Enhanced Cardiac Vagal Activity and Mood After Low-Dose Hypoxic Gas Inhalation in Healthy Young Adults

Enhanced Cardiac Vagal Activity and Mood After Low-Dose Hypoxic Gas Inhalation in Healthy Young Adults | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Enhanced Cardiac Vagal Activity and Mood After Low-Dose Hypoxic Gas Inhalation in Healthy Young Adults Dongmin Lee, Yudai Yamazaki, Ryuta Kuwamizu, Naoki Aoike, Masahiro Okamoto, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4609378/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Purpose Developing mindfulness-based strategies to efficiently improve cardiac vagal activity (CVA) is crucial for enhancing mood and managing stress. Recent studies have suggested that inhaling hypoxic gas could enhance CVA. However, the dynamics of CVA in response to acute hypoxia remain unelucidated, indicating that the proper hypoxic conditions expected to trigger the hormetic stress effect on CVA are unknown. Therefore, we aimed to achieve a comprehensive understanding of the hypoxic conditions required to improve CVA and mood following hypoxia. Methods Twenty-one healthy adults were assigned to participate in both hypoxic (NH) and normoxic (NN) conditions. Heart rate variability, saturation of percutaneous oxygen (SpO 2 ), and mood were monitored across the following sessions: Pre (5 min), Hypoxia 1–2 (10 min; NH, fraction of inspiratory oxygen (FIO 2 ): 13.5% or NN, FIO 2 : 20.9%), and Post 1–4 (20 min). The Baevsky stress index (SI) was incorporated into the square root. For time domain analysis of CVA, both the standard deviation of NN intervals (SDNN) and the root mean square of successive differences (RMSSD) were utilized. Results In the NH condition, SpO 2 decreased to 88.1 ± 0.6 during hypoxia, accompanied by reductions in log transformed (ln) SDNN and lnRMSSD. After hypoxia, both indicators rebounded, exhibiting a supercompensation phenomenon. Pleasure levels declined during hypoxia but rapidly rebounded afterward, which was linked to fluctuations in lnRMSSD and SI. Conclusion We discovered that acute short-term inhalation of low-dose hypoxic gas with an FIO 2 of 13.5% enhances both CVA and mood following hypoxia. This strategy could provide a practical resilience-building method. Low-dose hypoxia Autonomic nervous system Cardiac vagal activity Supercompensation Pleasant mood Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The capability to effectively manage psychophysiological stress is vital for maintaining health, especially given its heightened significance in today's fast-paced society. Cardiac vagal activity (CVA), which represents the dynamic influence of vagally-mediated parasympathetic activity in regulating cardiac function, plays an important role in an individual's resilience to psychophysiological stresses and in preserving homeostasis [ 1 – 3 ]. Measuring heart rate variability (HRV) is a non-invasive way to analyze the variations in intervals between successive heartbeats and is primarily utilized to assess CVA [ 4 , 5 ]. Higher levels of HRV indicated a greater influence of the vagus nerve on cardiac function, which in turn is associated with greater CVA [ 6 ]. Enhanced CVA has been linked to a better self-regulation process (e.g., cognitive function and emotional regulation), which is fundamentally regulated by prefrontal function [ 7 – 10 ]. Given this relationship, strengthening CVA has been recognized as a promising approach to enhancing psychophysiological resource coordination, which is often a primary focus in mindfulness-based interventions (e.g., regular exercise, meditation, biofeedback) [ 11 – 13 ]. However, given that the quality of mindfulness practice is potentially more crucial than the quantity for achieving beneficial effects [ 14 , 15 ], maintaining a consistent daily practice that is sufficiently effective can be challenging for the novice, as they may not yet have the skill required for sufficient quality (i.e., early practices may not yield tangible effects). This highlights the necessity for quick and easy methods of mindfulness to apply in daily life. Previous studies have provided evidence that long-term intermittent inhalation of hypoxic gas increases parasympathetic activity beyond its initial level, as indicated by enhanced vagal-mediated HRV [ 16 , 17 ]. This suggests that autonomic compensatory regulation may work to augment vagal-mediated parasympathetic activity following exposure to hypoxia, emphasizing hypoxia-induced positive autonomic adaptation to prolonged hypoxic stress. However, the response of CVA following the acute inhalation of hypoxic gas remains unclear. During acute hypoxia, the sympathovagal balance shifts toward sympathetic dominance in a dose-response manner, with decreased saturation of percutaneous oxygen (SpO 2 ) leading to cardiac vagal withdrawal and resulting in tachycardia [ 18 – 20 ]. However, depending on the duration and severity of the initial exposure, the suppressed CVA recovers immediately after hypoxic stress, leading to a decreased heart rate (HR). This indicates that acute hypoxia may trigger a reciprocal action in the sympathovagal balance. It has been reported that exposure to 12 hours of long-term and severe hypoxia (at an altitude of 4,000 m) significantly reduced vagally-mediated HRV, and this effect persisted even beyond the first hour of recovery under normoxic conditions [ 21 ]. On the other hand, after 15 minutes of short-term and