Specific age-correlated activation of top hierarchical motor control areas during gait-like plantar stimulation: An fMRI study.

A better understanding of gait disorders that are associated with aging is crucial to prevent adverse outcomes. The functional study of gait remains a thorny issue due to technical constraints inherent to neuroimaging procedures, as most of them require to stay supine and motionless. Using an MRI-compatible system of boots reproducing gait-like plantar stimulation, we investigated the correlation between age and brain fMRI activation during simulated gait in healthy adults. Sixty-seven right-handed healthy volunteers aged between 20 and 77 years old (49.2 ± 18.0 years; 35 women) were recruited. Two paradigms were assessed consecutively: (a) gait-like plantar stimulation and (b) chaotic and not gait-related plantar stimulation. Resulting statistical parametric maps were analyzed with a multiple-factor regression that included age and a threshold determined by Monte-Carlo simulation to fulfill a family-wise error rate correction of p < .05. In the first paradigm, there was an age-correlated activation of the right pallidum, thalamus and putamen. The second paradigm showed an age-correlated deactivation of both primary visual areas (V1). The subtraction between results of the first and second paradigms showed age-correlated activation of the right presupplementary motor area (Brodmann Area [BA] 6) and right mid-dorsolateral prefrontal cortex (BA9-10). Our results show age-correlated activity in areas that have been associated with the control of gait, highlighting the relevance of this simulation model for functional gait study. The specific progressive activation of top hierarchical control areas in simulated gait and advancing age corroborate a progressive loss of automation in healthy older adults.

Spinal changes after 5-day dry immersion as shown by magnetic resonance imaging (DI-5-CUFFS).

Astronauts frequently report microgravity-induced back pain, which is generally more pronounced in the beginning of a spaceflight. The dry immersion (DI) model reproduces the early effects of microgravity in terms of global support unloading and fluid shift, both of which are involved in back pain pathogenesis. Here, we assessed spinal changes induced by exposure to 5 days of strict DI in 18 healthy men (25-43-yr old) with (n = 9) or without (n = 9) thigh cuffs countermeasure. Intervertebral disk (IVD) height, spinal cord position, and apparent diffusion coefficient (ADC; reflecting global water motion) were measured using magnetic resonance imaging before and after DI. After DI, IVD height increased in thoracic (+3.3 ± 0.8 mm; C7-T12) and lumbar (+4.5 ± 0.4 mm; T12-L5) regions but not in the cervical region (C2-C7) of the spine. An increase in ADC after DI was observed at the L1 (∼6% increase, from 3.2 to 3.4 × 10-3 mm2/s; P < 0.001) and L2 (∼3% increase, from 3.4 to 3.5 × 10-3 mm2/s; P = 0.005) levels. There was no effect of thigh cuffs on spinal parameters. This change in IVD after DI follows the same "gradient" pattern of height increase from the cervical to the lumbar region as observed after bed rest and spaceflight. The increase in ADC at L1 level positively correlated with reported back pain. These findings emphasize the utility of the DI model for studying early spinal changes observed in microgravity.

DI-5-Cuffs: Lumbar Intervertebral Disc Proteoglycan and Water Content Changes in Humans after Five Days of Dry Immersion to Simulate Microgravity.

Most astronauts experience back pain after spaceflight, primarily located in the lumbar region. Intervertebral disc herniations have been observed after real and simulated microgravity. Spinal deconditioning after exposure to microgravity has been described, but the underlying mechanisms are not well understood. The dry immersion (DI) model of microgravity was used with eighteen male volunteers. Half of the participants wore thigh cuffs as a potential countermeasure. The spinal changes and intervertebral disc (IVD) content changes were investigated using magnetic resonance imaging (MRI) analyses with T1-T2 mapping sequences. IVD water content was estimated by the apparent diffusion coefficient (ADC), with proteoglycan content measured using MRI T1-mapping sequences centered in the nucleus pulposus. The use of thigh cuffs had no effect on any of the spinal variables measured. There was significant spinal lengthening for all of the subjects. The ADC and IVD proteoglycan content both increased significantly with DI (7.34 ± 2.23% and 10.09 ± 1.39%, respectively; mean ± standard deviation), p < 0.05). The ADC changes suggest dynamic and rapid water diffusion inside IVDs, linked to gravitational unloading. Further investigation is needed to determine whether similar changes occur in the cervical IVDs. A better understanding of the mechanisms involved in spinal deconditioning with spaceflight would assist in the development of alternative countermeasures to prevent IVD herniation.

