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Hyperthermia stimulates ventilation in humans. This hyperthermia-induced hyperventilation may be mediated by the activation of peripheral chemoreceptors implicated in the regulation of respiration in reaction to various chemical stimuli, including reductions in arterial pH. Here, we investigated the hypothesis that during passive heating at rest, the increases in arterial pH achieved with sodium bicarbonate ingestion, which could attenuate peripheral chemoreceptor activity, mitigate hyperthermia-induced hyperventilation. We also assessed the effect of sodium bicarbonate ingestion on cerebral blood flow responses, which are associated with hyperthermia-induced hyperventilation. Twelve healthy men ingested sodium bicarbonate (0.3 g/kg body weight) or sodium chloride (0.208 g/kg). One hundred minutes after the ingestion, the participants were passively heated using hot-water immersion (42°C) combined with a water-perfused suit. Increases in esophageal temperature (an index of core temperature) and minute ventilation (V̇ E ) during the heating were similar in the two trials. Moreover, when V̇ E is expressed as a function of esophageal temperature, there were no between-trial differences in the core temperature threshold for hyperventilation (38.0 ± 0.3 vs. 38.0 ± 0.4°C, P = 0.469) and sensitivity of hyperthermia-induced hyperventilation as assessed by the slope of the core temperature-V̇ E relation (13.5 ± 14.2 vs. 15.8 ± 15.5 L/min/°C, P = 0.831). Furthermore, middle cerebral artery mean blood velocity (an index of cerebral blood flow) decreased similarly with heating duration in both trials. These results suggest that sodium bicarbonate ingestion does not mitigate hyperthermia-induced hyperventilation and the reductions in cerebral blood flow index in resting heated humans. NEW & NOTEWORTHY Hyperthermia leads to hyperventilation and associated cerebral hypoperfusion, both of which may impair heat tolerance. This hyperthermia-induced hyperventilation may be mediated by peripheral chemoreceptors, which can be activated by reductions in arterial pH. However, our results suggest that sodium bicarbonate ingestion, which can increase arterial pH, is not an effective intervention in alleviating hyperthermia-induced hyperventilation and cerebral hypoperfusion in resting heated humans.

Childhood absence epilepsy is one of the most prevalent pediatric epilepsy syndromes, but diagnostic delay is common and consequential. Childhood absence epilepsy is diagnosed by history and physical examination including hyperventilation with electroencephalography (EEG) used to confirm the diagnosis. Hyperventilation produces generalized spike-wave discharges on EEG in >90% of patients with childhood absence epilepsy and provokes clinical absence seizures consisting of brief loss of consciousness typically within 90 seconds. Child neurologists report a high volume of referrals for children with "staring spells" that strain already limited health care resources. Resources are further strained by the use of EEG for monitoring antiseizure medication effectiveness with unclear benefit. In this review, we examine the safety and efficacy of hyperventilation activation as a tool for the diagnosis and management of childhood absence seizures., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A 7-year-old right-handed girl presented to the pediatric neurology outpatient clinic after 5 episodes of headache over the previous 3 months. Her family history was positive for migraine in the mother and maternal grandmother and for febrile seizures in the older sister. The neurologic examination and cognitive profile were normal. Five seconds after the end of hyperventilation, video-EEG showed high-amplitude delta waves predominantly over the left hemisphere with concomitant acute aphasia and right-sided weakness. After the event, which self-resolved over 8 minutes, the girl showed intact recall. A second instance of hyperventilation evoked the appearance of pseudo-rhythmic slow activity localized to the right hemisphere, associated with left-sided weakness, 20 seconds after the end of the test. This event spontaneously resolved in 3 minutes and was followed by headache.An exaggerated physiologic response to hyperventilation, the possible epileptic nature of the events, and a migraine variant were all considered in the differential. Nonetheless, the EEG slowing is shorter in duration and generalized in physiologic and paraphysiological conditions. A clear ictal morphology and evolution of the EEG activity were lacking in this case, and migraine attacks induced by hyperpnea have not been reported to date. Instead, EEG alterations similar to that observed in our patient are described in association with vascular abnormalities. We report the clinical presentation and diagnostic workup of a rare cerebrovascular disorder, highlighting the key features in the differential. Our case emphasizes the clinical value of the EEG rebuild-up phenomenon, which can help the clinician in achieving a prompt diagnosis.

Background: Postural control can be challenged by breathing., Research Question: What is the effect of an acute increase in respiratory demand on postural control compared to quiet breathing?, Methods: A systematic review was conducted. Electronic databases were systematically searched until October 18, 2022 on studies reporting changes in center of pressure (CoP) motion related to an acute manipulation of respiratory demand compared to quiet breathing during upright standing in healthy participants and/or participants with a clinical condition., Results: Twenty-one studies in healthy participants showed that voluntary (not metabolic-induced) hyperventilation or inspiratory resistive loading significantly increased CoP motion, while breath-holding decreased CoP motion, compared to quiet breathing (p< 0.05). Manipulating respiratory rate or breathing patterns did not reveal consistent results. Four studies showed that people with low back pain showed similar CoP responses to increasing respiratory demand (p> 0.05), except for breathing at different rates, whereas they showed greater CoP motion during quiet breathing., Significance: The extent of postural disturbance depended on the breathing mode and how it was quantified (i.e., CoP coupled with breathing movement or overall CoP measures). Voluntary hyperventilation and inspiratory resistive loading increased postural sway. For voluntary hyperventilation, this could be explained by CoP motion being directly coupled to chest wall movements whereas metabolic-induced hyperventilation did not increase CoP motion or CoP coupling with breathing. Breath-holding decreased postural sway. Patients with low back pain show greater postural sways than pain-free individuals during quiet breathing, although they exhibit similar postural adaptations to respiratory-related challenges as controls., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We report two cases of temporo-perisylvian epilepsy with habitual seizures consistently inducible by hyperventilation (HV). One case was non-lesional, while the other was a lesional temporo-perisylvian epilepsy. Both underwent surgical resection and were seizure-free or nearly seizure-free thereafter. We discuss the pathophysiological changes evoked by HV in healthy brains, and those with generalized and focal epilepsy. We provide a comprehensive and critical review of the literature on the role of HV in focal epilepsy. We suggest HV should be considered an activation method for patients with focal epilepsy during epilepsy monitoring unit admissions and may help in the localization of the epileptogenic network/zone., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