severe hypoxic exposure (fraction of inspired oxygen [FIO 2 ]: 11%, equivalent to an altitude of 4,800 m), vagally-mediated HRV returned to its original levels within 20 minutes, and HR significantly decreased below baseline levels [ 22 ]. Interestingly, just 6 minutes after a 10-minute exposure to hypoxia (FIO 2 : 9.6%, equivalent to an altitude of 6,200 m), the global HRV (i.e., overall autonomic activity) rebounded above the baseline level, accompanied by bradycardia in females [ 23 ]. A series of previous studies suggest that acute, short-term inhalation of hypoxic gas may trigger cardiac parasympathetic overactivation, manifesting as bradycardia following hypoxic stress. However, these studies have so far primarily focused on severe hypoxia, so the proper hypoxic conditions to potentially improve CVA after acute hypoxia have not yet been clearly identified. According to the hormesis principle, low doses of a stressor typically induce a positive adaptive response with potential beneficial effects, whereas high doses generally result in detrimental effects [ 24 ]. This biological concept leads us to hypothesize that the hormetic region of hypoxia (i.e., supercompensation in CVA following acute hypoxic stress) is located at milder levels than in previous studies. Physical exercise, similar to the physiological stressor of hypoxia, has been widely demonstrated to support the hormesis principle [ 24 ]. Consistent with this, our accumulated findings strongly suggest that milder levels of exercise have beneficial effects on brain function [ 25 – 29 ], further supporting this hypothesis. Based on our empirical evidence, it is possible that levels of hypoxia milder than those previously studied may exist, which could act as hormetic stressors. The major physiological reason for the deterioration of vagal-mediated HRV under hypoxic conditions is decreased SpO 2 , which leads to cardiac vagal withdrawal. However, changes in psychological factors resulting from the acute fluctuation of CVA during hypoxia may also contribute to this effect. The acute deterioration in CVA that occurs during the initial stage of hypoxic stress can influence the psychological state, highlighting the importance of evaluating acute mountain-sickness symptoms in high-altitude areas after 6 hours of climbing to avoid potential confounding effects from initial vagal responses [ 30 ]. Several previous studies have consistently shown a strong association between suppressed CVA and negative psychological conditions, such as major depressive disorder, generalized anxiety disorder, and other forms of negative emotional states [ 3 , 31 ]. However, it is interesting to note that significant rebounds in CVA occur during the initial recovery phase after a bout of psychological stress [ 32 ], and this phenomenon is potentially associated with changes in pleasant mood following psychological stress [ 33 ]. This relationship implies that the rebound of CVA may indicate underlying emotional and psychological states associated with pleasant mood conditions following stress. While various studies have indicated potential positive effects in CVA after the inhalation of hypoxic gas, the majority of these studies have concentrated on relatively severe and prolonged hypoxic conditions. It has been reported that an FIO 2 of 15% might not lead to changes in CVA [ 34 ], indicating the existence of a hormetic region above this level where benefits can be observed. Nonetheless, severe hypoxic conditions can evoke acute mountain sickness (e.g., headaches, nausea, dizziness) [ 35 ] and can also cause cognitive fatigue characterized by impaired executive function in the prefrontal cortex, even during short-term hypoxia [ 36 , 37 ]. This raises concerns regarding the safety of deliberately triggering acute hypoxia, despite its potential benefits. Furthermore, to the best of our knowledge, no prior study has explored the relationship between acute fluctuations in CVA and emotional states in relation to acute hypoxia. Therefore, in this study, our primary purposes were twofold: 1) to investigate whether short-term inhalation of acute low-dose hypoxia at an FIO 2 of 13.5% enhances CVA after hypoxic stress, and 2) to examine whether fluctuation of CVA is associated with mood changes, particularly pleasant states. Methods Participants Twenty-one healthy, non-smoking young adults who had not been exposed to normobaric hypoxia or an altitude greater than 3,500 m within two years of their participation were included in this study. Because vagal-mediated HRV is vulnerable to adverse emotional arousal responses linked to psychological stress, depression, and sleep disorders, all participants underwent pre-screening with relevant self-report questionnaires [ 38 – 40 ]. The screening criteria included specific cutoff scores on the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression Scale (CESD), and the Pittsburgh Sleep Quality Index (PSQI). Through G*Power 3.1 analysis, we determined that a minimum of 18 participants were required to achieve a power of 0.80, a two-sided alpha of 0.05, and a medium effect size (Cohen's f = 0.25) in this experiment. The Institutional Ethics Committee of Tsukuba University approved this study, and all participants provided written informed consent before the experiments. Table 1 presents a detailed list of the characteristics of the participants. Table 1 Anthropological characteristics and psychological states