The Effects of Spaceflight Factors on the Human Plasma Proteome, Including Both Real Space Missions and Ground-Based Experiments.

The aim of the study was to compare proteomic data on the effects of spaceflight factors on the human body, including both real space missions and ground-based experiments. LC-MS/MS-based proteomic analysis of blood plasma samples obtained from 13 cosmonauts before and after long-duration (169-199 days) missions on the International Space Station (ISS) and for five healthy men included in 21-day-long head-down bed rest (HDBR) and dry immersion experiments were performed. The semi-quantitative label-free analysis revealed significantly changed proteins: 19 proteins were significantly different on the first (+1) day after landing with respect to background levels; 44 proteins significantly changed during HDBR and 31 changed in the dry immersion experiment. Comparative analysis revealed nine common proteins (A1BG, A2M, SERPINA1, SERPINA3, SERPING1, SERPINC1, HP, CFB, TF), which changed their levels after landing, as well as in both ground-based experiments. Common processes, such as platelet degranulation, hemostasis, post-translational protein phosphorylation and processes of protein metabolism, indicate common pathogenesis in ground experiments and during spaceflight. Dissimilarity in the lists of significantly changed proteins could be explained by the differences in the dynamics of effective development in the ground-based experiments. Data are available via ProteomeXchange using the identifier PXD013305.

Effects of plantar stimulation on cardiovascular response to orthostatism.

PURPOSE: Walking is a complex locomotor process that involves both spinal cord reflexes and cortical integration of peripheral nerve input. Maintaining an upright body position requires not only neuromuscular activity but also cardiovascular regulation. We postulated that plantar mechanical stimulation might modulate autonomic nervous system activity and, thereby, impact blood pressure adaptation during standing. METHODS: Twelve healthy subjects underwent three randomly ordered 45-min 70°-saddle tilt tests while the plantar surfaces of the feet were stimulated using specially engineered Korvit boots in the following modes: (1) no stimulation, (2) disrupted stimulation, and (3) walking mode. Orthostatic tolerance time was measured for each trial. During testing, we obtained an electrocardiogram and measured blood pressure, skin blood flow, and popliteal vein cross-sectional area. We estimated central hemodynamics, baroreflex sensitivity and heart rate variability. RESULTS: Orthostatic tolerance time was not found to differ significantly between test conditions (37.2 ± 10.4, 40.9 ± 7.6, and 41.8 ± 8.2 min, for no stimulation, disrupted stimulation, and walking mode, respectively). No significant differences between treatment groups were observed for stroke volume or cardiac baroreflex sensitivity, both of which decreased significantly from baseline during tilt testing in all groups. Cardiac sympathetic index and popliteal vein cross-sectional area increased at the end of the tilt period in all groups, without significant differences between treatments. CONCLUSIONS: Plantar mechanical stimulation is insufficient for immediate modulation of cardiac sympathetic and parasympathetic activity under orthostatic stress.

Effect of Chinese herbal medicine on vascular functions during 60-day head-down bed rest.

PURPOSE: Chinese herbal medicine is a promising countermeasure against cardiovascular dysfunction associated with a sedentary lifestyle. We examined the impact of the Chinese herb, Taikong Yangxin, on the micro- and macrovascular dysfunction associated with a 60-day bed rest. METHODS: Fourteen healthy men were randomly divided into two groups: those given herbal supplement, and the control group; the two groups underwent a 60-day bed rest. The macrovasculature was assessed by sonography. Skin microvascular functions were assessed with laser Doppler. The plasma level of endothelial microparticles (EMPs), markers of endothelial injury, was determined. RESULTS: Bed rest induced a 33 % decrease in the femoral artery diameter and compliance whereas carotid wall thickness, diameter, and compliance remained unchanged. The early phase of endothelium-dependent vasodilation to ACh was unmodified by bed rest, while the late phase was reduced by 30 % along with a twofold increase in EMPs. In those given Taikong Yangxin, the early phase was amplified by 2.5-fold, and the effects of bed rest on the late phase were prevented. CONCLUSION: These findings indicate that Taikong Yangxin ameliorates endothelium-dependent vasodilation, likely by improving the NO pathway. The study suggests Taikong Yangxin as a new countermeasure to prevent the changes in microvascular function induced by physical inactivity.

