Exercise MR of Skeletal Muscles, the Heart, and the Brain.

Magnetic resonance (MR) imaging (MRI) is routinely used to evaluate organ morphology and pathology in the human body at rest or in combination with pharmacological stress as an exercise surrogate. With MR during actual physical exercise, we can assess functional characteristics of tissues and organs under real-life stress conditions. This is particularly relevant in patients with limited exercise capacity or exercise intolerance, and where complaints typically present only during physical activity, such as in neuromuscular disorders, inherited metabolic diseases, and heart failure. This review describes practical and physiological aspects of exercise MR of skeletal muscles, the heart, and the brain. The acute effects of physical exercise on these organs are addressed in the light of various dynamic quantitative MR readouts, including phosphorus-31 MR spectroscopy (31P-MRS) of tissue energy metabolism, phase-contrast MRI of blood flow and muscle contraction, real-time cine MRI of cardiac performance, and arterial spin labeling MRI of muscle and brain perfusion. Exercise MR will help advancing our understanding of underlying mechanisms that contribute to exercise intolerance, which often proceed structural and anatomical changes in disease. Its potential to detect disease-driven alterations in organ function, perfusion, and metabolism under physiological stress renders exercise MR stress testing a powerful noninvasive imaging modality to aid in disease diagnosis and risk stratification. Although not yet integrated in most clinical workflows, and while some applications still require thorough validation, exercise MR has established itself as a comprehensive and versatile modality for characterizing physiology in health and disease in a noninvasive and quantitative way. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

Recent insights into mechanisms of hypoxia-induced vasodilatation in the human brain.

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in-flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro- and macrovascular dilatation. This contemporary review focuses on in vivo human work - with reference to seminal preclinical work where necessary - on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a - likely non-obligatory - combination of: (1) nitric oxide synthases, (2) deoxygenation-coupled S-nitrosothiols, (3) potassium channel-related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin-related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex-, heredity-, age-, and disease-related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury.

Adapting to a new environment: postnatal maturation of the human cardiomyocyte.

The postnatal mammalian heart undergoes remarkable developmental changes, which are stimulated by the transition from the intrauterine to extrauterine environment. With birth, increased oxygen levels promote metabolic, structural and biophysical maturation of cardiomyocytes, resulting in mature muscle with increased efficiency, contractility and electrical conduction. In this Topical Review article, we highlight key studies that inform our current understanding of human cardiomyocyte maturation. Collectively, these studies suggest that human atrial and ventricular myocytes evolve quickly within the first year but might not reach a fully mature adult phenotype until nearly the first decade of life. However, it is important to note that fetal, neonatal and paediatric cardiac physiology studies are hindered by a number of limitations, including the scarcity of human tissue, small sample size and a heavy reliance on diseased tissue samples, often without age-matched healthy controls. Future developmental studies are warranted to expand our understanding of normal cardiac physiology/pathophysiology and inform age-appropriate treatment strategies for cardiac disease.

Developing intuitive and explainable algorithms through inspiration from human physiology and computational biology.

In this letter, we explain how intuitive and explainable methods inspired from human physiology and computational biology can serve to simplify and ameliorate the way we process and generate knowledge resources.

A 3-D-printed synaptic puzzle contributes to students' synaptic transmission comprehension.

We created the "3-dimensional synaptic puzzle" (3Dsp) as an educational resource for the physiology teaching of synaptic transmission (ST). In this study, we aimed to apply and evaluate the use of 3Dsp. For this, we divided 175 university students from public and private universities into two groups: 1) control (CT; students that were only exposed to traditional class or video lessons about ST), and; 2) test (3Dsp; students that were exposed to the 3Dsp practical class in addition to the traditional theoretical class). ST knowledge of students was evaluated before, immediately after, and 15 days after interventions. Additionally, students completed a questionnaire about their perception of teaching-learning methods used in physiology classes and their self-perception of engagement in the physiology content. The CT groups improved their ST knowledge score from pretest to immediate (P < 0.0001 for all groups) and late posttest (P < 0.0001 for all groups). 3Dsp groups also enhanced their score from pretest to immediate (P = 0.029 for public university students; P < 0.0001 for private university students) and late posttest (P < 0.0001 for all groups). We also observed improvement from the immediate to late posttest in the 3Dsp group from private universities (P < 0.001). Both private groups performed better in general ST and specific electrical synapse questions in the pretest and immediate posttest compared to the public CT group (P < 0.05 for all comparisons). More than 90% of the students from both universities affirmed that the 3Dsp contributed to their physiology comprehension and that they would recommend the use of the 3-D models to other teachers in their classes.NEW & NOTEWORTHY We included a 3-dimensional puzzle (3Dsp) of electrical and chemical synapses in the physiology of synaptic transmission (ST) teaching. After a traditional or video lesson class, students from private and public universities were oriented to use the educational resource. More than 90% of the students affirmed that the 3Dsp improved their comprehension of ST content.