Variables N = 21 Anthropological Characteristics Gender (male/female) 15 / 6 Age (yr) 23.7 ± 3.0 Weight (kg) 61.9 ± 11.3 Height (cm) 168.8 ± 9.8 BMI (kg/m 2 ) 21.5 ± 2.4 Psychological States CESD 7.0 ± 3.8 BDI-II 4.1 ± 2.5 PSQI 3.2 ± 0.8 Values are mean ± standard deviation BMI Body Mass Index, CESD Center for Epidemiologic Studies Depression Scale, BDI-II Beck Depression Inventory-II, PSQI Pittsburgh Sleep Quality Index Experimental protocol All experiments were carried out between 9 am and 5 pm, and a consistent laboratory temperature of 22 to 24 degrees Celsius was ensured. Participants were instructed to abstain from consuming coffee, tea, or medications that could directly affect sympathovagal balance or engaging in exhaustive physical exercise 24 hours prior to the experiment. Each participant's psychophysiological condition (e.g., mental health and physical activity for the day) was checked prior to the experiment to ensure they were in an appropriate state. As recommended by Task Force [ 4 , 6 ], participants were directed to adopt a seated position with their eyes closed for 5 minutes in a quiet, noise-free environment prior to beginning the experiments, ensuring they reached a stable state. Each participant participated in both a normobaric hypoxia (NH) condition and a normobaric normoxia (NN) condition, with each condition taking place in random order on different days at the same time of day, employing a single-blind, counterbalanced design. All participants were seated at rest on an ergometer in normoxia for 5 minutes, followed by 10 minutes of exposure to either hypoxic gas (NH; FIO 2 : 13.5%, corresponding to an altitude of 3,500 m) or ambient air (NN; FIO 2 : 20.9%, sea level). After inhalation, participants rested for 20 minutes while inhaling ambient air. The hypoxic gas mixture was prepared in advance of the experiment and stored in a 250-liter Douglas bag generated through a hypoxicator (Everest Summit II, Will Co. Ltd., Tokyo, Japan). In the NH condition, gas inhalation was switched (either from normoxia to hypoxia or from hypoxia to normoxia) by attaching and detaching a gas hose connected to Douglas bags supplying hypoxic gas or ambient air to the mask. To account for the experimental design and control for the potential impact of the hose on psychophysiological factors, the NN condition was conducted in the same way as the NH condition, but with participants inhaling ambient air. The mood was assessed every 5 minutes. Throughout the experiment, SpO 2 , HR, and electrocardiogram (ECG) signals were monitored continuously, and the data were sampled as 5-minute averages for each of the seven sessions (Pre, Normoxia 1–2 or Hypoxia 1–2 , Post 1–4 ). The summarized experimental design is illustrated in Fig. 1 . SpO 2 , ventilation, and respiratory rate The SpO 2 levels were continuously monitored using a pulse oximeter (OLV-3100, Nihon Kohden, Japan) placed on the right index finger, and the data were recorded in real-time through an A/D converter (PowerLab, AD Instruments, Colorado Springs, CO, USA). Given the susceptibility of short-term HRV to ventilation and frequency of respiration [ 41 , 42 ], we continuously monitored both indices using breath-by-breath methods with a gas analyzer (Aeromonitor AE300, Minato Medical Science, Osaka, Japan) throughout the experiments. Although the respiratory rate was not controlled during the experiment, participants were instructed to breathe normally and maintain a regular breathing pattern. Heart rate variability The ECG signal was recorded continuously using an A/D converter at a sampling rate of 1,000 Hz throughout the experiment. After removing abnormal beats, the HRV analysis was computed based on 256 NN interval segments within the 300 s recorded during the Pre, Hypoxia 1–2 , and Post 1–4 periods to ensure data stability. The time-domain analysis of HRV was chosen for the current study because it is appropriate for short-term analysis and is resilient to variations in respiratory rate, offering a reliable assessment of cardiac autonomic modulation [ 43 – 45 ]. The standard deviation of normal-to-normal intervals (SDNN) was evaluated as a measure of the global HRV activity and the root mean square of successive differences (RMSSD) were evaluated as a measure of parasympathetic nervous activity, specifically reflecting CVA. The SDNN/RMSSD ratio was used to calculate the sympathovagal balance, which is a measure of the interaction between sympathetic and parasympathetic nervous activity [ 46 ]. Additionally, we employed the square root of the Baevsky stress index (SI), a geometric indicator of HRV, to assess the psychophysiological stress induced by hypoxia [ 47 , 48 ]. The SI was normalized and calculated using the following equation: SI = AM o /2M o *M x DM n [ 48 ]. The mode (M o ) indicates the most frequently observed value in the dynamic sequence of cardiac intervals, indicating the most common HR interval during a given measurement period. The amplitude of the mode (AM o ) quantifies the proportion of cardiac intervals that correspond to the mode value, expressed as a percentage. The variation scope (M x DM n ) represents the range of variability among cardiac interval values within the dynamic sequence, offering a gauge of the heart rate's fluctuation range. These parameters are calculated using data from variational pulsometry, a technique for assessing the variability and dynamics of pulse rate. These data were then