AGEs breaking and antioxidant treatment improves endothelium-dependent dilation without effect on flow-mediated remodeling of resistance arteries in old Zucker diabetic rats.

BACKGROUND: A chronic increase in blood flow in resistance arteries is associated with increased lumen diameter (outward remodeling) and improved endothelium (NO)-mediated relaxation. Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases. Nevertheless, it is impaired in 12 to 24-month old rats and in young Zucker Diabetic Fatty (ZDF) rats due to advanced glycation end products (AGEs) and oxidative stress. As type 2 diabetes occurs preferentially in older subjects we investigated flow-mediated remodeling and the effect of the AGEs breaker ALT-711 associated or not to the antioxidant TEMPOL in one-year old lean (LZ) and ZDF rats. METHODS: Mesenteric resistance arteries were exposed to high (HF) or normal blood flow (NF) in vivo. They were collected after 2 weeks for in vitro analysis. RESULTS: In LZ rats, diameter expansion did not occur despite a significant increase in blood flow in HF arteries. Nevertheless, endothelium-mediated relaxation was higher in HF than in NF arteries. ALT-711, alone or in combination with TEMPOL, restored outward remodeling in HF arteries in association with AGEs reduction. TEMPOL alone had no effect. ALT-711, TEMPOL or the combination of the 2 drugs did not significantly affect endothelium-mediated relaxation in HF and NF arteries.In ZDF rats, diameter did not increase despite the increase in blood flow and endothelium-mediated relaxation was further decreased in HF arteries in association with AGEs accumulation and excessive oxidative stress. In both NF and HF arteries, endothelium-mediated relaxation was lower in ZDF than in LZ rats. ALT-711, TEMPOL or their combination did not improve remodeling (diameter equivalent in HF and NF arteries). In parallel, they did not reduce AGEs level and did not improve MMPs activity. Nevertheless, ALT-711 and TEMPOL partly improved endothelium-mediated relaxation through a reduction of oxidative stress and the association of ALT-711 and TEMPOL fully restored relaxation to the level found in LZ rats. CONCLUSIONS: ALT-711 did not improve outward remodeling in mature ZDF rats but it reduced oxidative stress and consequently improved endothelium-dependent relaxation. In mature LZ rats, ALT-711 improved outward remodeling and reduced AGEs level. Consequently, AGEs breaking is differently useful in ageing whether it is associated with diabetes or not.

Baroreflex and cerebral autoregulation are inversely correlated.

BACKGROUND: The relative stability of cerebral blood flow is maintained by the baroreflex and cerebral autoregulation (CA). We assessed the relationship between baroreflex sensitivity (BRS) and CA in patients with atherosclerotic carotid stenosis or occlusion. METHODS AND RESULTS: Patients referred for assessment of atherosclerotic unilateral >50% carotid stenosis or occlusion were included. Ten healthy volunteers served as a reference group. BRS was measured using the sequence method. CA was quantified by the correlation coefficient (Mx) between slow oscillations in mean arterial blood pressure and mean cerebral blood flow velocities from transcranial Doppler. Forty-five patients (M/F: 36/9), with a median age of 68 years (IQR:17) were included. Thirty-four patients had carotid stenosis, and 11 patients had carotid occlusion (asymptomatic: 31 patients; symptomatic: 14 patients). The median degree of carotid steno-occlusive disease was 90% (IQR:18). Both CA (P=0.02) and BRS (P<0.001) were impaired in patients as compared with healthy volunteers. CA and BRS were inversely and strongly correlated with each other in patients (rho=0.58, P<0.001) and in healthy volunteers (rho=0.939; P<0.001). Increasing BRS remained strongly associated with impaired CA on multivariate analysis (P=0.004). CONCLUSIONS: There was an inverse correlation between CA and BRS in healthy volunteers and in patients with carotid stenosis or occlusion. This might be due to a relative increase in sympathetic drive associated with weak baroreflex enhancing cerebral vasomotor tone and CA.

