Hypoxia increases cerebral blood flow (CBF), but it is unknown whether this increase is uniform across all brain regions. We used H(2)(15)O positron emission tomography imaging to measure absolute blood flow in 50 regions of interest across the human brain (n = 5) during normoxia and moderate hypoxia. Pco(2) was kept constant ( approximately 44 Torr) throughout the study to avoid decreases in CBF associated with the hypocapnia that normally occurs with hypoxia. Breathing was controlled by mechanical ventilation. During hypoxia (inspired Po(2) = 70 Torr), mean end-tidal Po(2) fell to 45 +/- 6.3 Torr (means +/- SD). Mean global CBF increased from normoxic levels of 0.39 +/- 0.13 to 0.45 +/- 0.13 ml/g during hypoxia. Increases in regional CBF were not uniform and ranged from 9.9 +/- 8.6% in the occipital lobe to 28.9 +/- 10.3% in the nucleus accumbens. Regions of interest that were better perfused during normoxia generally showed a greater regional CBF response. Phylogenetically older regions of the brain tended to show larger vascular responses to hypoxia than evolutionary younger regions, e.g., the putamen, brain stem, thalamus, caudate nucleus, nucleus accumbens, and pallidum received greater than average increases in blood flow, while cortical regions generally received below average increases. The heterogeneous blood flow distribution during hypoxia may serve to protect regions of the brain with essential homeostatic roles. This may be relevant to conditions such as altitude, breath-hold diving, and obstructive sleep apnea, and may have implications for functional brain imaging studies that involve hypoxia.

Anecdotal observations suggest that hypoxia does not elicit dyspnea. An opposing view is that any stimulus to medullary respiratory centers generates dyspnea via "corollary discharge" to higher centers; absence of dyspnea during low inspired Po(2) may result from increased ventilation and hypocapnia. We hypothesized that, with fixed ventilation, hypoxia and hypercapnia generate equal dyspnea when matched by ventilatory drive. Steady-state levels of hypoxic normocapnia (end-tidal Po(2) = 60-40 Torr) and hypercapnic hyperoxia (end-tidal Pco(2) = 40-50 Torr) were induced in naive subjects when they were free breathing and during fixed mechanical ventilation. In a separate experiment, normocapnic hypoxia and normoxic hypercapnia, "matched" by ventilation in free-breathing trials, were presented to experienced subjects breathing with constrained rate and tidal volume. "Air hunger" was rated every 30 s on a visual analog scale. Air hunger-Pet(O(2)) curves rose sharply at Pet(O(2)) <50 Torr. Air hunger was not different between matched stimuli (P > 0.05). Hypercapnia had unpleasant nonrespiratory effects but was otherwise perceptually indistinguishable from hypoxia. We conclude that hypoxia and hypercapnia have equal potency for air hunger when matched by ventilatory drive. Air hunger may, therefore, arise via brain stem respiratory drive.

Issue: Calls to change medical education have been frequent, persistent, and generally limited to alterations in content or structural reorganization. Self-imposed barriers have prevented adoption of more radical pedagogical approaches, so recent predictions of the 'inevitability' of medical education transitioning to online delivery seemed unlikely. Then in March 2020 the COVID-19 pandemic forced medical schools to overcome established barriers overnight and make the most rapid curricular shift in medical education's history. We share the collated reports of nine medical schools and postulate how recent responses may influence future medical education. Evidence: While extraneous pandemic-related factors make it impossible to scientifically distinguish the impact of the curricular changes, some themes emerged. The rapid transition to online delivery was made possible by all schools having learning management systems and key electronic resources already blended into their curricula; we were closer to online delivery than anticipated. Student engagement with online delivery varied with different pedagogies used and the importance of social learning and interaction along with autonomy in learning were apparent. These are factors known to enhance online learning, and the student-centered modalities (e.g. problem-based learning) that included them appeared to be more engaging. Assumptions that the new online environment would be easily adopted and embraced by 'technophilic' students did not always hold true. Achieving true distance medical education will take longer than this 'overnight' response, but adhering to best practices for online education may open a new realm of possibilities. Implications: While this experience did not confirm that online medical education is really 'inevitable, ' it revealed that it is possible. Thoughtfully blending more online components into a medical curriculum will allow us to take advantage of this environment's strengths such as efficiency and the ability to support asynchronous and autonomous learning that engage and foster intrinsic learning in our students. While maintaining aspects of social interaction, online learning could enhance pre-clinical medical education by allowing integration and collaboration among classes of medical students, other health professionals, and even between medical schools. What remains to be seen is whether COVID-19 provided the experience, vision and courage for medical education to change, or whether the old barriers will rise again when the pandemic is over.

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Asthma evokes several uncomfortable sensations including increased "effort to breathe" and chest "tightness." We have tested the hypotheses that "effort" and "tightness" are due to perception of increased work performed by the respiratory muscles. Bronchoconstriction was induced by inhaled methacholine in 15 subjects with mild asthma (FEV(1)/FVC baseline = 81.9% +/- 5.8; bronchoconstriction = 64.0% +/- 8.6). To relieve the work of breathing, and thereby minimize activation of respiratory muscle afferents and motor command, subjects were mechanically ventilated. Subjects separately rated effort to breathe and tightness during mechanical ventilation and during spontaneous breathing. Bronchoconstriction produced elevated end-expiratory lung volume (279 +/- 62 ml); in a control study, end-expiratory lung volume was increased equally in the absence of bronchoconstriction by increasing end-expiratory pressure. During bronchoconstriction, ratings of effort were greater during spontaneous breathing than during mechanical ventilation (p < 0.05). Ratings of tightness were unchanged by the absence of respiratory muscle activity (p = 0.12). Hyperinflation alone did not produce tightness or effort. We conclude that tightness is not related to the increase in respiratory work during bronchoconstriction.