analyzed for HRV with the Kubios HRV software (Kubios Oy, Kuopio, Finland), using 5-minute segments for short-term analysis. Since the indices of SDNN and RMSSD were not normally distributed according to the Kolmogorov-Smirnov test, all analyses were conducted on the natural logarithm (ln) transformed values to ensure the data met the assumptions of parametric statistical tests. Mood change Two-dimensional mood scale (TDMS) questionnaires were used to assess psychological states before, during, and after the acute inhilation of hypoxic gas. This scale is employed for the assessment of individual self-monitoring and self-regulation of mood states [ 49 ]. The TDMS is a psychometric scale comprising eight self-assessment items that measure mood using descriptive words such as energetic, lively, lethargic, listless, relaxed, calm, irritated, and nervous. Participants were asked to rate their current mood on a 6-point Likert scale ranging from 0 ("Not at all") to 5 ("Extremely"). The recorded TDMS score was used to calculate the pleasure level of each participant at that specific point in time, which is determined by adding the vitality and stability levels, which range from − 20 to + 20. Statistical analysis Repeated measures analyses of variance (ANOVA) were performed using R Studio software (ver. 4.3.1) to assess variations in the data based on two within-subject factors: two Conditions (NH and NN) and seven Sessions (Pre, Hypoxia 1–2 , and Post 1–4 ). In cases where the assumption of sphericity was violated (as indicated by Mauchly's test statistic with a significance level of p < 0.05), a Greenhouse-Geisser correction was applied. When the ANOVA showed a significant effect, the Bonferroni post-hoc test was used for multiple comparisons. To explore how changes in pleasant mood synchronize with both CVA and psychophysiological stress, induced by hypoxia, we employed the lnRMSSD and the SI for analysis. We conducted repeated measures correlation analysis using R Studio software, equipped with the 'rmcorr' package [ 50 ]. The significance level for all tests was set at p < 0.05. Results Changes in SpO 2 in response to hypoxia and corresponding dynamics in HR and HRV Figure 2 illustrates the alterations in SpO 2 in reaction to low-dose hypoxic stress, accompanied by the corresponding variations in HR and HRV indices. First, SpO 2 , which triggers physiological and autonomical responses as well as representing the severity of hypoxia, showed a significant interaction ( F (1.61, 32.14) = 186.06, p < 0.001, 𝜂 p 2 = 0.903). In the NH condition, SpO 2 levels decreased to approximately 90% during hypoxia, significantly lower than those in the NN condition for both segments: Hypoxia 1 ( F (1, 20) = 250.59, p < 0.001, 𝜂 p 2 = 0.926), Hypoxia 2 ( F (1, 20) = 252.54, p < 0.001, 𝜂 p 2 = 0.927). These levels subsequently returned to their baseline state by the Post 2 segment (Fig. 2 a). The corresponding fluctuation of HR and HRV indices are shown Figs. 2 b-f. HR, which reflects cardiac function in response to hypoxia, revealed a significant interaction ( F (3.50, 69.91) = 48.25, p < 0.001, 𝜂 p 2 = 0.707). Post-hoc comparisons using the Bonferroni correction showed that HR in the NH condition was significantly higher during hypoxia (Hypoxia 1 : F (1, 20) = 8.01, p < 0.01, 𝜂 p 2 = 0.286; Hypoxia 2 : F (1, 20) = 16.22, p < 0.001, 𝜂 p 2 = 0.448) and lower post-hypoxia until Post 3 ( F (1, 20) = 4.87, p = 0.039, 𝜂 p 2 = 0.196) compared to the NN condition, remaining low below their Pre levels up to Post 2 ( p < 0.001) (Fig. 2 b). Figures c and d (lnSDNN and lnRMSSD) illustrate the fluctuations in cardiac autonomic activity in response to hypoxia. Significant interactions were found for both HRV indices: lnSDNN ( F (3.52, 70.37) = 6.28, p < 0.001, 𝜂 p 2 = 0.239) and lnRMSSD ( F (3.42, 68.44) = 20.03, p < 0.001, 𝜂 p 2 = 0.500). Bonferroni corrected post-hoc analysis revealed that lnSDNN in the NH condition was lower during hypoxia (Hypoxia 2 : F (1, 20) = 4.48, p = 0.047, 𝜂 p 2 = 0.183), significantly rebounded during post-hypoxia (Post 1 : F (1, 20) = 8.58, p = 0.008, 𝜂 p 2 = 0.300) compared to the NN condition, and remained higher than their Pre levels up to Post 4 ( p < 0.001) (Fig. 2 c). Similarly, lnRMSSD in the NH condition was lower during hypoxia (Hypoxia 1 : F (1, 20) = 4.64, p = 0.044, 𝜂 p 2 = 0.188; Hypoxia 2 : F (1, 20) = 18.71, p < 0.001, 𝜂 p 2 = 0.483) and significantly rebounded in post-hypoxia (Post 1 : F (1, 20) = 6.75, p = 0.017, 𝜂 p 2 = 0.252) than in the NN condition, remaining elevated above their Pre levels up to Post 2 ( p < 0.05) (Fig. 2 d). These results indicated supercompensation in CVA immediately following hypoxic stress. Figures e and f (lnSDNN/lnRMSSD ratio and SI) illustrate the changes in stress levels triggered by hypoxia. The lnSDNN/lnRMSSD ratio exhibited a significant interaction ( F (6, 120) = 5.98, p < 0.001, 𝜂 p 2 = 0.230). Post-hoc analysis with Bonferroni correction revealed that the lnSDNN/lnRMSSD ratio in the NH condition was significantly higher during hypoxia (Hypoxia 1 : F (1, 20) = 6.98, p = 0.016, 𝜂 p 2 = 0.259; Hypoxia 2 : F (1, 20) = 13.11, p = 0.002, 𝜂 p 2 = 0.396) compared to the NN condition (Fig. 2 e). SI revealed a significant interaction ( F (2.65, 33.96) = 6.24, p = 0.002, 𝜂 p 2 = 0.238). Post-hoc analysis with Bonferroni correction showed that during hypoxia, the SI in the NH condition was significantly higher (Hypoxia 2 : F (1, 20) = 10.52, p = 0.004, 𝜂 p 2 = 0.345) than in the NN condition, and subsequently decreased below Pre levels up to Post 2 ( p = 0.045) (Fig. 2 f). These results show that stress levels temporarily increased during hypoxia, followed by a significant decrease below baseline after the hypoxic stress. There were no significant differences observed between the Pre-session values in either condition for all parameters ( p > 0.5). Comparison of respiratory rate and ventilation We evaluated whether participants maintained consistent respiratory rate and ventilation volume across different conditions and sessions throughout the experiment. A repeated measures two-way ANOVA with experimental conditions (NH, NN) and sessions (Pre, Hypoxia 1–2 , Post 1–4 ) revealed no significant interaction for either respiratory rate ( F (2.68, 53.52) = 0.66, p = 0.566, 𝜂 p 2 = 0.032) or ventilation ( F (2.37, 47.32) = 0.58, p = 0.590, 𝜂 p 2 = 0.028). Variations in pleasant mood with respect to CVA and SI Figure 3 indicates the alternations in pleasure level triggered by low-dose hypoxia and their synchronization with CVA and SI. Repeated measures two-way ANOVA for pleasure level indicated a significant interaction ( F (3.38, 67.55) = 11.02, p < 0.001, 𝜂 p 2 = 0.355). Bonferroni-corrected post hoc comparisons revealed that pleasure levels in the NH condition significantly decreased during hypoxia (Hypoxia 1 : F (1, 20) = 9.16, p = 0.007, 𝜂 p 2 = 0.314; Hypoxia 2 : F (1, 20) = 18.54, p < 0.001, 𝜂 p 2 = 0.481) and subsequently rebounded to levels higher than their Pre levels at Post 1 ( p 0.05). Furthermore, there was a significant correlation between pleasure level and lnRMSSD fluctuation ( r rm (294) = 0.21, p < 0.001) (Fig. 3 b) as well as SI changes ( r rm (294) = -0.13, p = 0.027) (Fig. 3 c). Discussion The primary purpose of the present study was to investigate whether inhaling acute short-term and low-dose hypoxic gas enhances both CVA and related positive mood after transitory hypoxic stress. We observed a supercompensation phenomenon in CVA immediately following the cessation of hypoxic gas inhalation. Moreover, pleasure levels rebounded above the baseline post-hypoxia, correlating with fluctuations in CVA and SI. These results provide practical evidence, for the first time, that briefly inhaling low-dose hypoxic gas as a hormetic stress inducer can improve both CVA and mood following the cessation of inhalation. During acute low-dose hypoxic gas inhalation, we observed significant cardiac vagal withdrawal accompanied by an increase in HR, indicative of heightened sympathetic activation; interestingly, upon cessation of hypoxic gas inhalation, the sympathovagal balance quickly shifted toward more vagal activity dominance, resulting in a decreased HR (Fig. 2 b, d). This vagal rebound phenomenon following relative sympathetic dominance has been well-documented in animal studies involving stimulation of specific regions of the hypothalamus, demonstrating that the sympathovagal balance functions reciprocally [ 51 , 52 ]. Similarly, it is widely recognized that acute physical exercise increases sympathetic activity and inhibits vagal tone, but immediately following exercise, the sympathovagal balance reverses, shifting toward vagal dominance [ 53 , 54 ]. The findings of this study indicate that a similar reciprocal pattern of sympathovagal balance occurs in response to hypoxic stress. Despite the importance of identifying the potential mechanisms that may play a crucial role in the supercompensation of CVA following acute hypoxic stress, these remain largely unexplored. SpO 2 is an acknowledged physiological indicator that influences the rebalancing of sympathovagal activity in response to hypoxia [ 18 , 19 ]. In the NH condition, we observed a positive correlation between the degree of desaturation and the cardiac vagal withdrawal during hypoxia (Hypoxia 2 – Pre; r = 0.473, p = 0.030), as well as a similar correlation between oxygen restoration and CVA recovery post-hypoxia (Post 1 – Hypoxia 2 ; r = 0.625, p = 0.002). However, these alternations in SpO 2 levels did not directly correlate with the amount of CVA rebound (Post 1 – Pre), suggesting the possibility of an unidentified mechanism involving overactivation in CVA after acute hypoxia. Classically, baroreceptor activation has been described as initiating a switch from sympathetic dominance to augmented vagal activity [ 52 ]. Within this framework, physical exercise may provide valuable insights into the potential mechanisms by which changes in post-exercise cardiac baroreflex sensitivity (BRS) contribute to the rebound of CVA after acute physiological stress. Moderate-intensity exercise has been reported to improve cardiac BRS and CVA one hour post-exercise [ 55 , 56 ]. Additionally, vagally mediated cardiac BRS increased three hours after the cessation of graded exercise to exhaustion [ 57 ]. Considering that the recovery of cardiac BRS post-exercise is modulated by exercise intensity [ 58 ], this suggests that the degree of physiological stress may determine the timing of CVA rebound post-stress. Interestingly, one previous study reported a rapid increase in BRS associated with bradycardia following 15 minutes of acute hypoxia (FIO 2 : 11%) [ 22 ]. Based on this evidence, it is postulated that post-inhibitory rebound potentiation of CVA could occur immediately after the acute inhalation of low-dose hypoxic gas, particularly in relation to BRS. Further studies are