Medical students' perceptions of factors that Impact their performance in human physiology course: suggestions for improving course presentation.

OBJECTIVES: The study aims to examine students' perceptions of factors that impact students' performance in the Human Physiology course at HU's College of Applied Health Sciences and their suggestions for improvement. METHOD: A cross sectional study was conducted between March 2022 and April 2022. A self-administered online questionnaire was distributed to undergraduate students in Physiology courses (online and blended) via Microsoft Teams. Data were analyzed descriptively and inferentially, and thematic analysis was employed based on the most frequent statements for the open-ended question. RESULTS: In total, 435 students participated in the study. Results indicated that students had high levels of agreement (M = 4.39) regarding faculty teaching style compared to (M = 4.24) towards course content and (M = 3.49) moderate levels towards technological aspects. In terms of the statistically significant differences at (α = 0.05) in students' perceptions of factors that influence their performance due to the variables (gender, GPA, college, and teaching methods: online or blended), results showed that course content was not affected by any variables. The technological aspects were affected by GPA and gender. In terms of faculty teaching style, it was affected by all variables (GPA, college, and teaching method) except gender. One open-ended question regarding suggested improvements revealed four main themes: assessment and evaluation, technical issues, teaching methods and tools, and Arabic language support. CONCLUSION: The study findings recommend greater use of assessment for learning methods and provision of interactive materials to help medical students overcome the challenges that might impact their performance.

Dynamic brain ADC variations over the cardiac cycle and their relation to tissue strain assessed with DENSE at high-field MRI.

PURPOSE: The ADC of brain tissue slightly varies over the cardiac cycle. This variation could reflect physiology, including mixing of the interstitial fluid, relevant for brain waste clearance. However, it is known from cardiac diffusion imaging that tissue deformation by itself affects the magnitude of the MRI signal, leading to artificial ADC variations as well. This study investigates to what extent tissue deformation causes artificial ADC variations in the brain. THEORY AND METHODS: We implemented a high-field MRI sequence with stimulated echo acquisition mode that simultaneously measures brain tissue deformation and ADC. Based on the measured tissue deformation, we simulated the artificial ADC variation by combining established theoretical frameworks and compared the results with the measured ADC variation. We acquired data in 8 healthy volunteers with diffusion weighting b = 300 and b = 1000 s/mm2 . RESULTS: Apparent diffusion coefficient variation was largest in the feet-to-head direction and showed the largest deviation from the mean ADC at peak systole. Artificial ADC variation estimated from tissue deformation was 1.3 ± 0.37·10-5  mm2 /s in the feet-to-head direction for gray matter, and 0.75 ± 0.29·10-5  mm2 /s for white matter. The measured ADC variation in the feet-to-head direction was 5.6·10-5 ± 1.5·10-5  mm2 /s for gray matter and 3.2·10-5 ± 1.0·10-5  mm2 /s for white matter, which was a factor of 3.5 ± 0.82 and 3.4 ± 0.57 larger than the artificial diffusion variations. The measured diffusion variations in the right-to-left/anterior-to-posterior direction were a factor of 1.5 ± 1.0/1.7 ± 1.4 and 2.0 ± 0.91/2.5 ± 0.94 larger than the artificial diffusion variations for gray matter and white matter, respectively. CONCLUSION: Apparent diffusion coefficient variations in the brain likely largely reflect physiology.

Systematic review and meta-analysis evaluating the effects electric bikes have on physiological parameters.