Dry immersion rapidly disturbs iron metabolism in men and women: results from the VIVALDI studies.

Iron is essential for cell respiration, muscle metabolism, and oxygen transport. Recent research has shown that simulated microgravity rapidly affects iron metabolism in men. However, its impact on women remains unclear. This study aims to compare iron metabolism alterations in both sexes exposed to 5 days of dry immersion. Our findings demonstrate that women, similarly to men, experience increased systemic iron availability and elevated serum hepcidin levels, indicative of iron misdistribution after short-term exposure to simulated microgravity.

Noisy fluctuation of heart rate indicates cardiovascular system instability.

Heart rate spontaneously fluctuates despite homeostatic regulatory mechanisms to stabilize it. Harmonic and fractal fluctuations have been described. Non-harmonic non-fractal fluctuation has not been studied because it is usually thought that it is caused by apparatus noise. We hypothesized that this fluctuation looking like apparatus noise (that we call "noisy fluctuation") is linked to challenged blood pressure stabilization and not to apparatus noise. We assessed noisy fluctuation by quantifying the small and fastest beat-to-beat fluctuation of RR-interval by means of spectral analysis (Nyquist power of heart rate variability: nyHRV) after filtering out its fractal component. We observed nyHRV in healthy supine subjects and in patients with vasovagal symptoms. We challenged stabilization of blood pressure by upright posture (by means of a head-up tilt table test). Head-up position on the tilt table dramatically decreased nyHRV (0.128 ± 0.063 vs. 0.004 ± 0.002, p < 0.01) in healthy subjects (n = 12). Head-up position also decreased nyHRV in patients without vasovagal symptoms (n = 24; 0.220 ± 0.058 vs. 0.034 ± 0.015, p < 0.05), but not in patients with vasovagal symptoms during a head-up tilt table test (age and sex paired, 0.103 ± 0.041 vs. 0.122 ± 0.069, not significant). Heart rate variability includes a physiological non-harmonic non-fractal noisy fluctuation. This noisy fluctuation indicates low engagement of regulatory mechanisms because it disappears when the cardiovascular system is challenged (upright posture). It also indicates cardiovascular instability because it does not disappear in upright patients before vasovagal syncope, a transient failure of cardiovascular regulation.

Corrigendum: Editorial: Rising stars in environmental, aviation and space physiology: 2022.

[This corrects the article DOI: 10.3389/fphys.2023.1230752.].

Comprehensive assessment of physiological responses in women during the ESA dry immersion VIVALDI microgravity simulation.

Astronauts in microgravity experience multi-system deconditioning, impacting their inflight efficiency and inducing dysfunctions upon return to Earth gravity. To fill the sex gap of knowledge in the health impact of spaceflights, we simulate microgravity with a 5-day dry immersion in 18 healthy women (ClinicalTrials.gov Identifier: NCT05043974). Here we show that dry immersion rapidly induces a sedentarily-like metabolism shift mimicking the beginning of a metabolic syndrome with a drop in glucose tolerance, an increase in the atherogenic index of plasma, and an impaired lipid profile. Bone remodeling markers suggest a decreased bone formation coupled with an increased bone resorption. Fluid shifts and muscular unloading participate to a marked cardiovascular and sensorimotor deconditioning with decreased orthostatic tolerance, aerobic capacity, and postural balance. Collected datasets provide a comprehensive multi-systemic assessment of dry immersion effects in women and pave the way for future sex-based evaluations of countermeasures.

Associations between gait speed and brain structure in amnestic mild cognitive impairment: a quantitative neuroimaging study.