required to investigate and elucidate the relationship and mechanisms underlying this phenomenon. The additional purpose of this study was to identify the proper hypoxic condition that can trigger a CVA rebound while also remaining safe. Consequently, we adopted a specific hypoxic condition (FIO 2 : 13.5%, 10 minutes). A prior study suggested that CVA might not be significantly changed with 10 minutes of exposure to normobaric hypoxia with an FIO 2 of 15% (SpO 2 = 92.4 ± 0.5% under hypoxia) [ 34 ], suggesting that more severe hypoxic conditions, with lower oxygen levels, might be required to trigger significant fluctuations in CVA. In the present study, we observed that during the initial 5 minutes of hypoxia inhalation (Hypoxia 1 ), lnRMSSD decreased and the lnSDNN/lnRMSSD ratio increased in the NH condition compared to the NN condition (Fig. 2 d, e). A previous study supports our findings, demonstrating a slight shift in the sympathovagal balance towards sympathetic dominance when participants were exposed to 5 minutes of an initial hypoxic condition of FIO 2 of 11.5% (arterial hemoglobin oxygen saturation [SaO 2 ] = 86.6 ± 3.4% under hypoxia) [ 59 ]. Subsequently, in our experiment, in the NH condition, there was a significant decrease in SpO 2 levels to 88.1 ± 0.6% in the Hypoxia 2 segment, which was markedly lower than both the Pre-session and the NN condition (Fig. 2 a). This decrease in SpO 2 levels resulted in a significant cardiac vagal withdrawal, when compared to both the Pre-session and the NN condition. Additionally, our supplementary experiments revealed CVA suppression in a dose-response manner to hypoxia. At an FIO 2 of 16% (equivalent to an altitude of 2,000 m), there was no fluctuation in CVA during and after hypoxia (SpO 2 = 93.0 ± 0.4% in Hypoxia 2 ). However, at an FIO 2 of 9.6% (equivalent to an altitude of 6,200 m), significant suppression of CVA was observed during hypoxia (SpO 2 = 87.5 ± 1.7% in Hypoxia 1 , SpO 2 = 77.2 ± 1.1% in Hypoxia 2 ). Despite this, there was no supercompensation in CVA following hypoxia under this severe hypoxic condition (refer to Supplementary Information for detailed results). It has been reported that a condition with a FIO 2 at 13.5% does not lead to cognitive fatigue during 10 minutes of hypoxia, whereas a condition with an FIO 2 of 10.5% is associated with a decrease in executive function [ 36 ]. Furthermore, symptoms of acute mountain sickness typically manifest within 6 to 12 hours after ascent [ 30 , 60 ]. Taken together, a series of results support our hypothesis that inhaling short-term and low-dose hypoxia (FIO 2 : 13.5% for 10 minutes) has the potential to act as a hormetic stressor that could enhance CVA post-hypoxia while ensuring safety. We found that pleasure levels rebounded immediately following acute hypoxia, and repeated-measures correlation results showed that this psychological fluctuation was significantly correlated with CVA and SI in both conditions (Fig. 3 a-c). It has been suggested that dynamic fluctuations in CVA predict instantaneous changes in psychological mood states, encompassing both negative mental states and emotional reactivity to mental stress [ 61 ]. Our present results are consistent with previous findings that significant rebounds in CVA occur during the initial recovery phase after a bout of psychological stress [ 32 , 33 ]. Interestingly, this phenomenon of enhanced recovery following stress may be related to a sense of pleasure experienced post-stress [ 33 ]. Taken together, these findings suggest that the rebound in CVA following acute hypoxic stress is associated with an improved mood, potentially resulting from reduced psychophysiological stress during recovery from hypoxia. The present study was unable to directly compare diverse hypoxic conditions using a within-subject design, considering it is plausible that prior hypoxic exposures might influence CVA responses in terms of acclimatization. Nevertheless, Fig. 4 provides a rough comparison of CVA rebound across three distinct hypoxic conditions compared to sea level. To investigate whether an FIO 2 of 13.5% is the proper condition for inducing CVA rebound, we monitored changes in CVA and SpO 2 with two other distinct hypoxic conditions: a milder hypoxic condition (FIO 2 : 16.0%) and a more severe hypoxic condition (FIO 2 : 9.6%). Based on our results, an FIO 2 of 13.5% appears to be the proper hypoxic condition for promptly enhancing CVA rebound post-hypoxia, acting as a form of hormetic stress (Fig. 4 ). For detailed results, please refer to the Supplementary Information. Here, we present the clinical evidence of the facilitative effects on both CVA and mood following low-dose hypoxic gas inhalation. Enhanced CVA, typically assessed through HRV, is recognized as a biomarker of improved stress resilience [ 62 , 63 ]. Therefore, short-term and low-dose hypoxia inhalation (e.g., inhaling hypoxic gas with an FIO 2 of 13.5% for 10 minutes) may develop into a feasible approach for resilience-building interventions, serving as a simple and time-efficient method to manage psychophysiological stress in modern society. This proposal is supported by a body of research on intermittent hypoxia, which suggests that modest hypoxia and low-cycle conditions offer substantial therapeutic potential characterized by both safety and efficacy [ 64 ]. Significantly, the CVA measured by HRV has been linked to the top-down regulation originating from the