BACKGROUND: There is a universal need to increase the number of adults meeting physical activity (PA) recommendations to help improve health. In recent years, electrically assisted bicycles (e-bikes) have emerged as a promising method for supporting people to initiate and maintain physical activity levels. To the best of our knowledge, there have been no meta-analyses conducted to quantify the difference in physiological responses between e-cycling with electrical assistance, e-cycling without assistance, conventional cycling, and walking. METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines. We identified short-term e-bike studies, which utilized a crossover design comparing physiological outcomes when e-cycling with electrical assistance, e-cycling without electrical assistance, conventional cycling, or walking. Energy expenditure (EE), heart rate (HR), oxygen consumption (VO2 ), power output (PO), and metabolic equivalents (METs) outcomes were included within the meta-analysis. RESULTS: Fourteen studies met our inclusion criteria (N = 239). E-cycling with electrical assistance resulted in a lower energy expenditure (EE) [SMD = -0.46 (-0.98, 0.06), p = 0.08], heart rate (HR) [MD = -11.41 (-17.15, -5.68), p < 0.000, beats per minute], oxygen uptake (VO2 ) [SMD = -0.57 (-0.96, -0.17), p = 0.005], power output (PO) [MD = -31.19 (-47.19 to -15.18), p = 0.000, Watts], and metabolic equivalent (MET) response [MD = -0.83 (-1.52, -0.14), p = 0.02, METs], compared with conventional cycling. E-cycling with moderate electrical assistance resulted in a greater HR response [MD 10.38 (-1.48, 22.23) p = 0.09, beats per minute], and VO2 response [SMD 0.34 (-0.14, 0.82) p = 0.16] compared with walking. CONCLUSIONS: E-cycling was associated with increased physiological responses that can confer health benefits.

Human microbiome and homeostasis: insights into the key role of prebiotics, probiotics, and symbiotics.

The interest in the study of the gut microbiome has grown exponentially. Indeed, its impact on health and disease has been increasingly reported, and the importance of keeping gut microbiome homeostasis clearly highlighted. However, and despite many advances, there are still some gaps, as well as the real discernment on the contribution of some species falls far short of what is needed. Anyway, it is already more than a solid fact of its importance in maintaining health and preventing disease, as well as in the treatment of some pathologies. In this sense, and given the existence of some ambiguous opinions, the present review aims to discuss the importance of gut microbiome in homeostasis maintenance, and even the role of probiotics, prebiotics, and symbiotics in both health promotion and disease prevention.

Report on the online course "Basic Concepts in Neurophysiology": a course promoted during the COVID-19 pandemic quarantine.

"Basic Concepts in Neurophysiology" was a 3-wk online course developed during six synchronous meetings combined with asynchronous activities. We proposed an active learning course that used free online platforms to teach physiology during a period in which undergraduates were not in classrooms or taking online classes due to the COVID-19 pandemic. Herein, we report the course organization and the students' involvement in, acceptance of, and evaluation of the course. To address the students' perceptions about these points, we sent a questionnaire to 49 participants who finished the course. We found that although most students (52.5%) had never taken a course with similar methods before, almost all of them (95%) liked the flipped class model. Additionally, a majority of the students (92.5%) said that the method increased their study frequency during the social distancing period, which is an important aspect to consider during this challenging time for both students and professors.

The relationships and interactions between age, exercise and physiological function.

This brief review focuses on the relationships and interactions between human ageing, exercise and physiological function. It explores the importance of the selection of participants for ageing research, the strengths and deficiencies of both cross-sectional and longitudinal studies, and the complexities involved in understanding time-dependent, lifelong physiological processes. As being physically active is crucial to fostering healthy ageing, it is essential that participants in health and ageing research are defined in terms of their physical activity/exercise status as well as other lifestyle factors. Comparisons of exercisers with non-exercisers has suggested that there is a mosaic of regulation of ageing both within and across physiological systems. We suggest that four broad categories exist which encompass this regulation. These are (i) systems and indices that are age dependent, but activity independent; (ii) systems that are age dependent, but also malleable by exercise; (iii) systems that are not age affected but are altered by exercise; and (iv) systems that are neither age nor activity dependent. We briefly explore the concept of a mosaic of regulation in a selection of physiological systems. These include skeletal muscle, the immune and endocrine systems, gastrointestinal as well as cognitive function. We go onto examine how these categories might fit within the broad framework of understanding the physiology of human ageing.

Functional brain networks and neuroanatomy underpinning nausea severity can predict nausea susceptibility using machine learning.

