. Anesthesiology 1977; 46:138-41. Reprinted with permission. Body Position Changes Redistribute Lung Computed-Tomographic Density in Patients with Acute Respiratory Failure. By L Gattinoni, P Pelosi, G Vitale, A Pesenti, L D'Andrea, D Mascheroni. Anesthesiology 1991; 74:15-23. Reprinted with permission. Dr. Gattinoni's scientific career was primarily driven by curiosity. His generation was not formally trained, but he was part of a community of young and enthusiastic colleagues who were forging a new discipline: intensive care medicine. The most significant opportunity of Dr. Gattinoni's career was becoming the research fellow of a visionary genius, Dr. Theodor Kolobow, who focused on extracorporeal carbon dioxide removal after the failure of the first trial on extracorporeal membrane oxygenation. CO2 removal, by allowing control over the intensity of mechanical ventilation, opened the path to "lung rest" to prevent ventilator-induced lung injury. A unique opportunity for research was the spontaneous birth of a network of scientists who became friends in the European Group of Research in Intensive Care Medicine. In this environment, it was possible to develop core concepts such as the "baby lung" and to understand the mechanisms underlying computed tomography-density redistribution in the prone position. Physiology guided us in the 1970s, and understanding mechanisms remains of paramount importance today.

FNIRS analysis of rostral prefrontal cortex activity and perception of inspiratory loads

It is well-established that the brainstem is responsible for the automatic control of breathing, however, cortical areas control perception and conscious breathing. This study investigated activity in the prefrontal cortex (PFC) during breathing difficulty using functional near-infrared spectroscopy (fNIRS). It was hypothesized that extrinsic inspiratory loads will elicit regional changes in PFC activity and increased perception ratings, as a function of load magnitude and type. Participants were exposed to varying magnitudes of resistive (R) and pressure threshold (PT) inspiratory loads to increase breathing effort. Perception ratings of breathing effort and load magnitude were positively correlated (p < 0.05). PT loads were rated more effortful than R loads (p < 0.05). Differences in perceived effort were a function of inspiratory pressure-time-product (PTP) and inspiratory work of breathing (WoB). PFC activity increased with the largest PT load (p < 0.01), suggesting that the PFC is involved in processing respiratory stimuli. The results support the hypothesis that the PFC is an element of the neural network mediating effortful breathing perception.

The astrocytic Na+ -HCO3 - cotransporter, NBCe1, is dispensable for respiratory chemosensitivity.

The interoceptive homeostatic mechanism that controls breathing, blood gases and acid-base balance in response to changes in CO2 /H+ is exquisitely sensitive, with convergent roles proposed for chemosensory brainstem neurons in the retrotrapezoid nucleus (RTN) and their supporting glial cells. For astrocytes, a central role for NBCe1, a Na+ -HCO3 - cotransporter encoded by Slc4a4, has been envisaged in multiple mechanistic models (i.e. underlying enhanced CO2 -induced local extracellular acidification or purinergic signalling). We tested these NBCe1-centric models by using conditional knockout mice in which Slc4a4 was deleted from astrocytes. In GFAP-Cre;Slc4a4fl/fl mice we found diminished expression of Slc4a4 in RTN astrocytes by comparison to control littermates, and a concomitant reduction in NBCe1-mediated current. Despite disrupted NBCe1 function in RTN-adjacent astrocytes from these conditional knockout mice, CO2 -induced activation of RTN neurons or astrocytes in vitro and in vivo, and CO2 -stimulated breathing, were indistinguishable from NBCe1-intact littermates; hypoxia-stimulated breathing and sighs were likewise unaffected. We obtained a more widespread deletion of NBCe1 in brainstem astrocytes by using tamoxifen-treated Aldh1l1-Cre/ERT2;Slc4a4fl/fl mice. Again, there was no difference in effects of CO2 or hypoxia on breathing or on neuron/astrocyte activation in NBCe1-deleted mice. These data indicate that astrocytic NBCe1 is not required for the respiratory responses to these chemoreceptor stimuli in mice, and that any physiologically relevant astrocytic contributions must involve NBCe1-independent mechanisms. KEY POINTS: The electrogenic NBCe1 transporter is proposed to mediate local astrocytic CO2 /H+ sensing that enables excitatory modulation of nearby retrotrapezoid nucleus (RTN) neurons to support chemosensory control of breathing. We used two different Cre mouse lines for cell-specific and/or temporally regulated deletion of the NBCe1 gene (Slc4a4) in astrocytes to test this hypothesis. In both mouse lines, Slc4a4 was depleted from RTN-associated astrocytes but CO2 -induced Fos expression (i.e. cell activation) in RTN neurons and local astrocytes was intact. Likewise, respiratory chemoreflexes evoked by changes in CO2 or O2 were unaffected by loss of astrocytic Slc4a4. These data do not support the previously proposed role for NBCe1 in respiratory chemosensitivity mediated by astrocytes.