prefrontal cortex, which governs self-regulatory processes, including cognitive function and emotional regulation [ 7 – 10 ]. Considering that vagally-mediated HRV has been shown to be strongly associated with executive functions, in comparison with other cognitive domains [ 65 , 66 ], the increased CVA following hypoxia could have potential clinical implications in this context. Further studies are needed to investigate whether enhanced CVA after short-term and low-dose hypoxia inhalation indeed influences self-regulatory processes in individuals. Conclusion In conclusion, our study demonstrates the facilitation of CVA and associated positive mood changes during periods following hypoxia. These findings highlight the potential of inhaling short-term and low-dose hypoxic gas as a novel approach for rapidly boosting parasympathetic activity and brightening the mood, distinguishing it as a unique and valuable addition to the current array of mindfulness-based interventions. Declarations Acknowledgements The authors are grateful to D. H. Lee (University of Anyang) for analysis support and discussion. We also extend our gratitude to Ms. Melissa Noguchi (ELCS English Language Consultation Services) for her assistance in proofreading the manuscript. Data availability All data supporting the findings of this study are available upon request from the corresponding author, subject to the constraints imposed by the Institutional Ethics Committee of the University of Tsukuba, which safeguards against the disclosure of personal information. Funding This work was supported in part by the Japan Society for the Promotion of Science (JSPS) 16H06405 (H.S.), 18H04081 (H.S.), 21H04858 (H.S.), and 23KJ0248 (D.L.); the Japan Science and Technology Agency (JST) Grant JPMJMI19D5 (H.S.), PMJSP2124 (D.L.). This work was partly supported by the Inviting Overseas Educational Research Units at the University of Tsukuba (2016–2023) (to H.S.). Conflict of interest D.L. and H.S. are named as inventors on patent applications filed both domestically and internationally. 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Gray-colored segments indicate periods of hypoxia in normobaric hypoxia condition\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4609378/v1/c6d19d07c18de33efce66e7c.png"},{"id":60156019,"identity":"9e0f07fb-b1c1-441e-9ea6-c1125199b939","added_by":"auto","created_at":"2024-07-12 11:58:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":712728,"visible":true,"origin":"","legend":"\u003cp\u003eFluctuation of SpO\u003csub\u003e2 \u003c/sub\u003e(\u003cstrong\u003ea\u003c/strong\u003e), heart rate (\u003cstrong\u003eb\u003c/strong\u003e) and HRV indices (\u003cstrong\u003ec-f\u003c/strong\u003e) during the entire experiment for both conditions. \u003cem\u003eNH\u003c/em\u003e normobaric hypoxia, \u003cem\u003eNN\u003c/em\u003e normobaric normoxia, \u003cem\u003eSpO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e saturation of percutaneous oxygen,\u003cem\u003e HR\u003c/em\u003e heart rate,\u003cem\u003e SI\u003c/em\u003e Baevsky stress index. The dashed gray line represents the mean Pre value of the NH condition. The gray colored box represents a 10-minute Hypoxia\u003csup\u003e1-2\u003c/sup\u003e session for both conditions. \u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, and \u003csup\u003e***\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 between two groups; \u003csup\u003ea\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05,\u003csup\u003e aa\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, and \u003csup\u003eaaa\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 compared to Pre-session\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4609378/v1/5bc1a84fdb9782e7324978fa.png"},{"id":60156678,"identity":"8610d7ac-036f-4d75-8f6a-e2a5c0a99bab","added_by":"auto","created_at":"2024-07-12 12:06:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":479366,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in pleasure levels before, during, and after hypoxia and their results for repeated measures relationship with lnRMSSD and SI. Fig. \u003cstrong\u003ea\u003c/strong\u003e: gray box represents the 10-minute Hypoxia\u003csup\u003e1-2\u003c/sup\u003e session for both conditions.\u003cem\u003e NH\u003c/em\u003e normobaric hypoxia, \u003cem\u003eNN\u003c/em\u003e normobaric normoxia. \u003csup\u003e**\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, \u003csup\u003e***\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 between two groups; \u003csup\u003ea\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, \u003csup\u003eaaa\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001 compared to Pre-session. Fig. \u003cstrong\u003eb\u003c/strong\u003e,\u003cstrong\u003ec\u003c/strong\u003e: scatter plots show individual data points (\u003cem\u003eN\u003c/em\u003e = 294) with a data point for each participant. The line in the scatter plot represents the linear regression for each participant. \u003cem\u003eSI\u003c/em\u003e Baevsky stress index.