KEY POINTS: Nausea is an adverse experience characterised by alterations in autonomic and cerebral function. Susceptibility to nausea is difficult to predict, but machine learning has yet to be applied to this field of study. The severity of nausea that individuals experience is related to the underlying morphology (shape) of the subcortex, namely of the amygdala, caudate and putamen; a functional brain network related to nausea severity was identified, which included the thalamus, cingulate cortices (anterior, mid- and posterior), caudate nucleus and nucleus accumbens. Sympathetic nervous system function and sympathovagal balance, by heart rate variability, was closely related to both this nausea-associated anatomical variation and the functional connectivity network, and machine learning accurately predicted susceptibility or resistance to nausea. These novel anatomical and functional brain biomarkers for nausea severity may permit objective identification of individuals susceptible to nausea, using artificial intelligence/machine learning; brain data may be useful to identify individuals more susceptible to nausea. ABSTRACT: Nausea is a highly individual and variable experience. The central processing of nausea remains poorly understood, although numerous influential factors have been proposed, including brain structure and function, as well as autonomic nervous system (ANS) activity. We investigated the role of these factors in nausea severity and if susceptibility to nausea could be predicted using machine learning. Twenty-eight healthy participants (15 males; mean age 24 years) underwent quantification of resting sympathetic and parasympathetic nervous system activity by heart rate variability. All were exposed to a 10-min motion-sickness video during fMRI. Neuroanatomical shape differences of the subcortex and functional brain networks associated with the severity of nausea were investigated. A machine learning neural network was trained to predict nausea susceptibility, or resistance, using resting ANS data and detected brain features. Increasing nausea scores positively correlated with shape variation of the left amygdala, right caudate and bilateral putamen (corrected P = 0.05). A functional brain network linked to increasing nausea severity was identified implicating the thalamus, anterior, middle and posterior cingulate cortices, caudate nucleus and nucleus accumbens (corrected P = 0.043). Both neuroanatomical differences and the functional nausea-brain network were closely related to sympathetic nervous system activity. Using these data, a machine learning model predicted susceptibility to nausea with an overall accuracy of 82.1%. Nausea severity relates to underlying subcortical morphology and a functional brain network; both measures are potential biomarkers in trials of anti-nausea therapies. The use of machine learning should be further investigated as an objective means to develop models predicting nausea susceptibility.

Effects of Water Loading on Observed and Predicted Plasma Sodium, and Fluid and Urine Cation Excretion in Healthy Individuals.

RATIONALE & OBJECTIVE: The discovery of sodium storage without concurrent water retention suggests the presence of an additional compartment for sodium distribution in the body. The osmoregulatory role of this compartment under hypotonic conditions is not known. STUDY DESIGN: Experimental interventional study. SETTING & PARTICIPANTS: Single-center study of 12 apparently healthy men. INTERVENTION: To investigate whether sodium can be released from its nonosmotic stores after a hypotonic fluid load, a water-loading test (20mL water/kg in 20 minutes) was performed. OUTCOMES: During a 240-minute follow-up, we compared the observed plasma sodium concentration ([Na+]) and fluid and urine cation excretion with values predicted by the Barsoum-Levine and Nguyen-Kurtz formulas. These formulas are used for guidance of fluid therapy during dysnatremia, but do not account for nonosmotic sodium stores. RESULTS: 30 minutes after water loading, mean plasma [Na+] decreased 3.2±1.6 (SD) mmol/L, after which plasma [Na+] increased gradually. 120 minutes after water loading, plasma [Na+] was significantly underestimated by the Barsoum-Levine (-1.3±1.4mmol/L; P=0.05) and Nguyen-Kurtz (-1.5±1.5mmol/L; P=0.03) formulas. In addition, the Barsoum-Levine and Nguyen-Kurtz formulas overestimated urine volume, while cation excretion was significantly underestimated, with a cation gap of 57±62 (P=0.009) and 63±63mmol (P=0.005), respectively. After 240 minutes, this gap was 28±59 (P=0.2) and 34±60mmol (P=0.08), respectively. LIMITATIONS: The compartment from which the mobilized sodium originated was not identified, and heterogeneity in responses to water loading was observed across participants. CONCLUSIONS: These data suggest that healthy individuals are able to mobilize osmotically inactivated sodium after an acute hypotonic fluid load. Further research is needed to expand knowledge about the compartment of osmotically inactivated sodium and its role in osmoregulation and therapy for dysnatremias. FUNDING: This investigator-initiated study was partly supported by a grant from Unilever Research and Development Vlaardingen, The Netherlands B.V. (MA-2014-01914).

Student perception on the integration of simulation experiences into human physiology curricula.