The Choice of Radiation Therapy Technology for Synchronous Primary Disseminated Breast Cancer

Radiation therapy of the primary tumor can be a stage of treatment of patients with initial IV stage breast cancer, being delievered out not only in purpose of decreasing symptom’s severity, but with an increase of progression-free survival.Modern technologies of radiation therapy, including intensity-modulated radiotherapy and radiation therapy with deep inspiration under the control of breathing (Respiratory Gating), can significantly reduce dose to risk organs and ensure a homogeneous isodose distribution in the irradiated area, which is especially important in patients receiving systemic treatment, which in itself has clinically significant cardio- and pulmonotoxicity.The presented clinical case demonstrates the possibility of dose reduction to organs at risk with usage of modern technologies of conformal radiation therapy.

The Effect ofBody Armor onPulmonary Function Using Plethysmography.

Military tactical athletes face the unique task of performing physically demanding occupational duties, often while wearing body armor. Forced vital capacity and forced expiratory volume measured using spirometry have been shown to decrease, while wearing plate-carrier style body armor, little is known about the comprehensive effects of wearing body armor on pulmonary function, including lung capacities. Further, the effects of loaded body armor vs. unloaded on pulmonary function are also unknown. Therefore, this study examined how loaded and unloaded body armor affects pulmonary function. Twelve college-aged males performed spirometry and plethysmography under three conditions (basic athletic attire [CNTL], unloaded plate carrier [UNL], and loaded plate carrier [LOAD]). Compared to CNTL, LOAD and UNL conditions significantly reduced functional residual capacity by 14% and 17%, respectively. Compared with CNTL, LOAD condition also showed a small but statistically significant lowered forced vital capacity (P = .02, d = 0.3), a 6% lower total lung capacity (P < .01, d = 0.5), and lowered maximal voluntary ventilation (P = .04, d = 0.4). A loaded plate-carrier style body armor exerts a restrictive effect on total lung capacity, and both loaded and unloaded body armor affects functional residual capacity, which could impact breathing mechanics during exercise. Resulting endurance performance decreases may need to be factored based on the style and loading of body armor, especially for longer-duration operations.

Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

AbstractOpioid drugs are widely used as analgesics but cause respiratory depression, a potentially lethal side effect with overdose, by acting on μ-opioid receptors (MORs) expressed in brainstem regions involved in the control of breathing. Although many brainstem regions have been shown to regulate opioid-induced respiratory depression, the types of neurons involved have not been identified. Somatostatin is a major neuropeptide found in brainstem circuits regulating breathing, but it is unknown whether somatostatin-expressing circuits regulate respiratory depression by opioids. We examined the coexpression ofSst(gene encoding somatostatin) andOprm1(gene encoding MORs) mRNAs in brainstem regions involved in respiratory depression. Interestingly,Oprm1mRNA expression was found in the majority (&gt;50%) ofSst-expressing cells in the preBötzinger Complex, the nucleus tractus solitarius, the nucleus ambiguus, and the Kölliker–Fuse nucleus. We then compared respiratory responses to fentanyl between wild-type andOprm1full knock-out mice and found that the lack of MORs prevented respiratory rate depression from occurring. Next, using transgenic knock-out mice lacking functional MORs specifically inSst-expressing cells, we compared respiratory responses to fentanyl between control and the conditional knock-out mice. We found that respiratory rate depression by fentanyl was preserved when MORs were deleted only inSst-expressing cells. Our results show that despite coexpression ofSstandOprm1in respiratory circuits and the importance of somatostatin-expressing cells in the regulation of breathing, these cells do not mediate opioid-induced respiratory rate depression. Instead, MORs found in respiratory cell populations other thanSst-expressing cells likely contribute to the respiratory effects of fentanyl.

Control of Breathing and Central Hypoventilation Syndromes.

Control of breathing in children varies with age and sleep state. There is overlap between central hypoventilation, autonomic dysfunction, and hypothalamic dysfunction in the rare disorders (congenital central hypoventilation syndrome and rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysregulation). Other, more common disorders that typically present in childhood also include central hypoventilation and disordered ventilatory responses.

Therapeutic Strategies Targeting Respiratory Recovery after Spinal Cord Injury: From Preclinical Development to Clinical Translation.

High spinal cord injuries (SCIs) lead to permanent functional deficits, including respiratory dysfunction. Patients living with such conditions often rely on ventilatory assistance to survive, and even those that can be weaned continue to suffer life-threatening impairments. There is currently no treatment for SCI that is capable of providing complete recovery of diaphragm activity and respiratory function. The diaphragm is the main inspiratory muscle, and its activity is controlled by phrenic motoneurons (phMNs) located in the cervical (C3-C5) spinal cord. Preserving and/or restoring phMN activity following a high SCI is essential for achieving voluntary control of breathing. In this review, we will highlight (1) the current knowledge of inflammatory and spontaneous pro-regenerative processes occurring after SCI, (2) key therapeutics developed to date, and (3) how these can be harnessed to drive respiratory recovery following SCIs. These therapeutic approaches are typically first developed and tested in relevant preclinical models, with some of them having been translated into clinical studies. A better understanding of inflammatory and pro-regenerative processes, as well as how they can be therapeutically manipulated, will be the key to achieving optimal functional recovery following SCIs.