During mild or moderate exercise, alveolar ventilation increases in direct proportion to metabolic rate, regulating arterial CO 2 pressure near resting levels. Mechanisms giving rise to the hyperpnoea of exercise are unsettled despite over a century of investigation. In the past three decades, neuroscience has advanced tremendously, raising optimism that the 'exercise hyperpnoea dilemma' can finally be solved. In this review, new perspectives are offered in the hope of stimulating original ideas based on modern neuroscience methods and current understanding. We first describe the ventilatory control system and the challenge exercise places upon blood-gas regulation. We highlight relevant system properties, including feedforward, feedback and adaptive (i.e., plasticity) control of breathing. We then elaborate a seldom explored hypothesis that the exercise ventilatory response continuously adapts (learns and relearns) throughout life and ponder if the memory 'engram' encoding the feedforward exercise ventilatory stimulus could reside within the cerebellum. Our hypotheses are based on accumulating evidence supporting the cerebellum's role in motor learning and the numerous direct and indirect projections from deep cerebellar nuclei to brainstem respiratory neurons. We propose that cerebellar learning may be obligatory for the accurate and adjustable exercise hyperpnoea capable of tracking changes in life conditions/experiences, and that learning arises from specific cerebellar microcircuits that can be interrogated using powerful techniques such as optogenetics and chemogenetics. Although this review is speculative, we consider it essential to reframe our perspective if we are to solve the till-now intractable exercise hyperpnoea dilemma., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Current guidelines suggest a target of partial pressure of carbon dioxide (PaCO 2 ) of 32-35 mmHg (mild hypocapnia) as tier 2 for the management of intracranial hypertension. However, the effects of mild hyperventilation on cerebrovascular dynamics are not completely elucidated. The aim of this study is to evaluate the changes of intracranial pressure (ICP), cerebral autoregulation (measured through pressure reactivity index, PRx), and regional cerebral oxygenation (rSO 2 ) parameters before and after induction of mild hyperventilation. Single center, observational study including patients with acute brain injury (ABI) admitted to the intensive care unit undergoing multimodal neuromonitoring and requiring titration of PaCO 2 values to mild hypocapnia as tier 2 for the management of intracranial hypertension. Twenty-five patients were included in this study (40% female), median age 64.7 years (Interquartile Range, IQR = 45.9-73.2). Median Glasgow Coma Scale was 6 (IQR = 3-11). After mild hyperventilation, PaCO 2 values decreased (from 42 (39-44) to 34 (32-34) mmHg, p < 0.0001), ICP and PRx significantly decreased (from 25.4 (24.1-26.4) to 17.5 (16-21.2) mmHg, p < 0.0001, and from 0.32 (0.1-0.52) to 0.12 (-0.03-0.23), p < 0.0001). rSO 2 was statistically but not clinically significantly reduced (from 60% (56-64) to 59% (54-61), p < 0.0001), but the arterial component of rSO 2 (ΔO 2 Hbi, changes in concentration of oxygenated hemoglobin of the total rSO 2 ) decreased from 3.83 (3-6.2) μM.cm to 1.6 (0.5-3.1) μM.cm, p = 0.0001. Mild hyperventilation can reduce ICP and improve cerebral autoregulation, with minimal clinical effects on cerebral oxygenation. However, the arterial component of rSO 2 was importantly reduced. Multimodal neuromonitoring is essential when titrating PaCO 2 values for ICP management., (© 2024. The Author(s).)

Background: TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle., Method: To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling., Results: We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression., Conclusion: Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model., (© 2024. The Author(s).)

Objective: To compare the thermographic pattern of regions of interest (ROI) of respiratory muscles in young asthmatics with and without bronchospasm induced by eucapnic voluntary hyperpnea (EVH)., Materials and Methods: Cross-sectional study carried out with 55 young (55% male and 45% females) aged 12.5 ± 3.3 years, divided in nine nonasthmatics, 22 asthmatics without exercise-induced bronchospasm compatible response (EIB-cr) and 24 asthmatics with EIB-cr. The diagnosis of EIB was given to subjects with a fall in forced expiratory volume in the first second (FEV 1 ) ≥ 10% compared to baseline. Thermographic recordings of respiratory muscles were delimited in ROI of the sternocleidomastoid (SCM), pectoral, and rectus abdominis intention area. Thermal captures and FEV 1 were taken before and 5, 10, 15 and 30 min after EVH., Results: Twenty-four (52.1%) of asthmatics had EIB-cr. There was a decrease in temperature at 10 min after EVH test in the SCM, pectoral and rectus abdominis ROIs in all groups (both with p < 0.05). There was a decrease in temperature (% basal) in asthmatic with EIB-cr compared to nonasthmatics in the rectus abdominis area (p < 0.05)., Conclusion: There was a decrease in temperature in the ROIs of different muscle groups, especially in asthmatics. The greater drop in FEV 1 observed in individuals with EIB-cr was initially associated with a decrease in skin temperature, with a difference between the nonasthmatics in the abdominal muscle area. It is likely that this decrease in temperature occurred due to a temporary displacement of blood flow to the most used muscle groups, with a decrease in the region of the skin evaluated in the thermography., (© 2024 Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Objectives: The purpose of this study was to investigate whether people with fibromyalgia (FM) have dysfunctional breathing by examining acid-base balance and comparing it with healthy controls., Methods: Thirty-six women diagnosed with FM and 36 healthy controls matched for age and gender participated in this cross-sectional study. To evaluate acid-base balance, arterial blood was sampled from the radial artery. Carbon dioxide, oxygen, bicarbonate, base excess, pH and lactate were analysed for between-group differences. Blood gas analyses were performed stepwise on each individual to detect acid-base disturbance, which was categorized as primary respiratory and possible compensation indicating chronicity. A three-step approach was employed to evaluate pH, carbon dioxide and bicarbonate in this order., Results: Women with FM had significantly lower carbon dioxide pressure ( p = 0.013) and higher lactate ( p = 0.038) compared to healthy controls at the group level. There were no significant differences in oxygen pressure, bicarbonate, pH and base excess. Employing a three-step acid-base analysis, 11 individuals in the FM group had a possible renally compensated mild chronic hyperventilation, compared to only 4 among the healthy controls ( p = 0.042)., Conclusions: In this study, we could identify a subgroup of individuals with FM who may be characterized as mild chronic hyperventilators. The results might point to a plausible dysfunctional breathing in some women with FM., (© 2024 the author(s), published by De Gruyter.)

Background: Given the limited access to invasive vasospastic reactivity testing in Western Countries, there is a need to further develop alternative non-invasive diagnostic methods for vasospastic angina (VSA). Hyperventilation testing (HVT) is defined as a class IIa recommendation to diagnose VSA by the Japanese Society of Cardiology., Methods: In this systematic review and meta-analysis reported according to the PRISMA statement, we review the mechanisms, methods, modalities and diagnostic accuracy of non-invasive HVT for the diagnostic of VSA., Results: A total of 106 articles published between 1980 and 2022 about VSA and HVT were included in the systematic review, among which 16 were included in the meta-analysis for diagnostic accuracy. Twelve electrocardiogram-HVT studies including 804 patients showed a pooled sensitivity of 54% (95% confidence intervals [CI]; 30%-76%) and a pooled specificity of 99% (95% CI; 88%-100%). Four transthoracic echocardiography-HVT studies including 197 patients revealed a pooled sensitivity of 90% (95% CI; 82%-94%) and a pooled specificity of 98% (95% CI; 86%-100%). Six myocardial perfusion imaging-HVT studies including 112 patients yielded a pooled sensitivity of 95% (95% CI; 63%-100%) and a pooled specificity of 78% (95% CI; 19%-98%). Non-invasive HVT resulted in a low rate of adverse events, ventricular arrhythmias being the most frequently reported, and were resolved with the administration of nitroglycerin., Conclusions: Non-invasive HVT offers a safe alternative with high diagnostic accuracy to diagnose VSA in patients with otherwise undiagnosed causes of chest pain., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

Objective: Recording seizures on video-EEG has a high diagnostic value. However, bilateral convulsive seizures constitute a risk for the patients. Our aim was to investigate the diagnostic yield and associated risks of provocation methods in short-term video-EEGs., Methods: We extracted data on seizures and provocation methods from a large database of short-term video-EEGs with standardized annotations using SCORE (Standardized Computer-based Organized reporting of EEG)., Results: 2742 paroxysmal clinical episodes were recorded in 11 919 consecutive EEGs. Most epileptic seizures (54%) were provoked. Hyperventilation provoked most of typical absence seizures (55%), intermittent photic stimulation (IPS) provoked myoclonic seizures (25%) and most of bilateral convulsive seizures (55%), while 43% of focal seizures were precipitated by sleep. All but one of the 16 bilateral convulsive seizures were provoked by IPS or sleep. Latency between start of generalized photoparoxysmal EEG response and bilateral convulsive seizures were ≤3 s in all but one patient., Significance: The large, structured database provides evidence for the diagnostic utility of various provocation methods in short-term video-EEGs. The risk of bilateral convulsive seizures is relatively small, but it cannot be prevented by stopping IPS after 3 s. A priori knowledge about seizure semiology helps planning patient-tailored provocation strategy in short-term video-EEGs., (© 2024 International League Against Epilepsy.)