BACKGROUND: Patients with amnestic mild cognitive impairment (aMCI) present gait disturbances including slower speed and higher variability when compared to cognitively healthy individuals (CHI). Brain neuroimaging could explore higher levels of motor control. Our purpose was to look for an association between morphometrics and gait parameters in each group. We hypothesized that the relation between morphological cerebral alteration and gait speed are different following the group. METHODS: Fifty-three participants (30 with aMCI and 23 CHI) were recruited in this French cross-sectional study (mean 72 ± 5 years, 38% female). Gait speed and gait variability (coefficients of variation of stride time (STV) and stride length (SLV)) were measured using GAITrite® system. CAT12 software was used to analyse volume and surface morphometry like gray matter volume (GMV) and cortical thickness (CT). Age, gender and education level were used as potential cofounders. RESULTS: aMCI had slower gait speed and higher STV when compared to CHI. In aMCI the full adjusted linear regression model showed that lower gait speed was associated with decreased GMV and lower CT in bilateral superior temporal gyri (p < 0.36). In CHI, no association was found between gait speed and brain structure. Higher SLV was correlated with reduced GMV in spread regions (p < 0.05) and thinner cortex in the middle right frontal gyrus (p = 0.001) in aMCI. In CHI, higher SLV was associated with reduced GMV in 1 cluster: the left lingual (p = 0.041). CONCLUSIONS: These findings indicate that lower gait speed is associated with specific brain structural changes as reduced GMV and CT during aMCI.

Running vs. resistance exercise to counteract deconditioning induced by 90-day head-down bedrest.

Spaceflight is associated with enhanced inactivity, resulting in muscular and cardiovascular deconditioning. Although physical exercise is commonly used as a countermeasure, separate applications of running and resistive exercise modalities have never been directly compared during long-term bedrest. This study aimed to compare the effectiveness of two exercise countermeasure programs, running and resistance training, applied separately, for counteracting cardiovascular deconditioning induced by 90-day head-down bedrest (HDBR). Maximal oxygen uptake ( V ˙ O2max), orthostatic tolerance, continuous ECG and blood pressure (BP), body composition, and leg circumferences were measured in the control group (CON: n = 8), running exercise group (RUN: n = 7), and resistive exercise group (RES: n = 7). After HDBR, the decrease in V ˙ O2max was prevented by RUN countermeasure and limited by RES countermeasure (-26% in CON p < 0.05, -15% in RES p < 0.05, and -4% in RUN ns). Subjects demonstrated surprisingly modest orthostatic tolerance decrease for different groups, including controls. Lean mass loss was limited by RES and RUN protocols (-10% in CON vs. -5% to 6% in RES and RUN). Both countermeasures prevented the loss in thigh circumference (-7% in CON p < 0.05, -2% in RES ns, and -0.6% in RUN ns) and limited loss in calf circumference (-10% in CON vs. -7% in RES vs. -5% in RUN). Day-night variations in systolic BP were preserved during HDBR. Decrease in V ˙ O2max positively correlated with decrease in thigh (r = 0.54 and p = 0.009) and calf (r = 0.52 and p = 0.012) circumferences. During this 90-day strict HDBR, running exercise successfully preserved V ˙ O2max, and resistance exercise limited its decline. Both countermeasures limited loss in global lean mass and leg circumferences. The V ˙ O2max reduction seems to be conditioned more by muscular than by cardiovascular parameters.

Low-magnitude whole body vibration with resistive exercise as a countermeasure against cardiovascular deconditioning after 60 days of head-down bed rest.

Whole body vibration with resistive exercise is a promising countermeasure against some weightlessness-induced dysfunctions. Our objective was to study whether the combination of low-magnitude whole body vibration with a resistive exercise can prevent the cardiovascular deconditioning induced by a nonstrict 60-day head-down bed rest (Earth Star International Bed Rest Experiment Project). Fourteen healthy men participated in this study. We recorded electrocardiograms and blood pressure waves by means of a noninvasive beat-by-beat measurement system (Cardiospace, integrated by Centre National d'Etudes Spatiales and Astronaut Center of China) during an orthostatic test (20 min of 75-degree head-up tilt test) before and immediately after bed rest. We estimated heart rate, blood pressure, cardiac output, stroke volume, total peripheral resistance, baroreflex sensitivity, and heart rate variability. Low-magnitude whole body vibration with resistive exercise prevented an increase of the sympathetic index (reflecting the sympathovagal balance of cardiac autonomic control) and limited the decrease of the spontaneous baroreflex sensitivity induced by 60 days of head-down bed rest. However, this countermeasure had very little effect on cardiac hemodynamics and did not improve the orthostatic tolerance. This combined countermeasure did not efficiently prevent orthostatic intolerance but prevents changes in the autonomic nervous system associated with cardiovascular deconditioning. The underlying mechanisms remain hypothetical but might involve cutaneous and muscular mechanoreceptors.