Several studies have mapped brain regions associated with acute dyspnea perception. However, the time-course of brain activity during sustained dyspnea is unknown. Our objective was to determine the time-course of neural activity when dyspnea is sustained. Eight healthy subjects underwent brain blood oxygen level dependent functional magnetic imaging (BOLD-fMRI) during mechanical ventilation with constant mild hypercapnia (~45 mmHg). Subjects rated dyspnea (air hunger) via visual analog scale (VAS). Tidal volume (VT) was alternated every 90 seconds between high VT (0.96±0.23 L) that provided respiratory comfort (12±6% full scale) and low VT (0.48±0.08 L) which evoked air hunger (56±11% full scale). BOLD signal was extracted from a priori brain regions and combined with VAS data to determine air hunger related neural time-course. Air hunger onset was associated with BOLD signal increases that followed two distinct temporal profiles within sub-regions of the anterior insula, anterior cingulate and prefrontal cortices (cortico-limbic circuitry): (1) fast, BOLD signal peak <30 seconds and (2) slow, BOLD signal peak >40 seconds. BOLD signal during air hunger offset followed fast and slow temporal profiles symmetrical, but inverse (signal decreases) to the time-courses of air hunger onset. We conclude that differential cortico-limbic circuit elements have unique contributions to dyspnea sensation over time. We suggest that previously unidentified sub-regions are responsible for either the acute awareness or maintenance of dyspnea. These data enhance interpretation of previous studies and inform hypotheses for future dyspnea research.

The sensation that develops as a long breath hold continues is what this chapter is about. We term this sensation of an urge to breathe "air hunger". Air hunger is a primal sensation that alerts us to a failure to meet an urgent homeostatic need -to maintain gas exchange. Anxiety, frustration, and fear evoked by air hunger motivate behavioral actions to address the failure. Air hunger can be reliably quantified by most experimental subjects using rating scales, i.e., there is a consistent relationship between stimulus and rating. Stimuli that increase air hunger include hypercapnia, hypoxia, exercise, and acidosis, while tidal expansion of the lungs reduces air hunger. As such, the defining experimental paradigm to evoke air hunger is to elevate the drive to breath while mechanically restricting ventilation. Functional brain imaging studies have shown that air hunger activates the insular cortex (an integration center for perceptions related to homeostasis, including pain, food hunger and thirst), as well as limbic structures involved with anxiety and fear. The unpleasantness and emotional consequences of air hunger make it the most debilitating component of dyspnea, a symptom commonly associated with respiratory, cardiovascular and metabolic diseases. Although much has been learned about air hunger in the past few decades, much remains to be discovered, such as an accepted method to quantify air hunger in non-human animals, fundamental questions about neural mechanisms, and adequate and safe methods to mitigate air hunger in clinical situations. DIDACTIC SYNOPSIS Air hunger is the conscious appreciation of an uncomfortable urge to breathe.  Air hunger can be reliably scaled by most people using various psychophysical rating scales.Although non-human vertebrates presumably sense air hunger, there is currently no accepted experimental model to scale air hunger in animals.  Air hunger is a primal sensation, alerting the animal to a threat to homeostasis that requires a behavioral response more complex than increasing respiratory muscle output or cardiac output.  Air hunger activates limbic and paralimbic regions in the brain giving rise to anxiety and fear.  Air hunger arises when minute ventilation is less than desired minute ventilation. Current understanding is that a copy of motor activity in medullary respiratory centers ('corollary discharge') projects to sensory cortex, and is compared to signals of tidal lung inflation arising mainly in pulmonary stretch receptors.  Air hunger is the most uncomfortable and most prominent of the sensations comprising clinical dyspnea.

Mouthpieces and masks change breathing, and distract the subject. Accepted non-invasive methods avoid this problem, inductive plethysmographs and respiratory magnetometers, but are expensive and unusable in magnetic resonance imaging (MRI) scanners. Because changes in ventilation affect arterial gases, and thus cerebral blood flow, measurement of breathing is desirable during many functional MRI studies. Using an old principle, we constructed an inexpensive, non-invasive device unaffected by magnetic fields. We adapted a simple calibration method to reduce error and make the method accessible to more users. 'Pneumobelts' consist of flexible corrugated silicon tubes worn around the rib cage (RC) and the abdomen (AB). Changes in RC and AB are determined from pressure changes within the 'pneumobelts'. Estimates of tidal volume are generated from the sum of the RC and AB changes. We empirically determined the appropriate RC weighting as 1.3:1 (RC:AB). Volume estimation was tested (n = 9) in different body positions and during different breathing maneuvers. The weighted sum of the two signals gave an accurate estimate of tidal volume with tidal volumes less than 1200 ml (mean error = 6-7%). Breaths over 1900 ml produced larger errors (mean error = 11-16%). Our results are generalizable to any linear circumference measuring device.