Objective: The objective of this study was to observe the effects of various clinical factors on the activation and appearance of epileptiform abnormalities (EAs) in routine electroencephalography (rEEG) by different provocation methods., Methods: This observational study involved a review of 136 patients presented for EEG recording due to various indications and their EEG showing EAs during various provocation methods., Results: Generalized spike-wave discharges (GSWDs) were the most frequent activated epileptiform pattern observed in, 81 (59.1%) recordings. This pattern was seen mainly in females 49 (P = 0.00), in patients with generalized seizures 48 (P = 0.00), in prolonged EEG records 3 (P = 0.03), and in both genetic 35 (P = 0.00) and lesional epilepsies 21 (P = 0.00). Focal sharp waves with bilateral synchrony (FSWSBS) were the most activated ictal pattern (P = 0.00). Ictal EAs after hyperventilation (HV) (P = 0.03) and intermittent photic stimulation (IPS) (P = 0.01) were mainly observed in patients with uncontrolled seizures (P = 0.00), and immune-mediated epilepsy (P = 0.02). Females sex (odds ratio [OR]: 1.33, confidence interval [CI]: 0.6-2.6; P = 0.25), bilateral tonic-clonic seizures (OR: 1.17, CI: 0.5-2.4; P = 0.31) and lesional epilepsies (OR: 1.45, CI: 0.7-2.9; P = 0.20) had risk of activation of EAs by provocation methods; however this risk was not statistically significant. While sleep deprivation (SD) (OR: 6.33, CI: 2.2-18.2; P = 0.00), nonrapid eye movement sleep (NREM) (OR: 2.41, CI: 1.0-5.4; P = 0.00), and prolong EEG recording (OR: 1.91, CI: 0.9-3.9; P = 0.04) were leading to a statistically significant risk of activation and appearances of EAs due to provocation., Conclusion: Different provocation methods can activate and augment the variety of EEG patterns of diverse clinical significance. Detection of activated ictal EAs is dependent on various patient factors, including seizure control, and the provocation method applied. Further larger prospective cohort studies with adequate sample sizes are warranted., (Copyright © 2024 Copyright: © 2024 Annals of African Medicine.)

Hyperventilation-induced nystagmus test (HINT) is capable of generating a response in 77.2% of cases of acute unilateral vestibulopathy (AUVP); both nystagmus toward the affected side (excitatory pattern) and toward the healthy side (inhibitory pattern) have been described. The aim of the study is to investigate the clinical and prognostic role of the test by evaluating its correlation with vestibulo-ocular reflex (VOR) gain. We evaluated 33 AUVP patients by performing the HINT and video head impulse test (V-HIT) during the acute phase and then at 15 and 90 days after the onset of the symptoms. The correlation between the VOR gain of the affected side and test responses was evaluated first, phase by phase, and then considering the pattern shown during the first assessments. Patients with a negative HINT had a higher mean VOR gain than patients with a positive test at both 15 and 90 days. Patients who showed an inhibitory pattern at the first assessment had a continuous improvement in V-HIT performance, while patients with an initial excitatory response had a transient decrease in gain at the subsequent evaluation (P=.001). No difference between these 2 groups emerged at 90 days (P=.09). The finding of a negative HINT during the follow-up correlates with good V-HIT performance and could be an indicator of good recovery. The inhibitory pattern is associated with a subsequent improvement; and it would be indicative of compensation. but, despite this, the prognostic value of the test is limited.

We reported that external dead space ventilation (EDSV) enhanced self-sustained muscle activity (SSMA) of the human soleus muscle, which is an indirect observation of plateau potentials. However, the main factor for EDSV to enhance SSMA remains unclear. The purpose of the present study was to examine the effects of EDSV-induced hypercapnia, hypoxia, and hyperventilation on SSMA. In Experiment 1 (n = 11; normal breathing [NB], EDSV, hypoxia, and voluntary hyperventilation conditions) and Experiment 2 (n = 9; NB and normoxic hypercapnia [NH] conditions), SSMA was evoked by electrical train stimulations of the right tibial nerve and measured using surface electromyography under each respiratory condition. In Experiment 1, SSMA was significantly higher than that in the NB condition only in the EDSV condition (P < 0.05). In Experiment 2, SSMA was higher in the NH condition than in the NB condition (P < 0.05). These results suggest that the EDSV-enhanced SSMA is due to hypercapnia, not hypoxia or increased ventilation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Excessive ventilation (V̇E) and abnormal gas exchange during exercise are features of chronic thromboembolic pulmonary hypertension (CTEPH). In selected CTEPH patients, balloon pulmonary angioplasty (BPA) improves symptoms and exercise capacity. How BPA affects exercise hyperventilation and gas exchange is poorly understood., Methods: In this longitudinal observational study, symptom-limited cardiopulmonary exercise tests and carbon monoxide lung diffusion (DLCO) were performed before and after BPA (interval, mean (SD): 3.1 (2.4) months) in 36 CTEPH patients without significant cardiac and/or pulmonary comorbidities., Results: Peak work rate improved by 20% after BPA whilst V̇E at peak did not change despite improved ventilatory efficiency (lower V̇E with respect to CO 2 output [V̇CO 2 ]). At the highest identical work rate pre- and post-BPA (75 (30) watts), V̇E and alveolar-arterial oxygen gradient (P(Ai-a)O 2 ) decreased by 17% and 19% after BPA, respectively. The physiological dead space fraction of tidal volume (VD/VT), calculated from measurements of arterial and mixed expired CO 2 , decreased by 20%. In the meantime, DLCO did not change. The best correlates of P(Ai-a)O 2 measured at peak exercise were physiological VD/VT before BPA and DLCO after BPA., Conclusions: Ventilatory efficiency, physiological VD/VT, and pulmonary gas exchange improved after BPA. The fact that DLCO did not change suggests that the pulmonary capillary blood volume and probably the true alveolar dead space were unaffected by BPA. The correlation between DLCO measured before BPA and P(Ai-a)O 2 measured after BPA suggests that DLCO may provide an easily accessible marker to predict the response to BPA in terms of pulmonary gas exchange., Competing Interests: Disclosure statement MBN, NP, AG, SD, MS, FT, CA, HB report no disclosures. CP reports personal fees from Boehringer Ingelheim, Glaxo Smith Kline, Astra Zeneca and Sanofi outside submitted work. BA reports honoraria and consulting fees grant funding from Boehringer Ingelheim, Glaxo Smith Kline, Menarini, Chiesi, Astra Zeneca and Sanofi unrelated to the submitted work. BD reports grant funding from Novartis and honoraria and consulting fees from Boehringer Ingelheim, Nuvaira, Menarini, Chiesi, Glaxo Smith Kline, Astra Zeneca and Sanofi unrelated to the submitted work., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