Long-term dry immersion: review and prospects.

Dry immersion, which is a ground-based model of prolonged conditions of microgravity, is widely used in Russia but is less well known elsewhere. Dry immersion involves immersing the subject in thermoneutral water covered with an elastic waterproof fabric. As a result, the immersed subject, who is freely suspended in the water mass, remains dry. For a relatively short duration, the model can faithfully reproduce most physiological effects of actual microgravity, including centralization of body fluids, support unloading, and hypokinesia. Unlike bed rest, dry immersion provides a unique opportunity to study the physiological effects of the lack of a supporting structure for the body (a phenomenon we call 'supportlessness'). In this review, we attempt to provide a detailed description of dry immersion. The main sections of the paper discuss the changes induced by long-term dry immersion in the neuromuscular and sensorimotor systems, fluid-electrolyte regulation, the cardiovascular system, metabolism, blood and immunity, respiration, and thermoregulation. The long-term effects of dry immersion are compared with those of bed rest and actual space flight. The actual and potential uses of dry immersion are discussed in the context of fundamental studies and applications for medical support during space flight and terrestrial health care.

NT-ProBNP levels, water and sodium homeostasis in healthy men: effects of 7 days of dry immersion.

Immersion is a useful tool for studying fluid-volume homeostasis. Natriuretic peptides play a vital role in renal, humoral, and cardiovascular regulation under changing environmental conditions. We hypothesized that dry immersion would rapidly induce a new steady state for water and sodium metabolism, and that serum NT-proBNP levels, a proxy measure for brain natriuretic peptide (BNP), would decrease during long-term dry immersion and increase during recovery. Eight healthy young men were studied before, during, and after 7 days of dry immersion. Body weight, water balance, and plasma volume changes were evaluated. Plasma and serum samples were analyzed for active renin, NT-proBNP, aldosterone, electrolytes, osmolality, total protein, and creatinine. Urine samples were analyzed to determine levels of electrolytes, osmolality, creatinine, and free cortisol. A stand test was performed before and after dry immersion to evaluate cardiovascular deconditioning. Long-term dry immersion induced acute changes in water and sodium homeostasis on day 1, followed by a new steady state. Plasma volume decreased significantly during dry immersion. The serum levels of NT-proBNP increased significantly in recovery (10 ± 3 ng/L before dry immersion vs. 26 ± 5 ng/L on the fourth recovery day). Heart rate in the standing position was significantly greater after immersion. Results suggest that chronic dry immersion rapidly induced a new level of water-electrolyte homeostasis. The increase in NT-proBNP levels during the recovery period may be related to greater cardiac work and might reflect the degree of cardiovascular deconditioning.

A dry immersion model of microgravity modulates platelet phenotype, miRNA signature, and circulating plasma protein biomarker profile.

Ground based research modalities of microgravity have been proposed as innovative methods to investigate the aetiology of chronic age-related conditions such as cardiovascular disease. Dry Immersion (DI), has been effectively used to interrogate the sequelae of physical inactivity (PI) and microgravity on multiple physiological systems. Herein we look at the causa et effectus of 3-day DI on platelet phenotype, and correlate with both miRomic and circulating biomarker expression. The miRomic profile of platelets is reflective of phenotype, which itself is sensitive and malleable to the exposome, undergoing responsive transitions in order to fulfil platelets role in thrombosis and haemostasis. Heterogeneous platelet subpopulations circulate at any given time, with varying degrees of sensitivity to activation. Employing a DI model, we investigate the effect of acute PI on platelet function in 12 healthy males. 3-day DI resulted in a significant increase in platelet count, plateletcrit, platelet adhesion, aggregation, and a modest elevation of platelet reactivity index (PRI). We identified 15 protein biomarkers and 22 miRNA whose expression levels were altered after DI. A 3-day DI model of microgravity/physical inactivity induced a prothrombotic platelet phenotype with an unique platelet miRNA signature, increased platelet count and plateletcrit. This correlated with a unique circulating protein biomarker signature. Taken together, these findings highlight platelets as sensitive adaptive sentinels and functional biomarkers of epigenetic drift within the cardiovascular compartment.