A variety of medical simulators have been developed over recent years for students of all medical professions. These simulators serve to teach basic science concepts, advanced clinical skills, as well as empathy and student confidence. This study aimed to understand the students' perception of the integration of high-fidelity simulation exercises into the teaching of human physiology. Research groups were made up of both osteopathic and podiatric medical students. Data were obtained using a Likert-scale survey. Results indicated that students believed the simulation experiences were beneficial to further understanding of physiological concepts, as well as seeing these concepts in a clinical setting. Variations were noted between podiatric and osteopathic medical students' perception on how the experiences helped them develop clinical and personal confidence, and if the experience helped illustrate correlations between laboratory values and accompanying physiology. Results illustrated no differences in perception between the sexes. Although all students agreed that the experience helped with the understanding of physiology, podiatric medical students did not necessarily find value in the simulation for their development as future clinicians. We predict that differences in perception are largely based on the different curriculums of the students questioned. The present study indicated that incorporation of simulation experiences in the first year of medical school enhanced learning basic science physiology concepts and promoted the development of self-confidence as future clinicians. Incorporating simulation into the didactic coursework should be promoted in other medical schools' curricula.

Detecting white matter activity using conventional 3 Tesla fMRI: An evaluation of standard field strength and hemodynamic response function.

Detection of functional magnetic resonance imaging (fMRI) activation in white matter has been increasingly reported despite historically being controversial. Much of the development work to-date has used high-field 4 T MRI and specialized pulse sequences. In the current study, we utilized conventional 3 T MRI and a commonly applied gradient-echo-planar imaging sequence to evaluate white matter (WM) fMRI sensitivity within a common framework. Functional WM activity was replicated in target regions of interest within the corpus callosum, at the group and individual levels. As expected there was a reduction in overall WM activation sensitivity. Individual analyses revealed that 8 of the 13 individuals showed white matter activation, showing a lower percentage of individuals with WM activation detected. Importantly, WM activation results were sensitive to analyses that applied alternate hemodynamic response functions, with an increase in the group level cluster when hemodynamic response function (HRF) onset slope was reduced. The findings supported the growing evidence that WM activation is detectable, with activation levels are closer to thresholds used for routine 3T MRI studies. Optimization factors, such as the HRF model, appear to be important to further enhance the characterization of WM activity in fMRI.

An overview of sleep and circadian dysfunction in Parkinson's disease.

Sleep and circadian alterations are amongst the very first symptoms experienced in Parkinson's disease, and sleep alterations are present in the majority of patients with overt clinical manifestation of Parkinson's disease. However, the magnitude of sleep and circadian dysfunction in Parkinson's disease, and its influence on the pathophysiology of Parkinson's disease remains often unclear and a matter of debate. In particular, the confounding influences of dopaminergic therapy on sleep and circadian dysfunction are a major challenge, and need to be more carefully addressed in clinical studies. The scope of this narrative review is to summarise the current knowledge around both sleep and circadian alterations in Parkinson's disease. We provide an overview on the frequency of excessive daytime sleepiness, insomnia, restless legs, obstructive apnea and nocturia in Parkinson's disease, as well as addressing sleep structure, rapid eye movement sleep behaviour disorder and circadian features in Parkinson's disease. Sleep and circadian disorders have been linked to pathological conditions that are often co-morbid in Parkinson's disease, including cognitive decline, memory impairment and neurodegeneration. Therefore, targeting sleep and circadian alterations could be one of the earliest and most promising opportunities to slow disease progression. We hope that this review will contribute to advance the discussion and inform new research efforts to progress our knowledge in this field.

Standardized Comparison of Selected Physiological Controllers for Rotary Blood Pumps: In Vitro Study.

Various physiological controllers for left ventricular assist devices (LVADs) have been developed to prevent flow conditions that may lead to left ventricular (LV) suction and overload. In the current study, we selected and implemented six of the most promising physiological controllers presented in literature. We tuned the controllers for the same objectives by using the loop-shaping method from control theory. The in vitro experiments were derived from literature and included different preload, afterload, and contractility variations. All experiments were repeated with an increased or decreased contractility from the baseline pathological circulation and with simulated sensor drift. The controller performances were compared with an LVAD operated at constant speed (CS) and a physiological circulation. During preload variations, all controllers resulted in a pump flow change that resembled the cardiac output response of the physiological circulation. For afterload variations, the response varied among the controllers, whereas some of them presented a high sensitivity to contractility or sensor drift, leading to LV suction and overload. In such cases, the need for recalibration of the controllers or the sensor is indicated. Preload-based physiological controllers showed their clinical significance by outperforming the CS operation and promise many benefits for the LVAD therapy. However, their clinical implementation in the near future for long-term use is highly dependent on the sensor technology and its reliability.