We recently demonstrated that peripheral and central administration of nesfatin-1 in fasting and satiety states generate hyperventilation activity by increasing tidal volume (TV), respiratory rate (RR), and respiratory minute ventilation (RVM). The present study aimed to investigate the mediation of central cholinergic receptors effective in respiratory control in the hyperventilation activity of nesfatin-1. Besides this, we intended to determine possible changes in blood gases due to hyperventilation activity caused by nesfatin-1 and investigate the mediation of central cholinergic receptors in these changes. Intracerebroventricular (ICV) administration of nesfatin-1 revealed a hyperventilation response with an increase in TV, RR, RMV, and pO 2 and a decrease in pCO 2 in saturated Sprague Dawley rats. ICV pretreatment with the muscarinic receptor antagonist atropine partially blocked the RR, RMV, pO 2 , and pCO 2 responses produced by nesfatin-1 while completely blocking the TV response. However, central pretreatment with nicotinic receptor antagonist mecamylamine blocked the respiratory and blood gas responses induced by nesfatin-1. The study's conclusion demonstrated that nesfatin-1 had active hyperventilation effects resulting in an increase in pO 2 and a decrease in pCO 2 . The critical finding of the study was that activation of central cholinergic receptors was involved in nesfatin-1-evoked hyperventilation and blood gas responses., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: During the ongoing pandemic of COVID-19, wearing face masks was recommended, including patients with epilepsy doing the hyperventilation (HV) test during electroencephalogram (EEG) examination somewhere. However, evidence was still limited about the effect of HV with face mask on cortical excitability of patients with epilepsy. The motivation of this work is to make use of the graph theory of EEG to characterize the cortical excitability of patients with epilepsy when they did HV under the condition wearing a surgical face mask., Methods: We recruited 19 patients with epilepsy and 17 normal controls. All of participants completed two HV experiments, including HV with face mask (HV+) and HV without a mask (HV). The interval was 30 min and the sequence was random. Each experiment consisted of three segments: resting EEG, EEG of HV, and EEG of post-HV. EEG were recorded successively during each experiment. Participants were asked to evaluate the discomfort degree using a questionnaire when every HV is completed., Results: All of the participants felt more uncomfortable after HV + . Moreover, not only HV decreased small-worldness index in patients with epilepsy, but also HV + significantly increased the clustering coefficient in patients with epilepsy. Importantly, the three-way of Mask*HV*Epilepsy showed interaction in the clustering coefficient in the delta band, as well as in the path length and the small-worldness index in the theta band., Conclusions: The results of this study indicated that patients with epilepsy showed the increased excitability of brain network during HV + . We should pay more attention to the adverse effect on brain network excitability caused by HV + in patients with epilepsy. In the clinical practice under the COVID-19 pandemic, it is important that the wearing face mask remain cautious for the individuals with epilepsy when they carried out HV behavior such as exercise (e.g., running, etc.)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Respiratory complaints are not uncommon in patients with Parkinson's disease (PD). While many are explained by pulmonary and cardiovascular problems unrelated to PD, secondary effects of PD, such as kyphoscoliosis, respiratory muscle rigidity, repeated pneumonias, or side effects of medication such as dyskinesias, there is a small group of patients with paroxysmal dyspnea for whom neither anxiety or other explanation has been found. This Point of View was written to call attention to this neglected, uncommon, but very distressing symptom., (Copyright © 2021. Published by Elsevier Ltd.)

The high metabolic demand of cerebral tissue requires that local perfusion is tightly coupled with local metabolic rate (neurovascular coupling; NVC). During chronic altitude exposure, where individuals are exposed to the antagonistic cerebrovascular effects of hypoxia and hypocapnia, pH is maintained through renal compensation and NVC remains stable. However, the potential independent effect of acute hypocapnia and respiratory alkalosis on NVC remains to be determined. We hypothesized that acute steady-state hypocapnia via voluntary hyperventilation would attenuate the magnitude of NVC. We recruited 17 healthy participants and insonated the posterior cerebral artery (PCA) with transcranial Doppler ultrasound. NVC was elicited using a standardized strobe light stimulus (6 Hz; 5 × 30 s on/off) where absolute delta responses from baseline (BL) in peak, mean, and total area under the curve (tAUC) were quantified. From a BL end-tidal (P ET )CO 2  level of 36.7 ± 3.2 Torr, participants were coached to hyperventilate to reach steady-state hypocapnic steps of Δ-5 Torr (31.6 ± 3.9) and Δ-10 Torr (26.0 ± 4.0; p < 0.001), which were maintained during the presentation of the visual stimuli. We observed a small but significant reduction in NVC peak (ΔPCAv) from BL during controlled hypocapnia at both Δ-5 (-1.58 cm/s) and Δ-10 (-1.37 cm/s), but no significant decrease in mean or tAUC NVC response was observed. These data demonstrate that acute respiratory alkalosis attenuates peak NVC magnitude at Δ-5 and Δ-10 Torr P ET CO 2 , equally. Although peak NVC magnitude was mildly attenuated, our data illustrate that mean and tAUC NVC are remarkably stable during acute respiratory alkalosis, suggesting multiple mechanisms underlying NVC., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Abstract Twenty minutes of voluntary hypocapnic hyperventilation prior to exercise reduces the aerobic metabolic rate with a compensatory increase in the anaerobic metabolic rate without affecting exercise performance during the Wingate anaerobic test (WAnT). Thus, pre-exercise hypocapnic hyperventilation may be a useful means of stressing the anaerobic energy system during training, ultimately improving anaerobic exercise performance. However, it remains unclear whether a shorter (e.g., 5 min) pre-exercise hypocapnic hyperventilation is sufficient to reduce the aerobic metabolic rate during high-intensity exercise. We therefore compared the effects of 5-min and 20-min pre-exercise hypocapnic hyperventilation on aerobic metabolism during the 30-s WAnT. Ten healthy young males and one female performed the WAnT following 20 min of spontaneous breathing (control trial) or 5 or 20 min of voluntary hypocapnic hyperventilation. Both the 5-min and 20-min hyperventilation reduced end-tidal CO 2 partial pressure (an index of arterial CO 2 partial pressure) to ∼23 mmHg, whereas it remained unchanged during the spontaneous breathing. The peak, mean and minimum power outputs during the WAnT did not differ among the three trials. Oxygen uptake during the WAnT was lower in both the 5-min (1493 ± 257 mL min -1 ) and 20-min (1397 ± 447 mL min -1 ) hyperventilation trials than during the control trial (1847 ± 286 mL min -1 ), and was similar in the two hyperventilation trials. These results suggest that 5 min of pre-exercise hypocapnic hyperventilation reduces aerobic metabolism during the 30-s WAnT to a level similar to that seen with the 20-min hyperventilation. Moreover, exercise performance was unaffected, which implies anaerobic metabolism was enhanced.

Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively., (© 2021. The Author(s).)

Caregivers of preschool and elementary school age children with Smith-Magenis syndrome (SMS), MBD5-associated neurodevelopmental disorder (MAND), and Pitt-Hopkins syndrome (PTHS) were surveyed to assess sleep disturbance and to identify disorder-specific sleep problems. Because of overlapping features of these rare genetic neurodevelopmental syndromes, data were compared to reports of sleep disturbance in children with autism spectrum disorder (ASD). While similarities were observed with ASD, specific concerns between disorders differed, including mean nighttime sleep duration, daytime sleepiness, night wakings, parasomnias, restless sleep, and bedwetting. Overall, sleep disturbance in PTHS is significant but less severe than in SMS and MAND. The complexity of these conditions and the challenges of underlying sleep disturbance indicate the need for more support, education, and ongoing management of sleep for these individuals.

Objective: We aimed to test whether patients who died of sudden unexpected death in epilepsy (SUDEP) had an abnormal cardiac autonomic response to sympathetic stimulation by hyperventilation., Methods: We conducted a retrospective, observational, case-control study of a group of patients who died of SUDEP and controls who were matched to the patients for epilepsy type, drug resistance, sex, age at EEG recording, age at onset of epilepsy, and duration of epilepsy. We analyzed the heart rate (HR) and HR variability (HRV) at rest and during and after hyperventilation performed during the patient's last EEG recording before SUDEP. In each group, changes over time in HRV indexes were analyzed with linear mixed models., Results: Twenty patients were included in each group. In the control group, the HR increased and the root mean square of successive RR-interval differences (RMSSD) decreased during the hyperventilation and then returned to the baseline values. In the SUDEP group, however, the HR and RMSSD did not change significantly during or after hyperventilation. A difference in HR between the end of the hyperventilation and 4 minutes after its end discriminated well between patients with SUDEP and control patients (area under the receiver operating characteristic curve 0.870, sensitivity 85%, specificity 75%)., Conclusion: Most of patients with subsequent SUDEP have an abnormal cardiac autonomic response to sympathetic stimulation through hyperventilation. An index reflecting the change in HR on hyperventilation might be predictive of the risk of SUDEP and could be used to select patients at risk of SUDEP for inclusion in trials assessing protective measures., (© 2021 American Academy of Neurology.)

We investigated the acute physiological responses of tapered flow resistive loading (TFRL) at 30, 50 and 70 % maximal inspiratory pressure (PI max ) in 12 healthy adults to determine an optimal resistive load. Increased end-inspiratory rib cage and decreased end-expiratory abdominal volumes equally contributed to the expansion of thoracoabdominal tidal volume (captured by optoelectronic plethysmography). A significant decrease in end-expiratory thoracoabdominal volume was observed from 30 to 50 % PI max , from 30 to 70 % PI max , and from 50 to 70 % PImax. Cardiac output (recorded by cardio-impedance) increased from rest by 30 % across the three loading trials. Borg dyspnoea increased from 2.36 ± 0.20 at 30 % PI max , to 3.45 ± 0.21 at 50 % PI max , and 4.91 ± 0.25 at 70 % PI max . End-tidal CO 2 decreased from rest during 30, 50 and 70 %PI max (26.23 ± 0.59, 25.87 ± 1.02 and 24.30 ± 0.82 mmHg, respectively). Optimal intensity for TFRL is at 50 % PI max to maximise global respiratory muscle and cardiovascular loading whilst minimising hyperventilation and breathlessness., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study aimed to analyse the effect of neuropsychological activation methods on interictal epileptiform discharges, compared to standard activation methods, for both focal and generalized epilepsies. This was a multicentre, prospective study including 429 consecutive EEG recordings of individuals with confirmed or suspected diagnosis of epilepsy. Neuropsychological activation included reading aloud in foreign and native language, praxis and a letter cancelation task (each with a duration of three minutes). After counting interictal discharges in three-minute time windows, activation and inhibition were assessed for each procedure, accounting for spontaneous fluctuations (95% CI) and compared to the baseline condition with eyes closed. Differences between generalized and focal epilepsies were explored. Interictal epileptiform discharges were present in 59.4% of the recordings. Activation was seen during hyperventilation in 31%, in at least one neuropsychological activation method in 15.4%), during intermittent photic simulation in 13.1% and in the resting condition with eyes open in 9.9%. The most frequent single cognitive task eliciting activation was praxis (10.3%). Lasting activation responses were found in 18-25%. Significant inhibition was found in 88/98 patients with baseline interictal epileptiform discharges, and was not task-specific. Adding a brief neuropsychological activation protocol to the standard EEG slightly increased its sensitivity in patients with either focal or generalized epilepsy. However, in unselected epilepsy patients, this effect seems only exceptionally to result in ultimate diagnostic gain, compared to standard procedures. From a diagnostic perspective, cognitive tasks should be reserved for patients with a suspicion of cognitive reflex epilepsy/seizures and probably require longer exposure times. Further research is needed to explore potential therapeutic applications of the observed inhibition of interictal epileptiform discharges by cognitive tasks in some patients.

The effects of high external ammonia (HEA) exposure on breathing and the potential involvement of ammonia transporting Rh proteins in ammonia sensing were assessed in larval and adult zebrafish. Acute exposure of adults to either 250 or 500 μM (NH 4 ) 2 SO 4 caused increases in ventilation amplitude (A VENT ) without affecting frequency (f VENT ), resembling the ventilatory response to hypercapnia rather than hypoxia, during which f VENT was increased exclusively. The hyperventilatory response to HEA was prevented by hyperoxia, indicating that control of breathing through ammonia sensing is likely secondary to O 2 chemoreception. Neuroepithelial cells (NECs) isolated from gill filaments exhibited a significant increase of intracellular [Ca 2+ ] in response to 1 mM NH 4 Cl but this response was small (roughly 30%) compared to the response to hypercapnia (37.5 mmHg; ~800% increase). Immunohistochemistry (IHC) failed to reveal the presence of Rh proteins (Rhcgb, Rhbg or Rhag) in gill filament NECs. Knockout of rhcgb did not affect the ventilatory response of adults to HEA. Larvae at 4 days post fertilization (dpf) responded to HEA with increases in f VENT (A VENT was not measured). The hyperventilatory response of larvae to HEA was attenuated (60% reduction) after treatment from 0 to 4 dpf with the sympathetic neurotoxin 6-hydroxydopamine. In larvae, Rhcgb, Rhbg and Rhag were undetectable by IHC in cutaneous NECs yet the f VENT to HEA following Rhbg knockdown was slightly (22%) attenuated. Thus, the hyperventilatory response to external ammonia in adult zebrafish, while apparently initiated by activation of NECs, does not require Rhcgb, nor is the entry of ammonia into NECs reliant on other Rh proteins. The lack of colocalization of Rh proteins with NECs suggests that the entry of ammonia into NECs in larvae, also is not facilitated by this family of ammonia channels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

New Findings: What is the central question of this study? How does sternocleidomastoid blood flow change in response to increasing ventilation and whole-body exercise intensity? What is the main finding and its importance? Sternocleidomastoid blood flow increased with increasing ventilation. For a given ventilation, sternocleidomastoid blood flow was lower during whole-body exercise compared to resting hyperpnoea. These findings suggest that locomotor muscle work exerts an effect on respiratory muscle blood flow that can be observed in the sternocleidomastoid., Abstract: Respiratory muscle work influences the distribution of blood flow during exercise. Most studies have focused on blood flow to the locomotor musculature rather than the respiratory muscles, owing to the complex anatomical arrangement of respiratory muscles. The purpose of this study was to examine how accessory respiratory (i.e. sternocleidomastoid, and muscles in the intercostal space) muscle blood flow changes in response to locomotor muscle work. Seven men performed 5 min bouts of constant load cycling exercise trials at 30%, 60% and 90% of peak work rate in a randomized order, followed by 5 min bouts of voluntary hyperpnoea (VH) matching the ventilation achieved during each exercise (EX) trial. Blood-flow index (BFI) of the vastus lateralis, sternocleidomastoid (SCM) and seventh intercostal space (IC) were estimated using near-infrared spectroscopy and indocyanine green and expressed relative to resting levels. BFI SCM was greater during VH compared to EX (P = 0.002) and increased with increasing exercise intensity (P = 0.036). BFI SCM reached 493 ± 219% and 301 ± 215% rest during VH and EX at 90% peak work rate, respectively. BFI IC increased to 242 ± 178% and 210 ± 117% rest at 30% peak work rate during VH and EX, respectively. No statistically significant differences in BFI IC were observed with increased work rate during VH or EX (both P > 0.05). Moreover, there was no observed difference in BFI IC between conditions (P > 0.05). BFI SCM was lower for a given minute ventilation during EX compared to VH, suggesting that accessory respiratory muscle blood flow is influenced by whole-body exercise., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Mechanically and metabolically sensitive thin fibre (group III and IV) muscle afferents are activated during exercise, causing reflex cardiovascular responses that are essential to normal cardiovascular control. Impaired exercise performance in some disease states can be linked to abnormal muscle mechanoreflex and muscle metaboreflex activity. A role for this same afferent feedback in contributing to the hyperpnoea of exercise and the dyspnoea experienced by some patient groups on exercise has recently received increased attention. Evidence is summarised here that supports a role for muscle mechanoreflex and muscle metaboreflex involvement in the human ventilatory response to exercise and also their synergistic interaction with the central chemoreflex during muscular activity. The effects of local muscle training induced attenuation of the human muscle metaboreflex on this synergistic interaction and associated decrease in ventilation is discussed., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

New Findings: What is the topic of this review? Elevated demand is placed on the respiratory muscles during whole-body exercise-induced hyperpnoea. What is the role of elevated demand in neural modulation of cardiovascular control in respiratory and locomotor skeletal muscle, and what are the mechanisms involved? What advances does it highlight? There is a sympathetic restraint of blood flow to locomotor muscles during near-maximal exercise, which might function to maintain blood pressure. During submaximal exercise, respiratory muscle blood flow might be also be reduced if ventilatory load is sufficiently high. Methodological advances (near-infrared spectroscopy with indocyanine green) confirm that blood flow is diverted away from respiratory muscles when the work of breathing is alleviated., Abstract: It is known that the respiratory muscles have a significant increasing oxygen demand in line with hyperpnoea during whole-body endurance exercise and are susceptible to fatigue, in much the same way as locomotor muscles. The act of ventilation can itself be considered a form of exercise. The manipulation of respiratory load at near-maximal exercise alters leg blood flow significantly, demonstrating a competitive relationship between different skeletal muscle vascular beds to perfuse both sets of muscles adequately with a finite cardiac output. In recent years, the question has moved towards whether this effect exists during submaximal exercise, and the use of more direct measurements of respiratory muscle blood flow itself to confirm assumptions that uphold the concept. Evidence thus far has shown that there is a reciprocal effect on blood flow redistribution during ventilatory load manipulation observed at the respiratory muscles themselves and that the effect is observable during submaximal exercise, where active limb blood flow was reduced in conditions that simulated a high work of breathing. This has clinical applications for populations with respiratory disease and heart failure, where the work of breathing is remarkably high, even during submaximal efforts., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Infant autonomic reactivity to stress is a potential predictor of later life health complications, but research has not sufficiently examined sympathetic activity, controlled for effects of physical activity and respiration, or studied associations among autonomic adjustments, cardiac activity, and affect in infants. We studied 278 infants during the repeated Still-Face Paradigm, a standardized stressor, while monitoring cardiac activity (ECG) and respiratory pattern (respiratory inductance plethysmography). Video ratings of physical activity and affect were also performed. Respiratory sinus arrhythmia (RSA) and T-wave amplitude (TWA) served as noninvasive indicators of cardiac parasympathetic and sympathetic activity, respectively. Responses were compared between infants who completed two still-face exposures and those who terminated after one exposure due to visible distress. Findings, controlled for physical activity, showed robust reductions in respiration-adjusted RSA and TWA, with more tonic attenuation of TWA. Infants completing only one still-face trial showed more pronounced autonomic changes and less recovery from stress. They also showed elevated minute ventilation, suggesting hyperventilation. Both reductions in adjusted RSA and TWA contributed equally to heart rate changes and were associated with higher negative and lower positive affect. These associations were more robust in the group of distressed infants unable to complete both still-face trials. Thus, cardiac sympathetic activation and parasympathetic withdrawal are part of the infant stress response, beyond associated physical activity and respiration changes. Their association with cardiac chronotropy and affect increases as infants' distress level increases. This excess reactivity to social stress should be examined as a predictor of future cardiovascular disease., (© 2020 Society for Psychophysiological Research.)

Background: Testing the hypoxic ventilatory response (HVR) at low-altitude helps to detect those who do not hyperventilate appropriately in hypoxia but might not necessarily predict the HVR and the risk to develop acute mountain sickness (AMS) at high altitude. However, a low HVR seems to be particularly prevalent in individuals susceptible to high-altitude pulmonary edema (HAPE+). In this short communication, we assessed differences in physiological parameters in two comparable women before and 3 hours after exposure to 3,480 meters. One woman had a (clinically diagnosed) history of high-altitude pulmonary edema (HAPE+) while the other did well at previous exposures to high altitude (HAPE-)., Methods: Heart rate, blood pressure, ventilation, arterial blood gas variables, arterial haemoglobin saturation, haemoglobin concentration, arterial oxygen content and delta plasma volume were measured or calculated before and after arrival at high altitude., Results: At high altitude, plasma volume decreased in the HAPE- woman which in turn increased haemoglobin concentration. Ventilation was elevated in the HAPE- but not in the HAPE + woman. Arterial oxygen content fell in the HAPE + while it was preserved in the HAPE- woman. This resulted from lower peripheral oxygen saturation (-35%), lower haemoglobin concentration (-12%) and lower arterial partial pressure of oxygen (-59%) in the HAPE+., Conclusion: Considerable haemoglobin desaturation and lack of haemoconcentration were characteristics of the HAPE + woman when exposed to high altitude, while the higher arterial oxygen content in the HAPE- woman was related to both haemoconcentration and hyperventilation (and associated haemoglobin saturation)., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Seizure-induced cardiorespiratory and autonomic dysfunction has long been recognized, and growing evidence points to its implication in sudden unexpected death in epilepsy (SUDEP). However, a comprehensive understanding of cardiorespiratory function in the preictal, ictal, and postictal periods are lacking., Methods: We examined continuous cardiorespiratory and autonomic function in 157 seizures (18 convulsive and 139 nonconvulsive) from 70 consecutive patients who had a seizure captured on concurrent video-encephalogram (EEG) monitoring and polysomnography between February 1, 2012 and May 31, 2017. Heart and respiratory rates, heart rate variability (HRV), and oxygen saturation were assessed across four distinct periods: baseline (120 s), preictal (60 s), ictal, and postictal (300 s). Heart and respiratory rates were further followed for up to 60 min after seizure termination to assess return to baseline., Results: Ictal tachycardia occurred during both convulsive and nonconvulsive seizures, but the maximum rate was higher for convulsive seizures (mean: 138.8 beats/min, 95% confidence interval (CI): 125.3-152.4) compared with nonconvulsive seizures (mean: 105.4 beats/min, 95% CI: 101.2-109.6; p < 0.001). Convulsive seizures were associated with a lower ictal minimum respiratory rate (mean: 0 breaths/min, 95% CI: 0-0) compared with nonconvulsive seizures (mean: 11.0 breaths/min, 95% CI: 9.5-12.6; p < 0.001). Ictal obstructive apnea was associated with convulsive compared with nonconvulsive seizures. The low-frequency (LF) power band of ictal HRV was higher among convulsive seizures than nonconvulsive seizures (ratio of means (ROM): 2.97, 95% CI: 1.34-6.60; p = 0.008). Postictal tachycardia was substantially prolonged, characterized by a longer return to baseline for convulsive seizures (median: 60.0 min, interquartile range (IQR): 46.5-60.0) than nonconvulsive seizures (median: 0.26 min, IQR: 0.008-0.9; p < 0.001). For postictal hyperventilation, the return to baseline was longer in convulsive seizures (median: 25.3 min, IQR: 8.1-60) than nonconvulsive seizures (median: 1.0 min, IQR: 0.07-3.2; p < 0.001). The LF power band of postictal HRV was lower in convulsive seizures than nonconvulsive seizures (ROM: 0.33, 95% CI: 0.11-0.96; p = 0.043). Convulsive seizures with postictal generalized EEG suppression (PGES; n = 12) were associated with lower postictal heart and respiratory rate, and increased HRV, compared with those without (n = 6)., Conclusions: Profound cardiorespiratory and autonomic dysfunction associated with convulsive seizures may explain why these seizures carry the greatest risk of SUDEP., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Exercise-induced bronchoconstriction (EIB) is an acute, transient narrowing of the airway as a result of exercise. Diurnal variation in asthma is well-established, however, few studies have investigated diurnal variability in EIB; no study has used eucapnic voluntary hyperpnea (EVH). The aim of this study was to examine circadian variability in EIB using EVH. Methods: Fourteen recreationally-active males with mild to moderate asthma and nine healthy controls were randomized to first complete either an AM (07:00-08:00) or PM (17:00-18:00) EVH challenge, followed by the alternate test 34 h to 7 days later. The EVH protocol comprised of six-minutes of hyperventilation of a 5% CO 2 gas at a minimum ventilation rate of 21 × FEV 1 min -1 . The primary outcome measure was FEV 1 pre- and post-EVH. Results: We observed no diurnal effect on EIB in the asthma group. The minimum observed post-EVH FEV 1 in the asthma cohort was 3.58 ± 0.95 L in AM and 3.62 ± 0.87 L in PM tests, corresponding to a 15.0 ± 15.3% vs. 14.9 ± 14.7% reduction from baseline, respectively. The asthma group showed similar baseline FEV 1 before AM (4.21 ± 0.79 L) and PM (4.25 ± 0.65 L) tests. No difference was observed in minute ventilation between AM (26.1 ± 3.4 × FEV 1 min -1 ) and PM (25.6 ± 3.8 × FEV 1 min -1 ) tests for the asthma cohort. Controls displayed no significant changes in FEV 1 or minute ventilation between tests. Conclusions: When baseline pulmonary function is similar, this study suggests that time-of-day has no effect on EIB in mild to moderate asthma.

Panic disorder (PD) pathophysiology is very heterogeneous, and the discrimination of distinct subtypes could be very useful. A subtype based on respiratory symptoms is known to constitute a specific subgroup. However, evidence to support the respiratory subtype (RS) as a distinct subgroup of PD with a well-defined phenotype remains controversial. Studies have focused on characterization of the RS based on symptoms and response to CO2. In this line, we described clinical and biological aspects focused on symptomatology and CO2 challenge tests in PD RS. The main symptoms that characterize RS are dyspnea (shortness of breath) and a choking sensation. Moreover, patients with the RS tended to be more responsive to CO2 challenge tests, which triggered more panic attacks in this subgroup. Future studies should focus on discriminating respiratory-related clusters and exploring psychophysiological and neuroimaging outcomes in order to provide robust evidence to confirm RS as a distinct subtype of PD.

Mammalian transcription factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities, such as Pitt-Hopkins syndrome (PTHS). Here, we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed widely in the Drosophila brain. Furthermore, silencing of da , using several central nervous system-specific Gal4 driver lines, impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and Discs large 1 (Dlg1), suggesting the involvement of Da in memory formation. Here, we demonstrate that Syn and dlg1 are direct target genes of Da in adult Drosophila heads, as Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels of Syn and dlg1 mRNA. Silencing of da also affects negative geotaxis of the adult flies, suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulates Drosophila larval memory and adult negative geotaxis, possibly via its synaptic target genes Syn and dlg1 These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

The anteroventral preoptic region (AVPO) of the hypothalamus is involved in both temperature and breathing regulation. This area densely express cannabinoid receptors type 1 (CB1) that modulate both excitatory and inhibitory synaptic transmission. However, it is still unknown if the endocannabinoid system located in the AVPO participates in breathing control and thermoregulation. Therefore, we tested the participation of CB1 in the AVPO in the modulation of ventilation and thermal control during normoxia and hypoxia. To this end, body temperature (Tb) of Wistar rats was monitored by datallogers and ventilation (V E ) by whole body plethysmography before and after intra-AVPO microinjection of AM-251 (CB1 antagonist, 50 and 100 pmol) followed by 60 min of hypoxia exposure (7% O 2 ). Intra-AVPO microinjection of the higher dose of AM-251 increased V E but did not change Tb under resting conditions. Exposure of rats to 7% of inspired oxygen evoked typical hypoxia-induced anapyrexia and hyperventilation after vehicle microinjection. The higher dose of the cannabinoid antagonist increased the hypoxia-induced hyperventilation, in the same magnitude as observed under normoxic condition, whereas the drop in Tb elicited by hypoxia was attenuated. Therefore, the present results demonstrate that the endocannabinoid system acting on CB1 receptors in the AVPO exerts a tonic inhibitory modulation on breathing but seem not be involved in thermoregulation during resting conditions. In addition, activation of CB1 receptors in the AVPO stimulate thermal response during hypoxia, reducing energetically expensive responses, such as the hypoxic hyperventilation., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In the 1940s, Seymour S. Kety and Carl F. Schmidt measured cerebral blood flow in awake humans by means of subanesthetic doses of inhaled nitrous oxide. The inhalation route obviated the need for an arterial injection of the indicator, and nitrous oxide had virtues of metabolic inertness, rapid diffusion through the blood-brain barrier, comparable blood and brain solubility, and ease of analytical detection. The technique was also applied to the heart. Follow-up work by Kety contributed to the development of brain scanning methods., (Copyright © 2020. Published by Elsevier Inc.)

This pilot study was aimed at developing an objective method to diagnose migraine by measuring the difference in vasomotor reactivity between migraineurs and non-migraineurs. Thirty patients diagnosed with migraine without aura and 30 healthy patients were recruited. Vasomotor reactivity of all patients was then assessed by measuring the breath holding index (BHI), hyperventilation index and a novel formula, the migraine vascular index (MVI), of the middle cerebral artery using transcranial Doppler ultrasonography. Migraineurs were found to have significantly lower BHI and MVI values (p < 0.001). Logistic regression analysis revealed that MVI was a significant independent predictor of migraine (p = 0.007). The sensitivity and specificity of MVI in diagnosing migraine with a cutoff value of 1.035 were 86.7% and 86.7%, respectively. In conclusion, MVI measurement is a reliable method for objectively diagnosing migraine. Further research is needed to validate the usage of MVI for migraine diagnosis., Competing Interests: Conflict of interest disclosure The whole process of this research was privately funded by the author and is free from conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

It is unsettled whether increased exercise ventilation in Fontan subjects is due to increased pulmonary dead space or augmented ventilatory drive. Twenty-six Fontan patients underwent symptom-limited treadmill cardiopulmonary exercise testing. Two groups of age- and sex- matched subjects served as controls: the biventricularly repaired (Bi, n = 18), and the "true" control (C, n = 29) groups. Peak oxygen uptake (V̇O 2peak ) was not different among groups (41.0 +/- 8.4 ml/min/kg, 43.5 +/- 6.6 ml/min/kg, and 45.9 +/- 11.6 ml/min/kg for Fontan, Bi, and C groups, respectively, p = 0.16). Fontan subjects, however, showed steeper alveolar ventilation/carbon-dioxide (V̇A/V̇CO 2 ) regression slope (35.5 +/- 5.3, 28.7 +/- 3.8, and 29.5 +/- 3.0 l/ml, for Fontan, Bi, and C groups, respectively, p<0.0001), and lower end-expiratory carbon-dioxide fraction (FetCO 2VAT ) at ventilatory threshold (VAT) (4.4 +/- 0.5%, 5.5 +/- 0.5%, and 5.5 +/- 0.4%, for Fontan, Bi, and C groups, respectively, p<0.001). The dead-space ventilation fraction at VAT was similar among groups (0.33 +/- 0.06, 0.33 +/- 0.04, 0.35 +/- 0.05 for Fontan, Bi, and C groups, respectively, p = 0.54). In Fontan subjects, arterial oxygen saturation at rest (SaO 2rest ) was correlated with V̇A/V̇CO 2 regression slope (r = -0.41, p = 0.04) and with FetCO 2VAT (p = -0.53, p<0.01). We conclude that Fontan patients show exercise hyperventilation due to augmented central and/or peripheral ventilatory drive, which is further augmented by residual hypoxemia., Competing Interests: None.

Objective: Most of the research on vasovagal reactions has focused on the contributions of cardiovascular activity to the development of symptoms. However, other research suggests that additional mechanisms like hyperventilation may contribute to the process. The goal of the present investigation was to examine the influences of cardiovascular and respiratory variables on vasovagal symptoms., Methods: This study was part of a randomized controlled trial investigating the effects of behavioral techniques on the prevention of vasovagal reactions in blood donors. Data from the no-treatment control group were analyzed. The final sample was composed of 160 college and university students. Observational and self-report measures of symptoms were obtained. Physiological variables were measured mainly using respiratory capnometry., Results: Although respiration rate remained stable throughout donation, change in end-tidal carbon dioxide was associated with requiring treatment for a reaction during donation (odds ratio = 0.57, 95% confidence interval [CI] = 0.41 to 0.79, p = .001) and self-reported symptoms measured in the postdonation period using the Blood Donation Reactions Inventory (β = -0.152, 95% CI = -0.28 to -0.02, t = -2.32, p = .022). Individuals with higher levels of predonation anxiety displayed larger decreases in end-tidal carbon dioxide throughout the procedure (F(2,236) = 3.64, p = .043, ηp = 0.030). Blood Donation Reactions Inventory scores were related to changes in systolic (β = -0.022, 95% CI = -0.04 to -0.004, t = -2.39, p = .019) and diastolic blood pressure (β = -0.038, 95% CI = -0.06 to -0.02, t = -4.03, p < .001)., Conclusions: Although the vasovagal reaction has traditionally been viewed as a primarily cardiovascular event, the present results suggest that hyperventilation also plays a role in the development of vasovagal symptoms.

How the involuntary (bulbospinal) and voluntary (corticospinal) pathways interact in respiratory muscle control is not established. To determine the role of excitatory corticobulbar pathways in humans, studies typically compare electromyographic activity (EMG) or evoked responses in respiratory muscles during hypercapnic and voluntary tasks. Although ventilation is matched between tasks by having participants track signals of ventilation, these tasks may not result in matched respiratory muscle activity. The aim of this study was to describe respiratory muscle activity and ribcage and abdominal excursions during two different voluntary conditions, compared to hypercapnic hyperventilation. Ventilation was matched in the voluntary conditions via (i) a simple target of lung volume ('volume tracking') or (ii) targets of both ribcage and abdominal excursions, adjusted to end-expiratory lung volume in hypercapnic hyperventilation ('bands tracking'). Compared to hypercapnic hyperventilation, respiratory parameters such as tidal volume were similar, but the ratio of ribcage to abdominal excursion was higher for both voluntary tasks. Inspiratory scalene and parasternal intercostal muscle activity was higher in volume tracking, but diaphragm and abdominal muscle activity showed little to no change. There were no differences in muscle activity in bands tracking for any muscle, compared to hypercapnic hyperventilation. An elevated ratio of ribcage to abdominal excursion in the bands tracking task indicates that participants could not accurately match the targets in this condition. Inspiratory muscle activity is altered in some muscles in some voluntary tasks, compared to hypercapnia. Therefore, differences in muscle activity should be considered in interpretation of studies that use these protocols to investigate respiratory muscle control., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Hyperventilation (HV) in children can lead to HV-induced high-amplitude rhythmic slowing (HIHARS) on the EEG (electroencephalogram) which is sometimes associated with altered awareness (AA) and concomitant semiological features. Our aims were to determine the frequency of HIHARS in children, to assess if the associated semiological features were temporally related to HV, and to evaluate if specific semiological features can differentiate HIHARS with AA from absence seizures., Methods: Consecutive children with suspected new onset seizure(s) underwent HV and awareness testing during video-EEG acquisition. Hyperventilation-induced high-amplitude rhythmic slowing was defined as 2.5- to 5-Hz generalized rhythmic slowing with amplitude ≥100 μv lasting for ≥3 s. The associated semiological features were compared between the group of children with HIHARS and AA, an age- and gender-matched control group without HIHARS, and in children who experienced absence seizures during HV., Results: One hundred sixteen children with a mean age of 9.8 years were included. Hyperventilation-induced high-amplitude rhythmic slowing occurred in 39 children (33.6%) with AA documented in 30 (76.9%). The probability of developing AA during HIHARS was significantly and positively correlated with the HIHARS duration. The frequencies of HIHARS were not significantly different between children diagnosed with seizure(s) and those with nonepileptic spells. Hyperventilation cessation and staring did not occur in any child of the control group. Fidgeting and yawning were significantly more common in the group with HIHARS with AA while staring and blinking were significantly more frequent in the group of children with absence seizures., Conclusions: We ascertained that HIHARS with AA is a relatively common occurrence in children and most likely represents an age-related nonepileptic phenomenon. When associated with fidgeting or yawning, it can help differentiate this phenomenon from absence seizures. However, recording the concomitant presence of generalized spike wave discharges on the EEG remains essential to confirm the diagnosis of absence seizures., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Hyperventilation is a controversial treatment in traumatic brain injury (TBI). Prophylactic severe hyperventilation (below 3.3 kPa/25 mm Hg) is generally avoided, due to the risk of cerebral ischemia. Mild hyperventilation (arterial pCO 2 within 4.0-4.5 kPa/30-34 mm Hg) in cases of intracranial hypertension is commonly used, but its safety and benefits are not fully elucidated. The aim of this study was to evaluate the use of mild hyperventilation and its relation to cerebral energy metabolism, pressure autoregulation, and clinical outcome in TBI., Methods: This retrospective study was based on 120 patients with severe TBI treated at the neurointensive care unit, Uppsala University Hospital, Sweden, between 2008 and 2018. Data from cerebral microdialysis (glucose, pyruvate, and lactate), arterial pCO 2 , and pressure reactivity index were analyzed for the first 3 days post-injury., Results: Mild hyperventilation, 4.0-4.5 kPa (30-34 mm Hg), was more frequently used early and the patients were gradually normoventilated. Low pCO 2 was associated with slightly higher intracranial pressure and slightly lower cerebral perfusion pressure (P < 0.01). There was no univariate correlation between low pCO 2 and worse cerebral energy metabolism. Multiple linear regression analysis showed that mild hyperventilation was associated with lower pressure reactivity index on day 2 (P = 0.03), suggesting better pressure autoregulation. Younger age and lower intracranial pressure were also associated with lower pressure reactivity index., Conclusions: These findings support the notion that mild hyperventilation is safe and may improve cerebrovascular reactivity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

An increase of heart rate to physical or mental stress reflects the ability of the autonomous nervous system and the heart to respond adequately. Hyperventilation is a user-controlled breathing maneuver that has a significant impact on coronary function and hemodynamics. Thus, we aimed to investigate if the heart rate response to hyperventilation (HRR HV ) can provide clinically useful information. A pooled analysis of the HRR HV after 60 s of hyperventilation was conducted in 282 participants including healthy controls; patients with heart failure (HF); coronary artery disease (CAD); a combination of both; or patients suspected of CAD but with a normal angiogram. Hyperventilation significantly increased heart rate in all groups, although healthy controls aged 55 years and older (15 ± 9 bpm) had a larger HRR HV than each of the disease groups (HF: 6 ± 6, CAD: 8 ± 8, CAD+/HF+: 6 ± 4, and CAD-/HF-: 8 ± 6 bpm, p < 0.001). No significant differences were found between disease groups. The HRR HV may serve as an easily measurable additional marker of cardiovascular health. Future studies should test its diagnostic potential as a simple, inexpensive pre-screening test to improve patient selection for other diagnostic exams.

New Findings: What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from thin-fibre skeletal muscle afferents, and highlight the frequently conflicting findings and difficulties encountered by researchers using a variety of experimental models. What advances does it highlight? There has been a recent resurgence of interest in the role of skeletal muscle afferent involvement, not only as a mechanism of healthy exercise hyperpnoea but also in the manifestation of breathlessness and exercise intolerance in chronic disease., Abstract: The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO 2 /H + ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from group III/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)