\u0026nbsp;\u003csup\u003e*\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05,\u003csup\u003e***\u003c/sup\u003e\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-4609378/v1/f5ee5687455872277a6259e9.png"},{"id":60156679,"identity":"43f0cdee-de08-4ccb-9211-679a5c537a3f","added_by":"auto","created_at":"2024-07-12 12:06:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":224972,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic illustration of hypoxic dose-dependent vagal response. The left graph illustrates the hormetic stress response in CVA following acute hypoxia, with the vertical double-headed arrow indicating the extent of rebound in CVA (ΔCVA = lnRMSSD\u003csub\u003ePost1\u003c/sub\u003e – lnRMSSD\u003csub\u003epre\u003c/sub\u003e). The plots displayed in the right graph represent FIO\u003csub\u003e2\u003c/sub\u003e levels of 9.6%, 13.5%, 16.0%, and sea level, respectively, arranged in non-equidistant intervals. Data of 13.5% and 20.9% were plotted based on the main results [Fig. 2], and data of 9.6% and 16.0% were drawn based on the supplemental experiment [Fig. S1, S2]. Data are presented as the mean with the gray bands indicating standard error. Note that all three conditions were conducted with different sample sizes. \u003cem\u003eFIO\u003c/em\u003e\u003csub\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sub\u003e fraction of inspired oxygen\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-4609378/v1/76ac3f2856783007567ec5ad.png"},{"id":60157186,"identity":"de130071-4dde-45f6-96b5-139072df7591","added_by":"auto","created_at":"2024-07-12 12:14:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1970474,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4609378/v1/a1b8593d-31a8-48ec-bf77-b482f6134cf8.pdf"},{"id":60156021,"identity":"94b7e152-687e-4bb0-ac72-2ff2434c6ac3","added_by":"auto","created_at":"2024-07-12 11:58:50","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":627530,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryinformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4609378/v1/ca536e2ca4bf0b2b32ece5e7.pdf"}],"financialInterests":"","formattedTitle":"Enhanced Cardiac Vagal Activity and Mood After Low-Dose Hypoxic Gas Inhalation in Healthy Young Adults","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe capability to effectively manage psychophysiological stress is vital for maintaining health, especially given its heightened significance in today's fast-paced society. Cardiac vagal activity (CVA), which represents the dynamic influence of vagally-mediated parasympathetic activity in regulating cardiac function, plays an important role in an individual's resilience to psychophysiological stresses and in preserving homeostasis [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Measuring heart rate variability (HRV) is a non-invasive way to analyze the variations in intervals between successive heartbeats and is primarily utilized to assess CVA [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Higher levels of HRV indicated a greater influence of the vagus nerve on cardiac function, which in turn is associated with greater CVA [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Enhanced CVA has been linked to a better self-regulation process (e.g., cognitive function and emotional regulation), which is fundamentally regulated by prefrontal function [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Given this relationship, strengthening CVA has been recognized as a promising approach to enhancing psychophysiological resource coordination, which is often a primary focus in mindfulness-based interventions (e.g., regular exercise, meditation, biofeedback) [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, given that the quality of mindfulness practice is potentially more crucial than the quantity for achieving beneficial effects [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], maintaining a consistent daily practice that is sufficiently effective can be challenging for the novice, as they may not yet have the skill required for sufficient quality (i.e., early practices may not yield tangible effects). This highlights the necessity for quick and easy methods of mindfulness to apply in daily life.\u003c/p\u003e \u003cp\u003ePrevious studies have provided evidence that long-term intermittent inhalation of hypoxic gas increases parasympathetic activity beyond its initial level, as indicated by enhanced vagal-mediated HRV [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. This suggests that autonomic compensatory regulation may work to augment vagal-mediated parasympathetic activity following exposure to hypoxia, emphasizing hypoxia-induced positive autonomic adaptation to prolonged hypoxic stress. However, the response of CVA following the acute inhalation of hypoxic gas remains unclear. During acute hypoxia, the sympathovagal balance shifts toward sympathetic dominance in a dose-response manner, with decreased saturation of percutaneous oxygen (SpO\u003csub\u003e2\u003c/sub\u003e) leading to cardiac vagal withdrawal and resulting in tachycardia [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, depending on the duration and severity of the initial exposure, the suppressed CVA recovers immediately after hypoxic stress, leading to a decreased heart rate (HR). This indicates that acute hypoxia may trigger a reciprocal action in the sympathovagal balance. It has been reported that exposure to 12 hours of long-term and severe hypoxia (at an altitude of 4,000 m) significantly reduced vagally-mediated HRV, and this effect persisted even beyond the first hour of recovery under normoxic conditions [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. On the other hand, after 15 minutes of short-term and severe hypoxic exposure (fraction of inspired oxygen [FIO\u003csub\u003e2\u003c/sub\u003e]: 11%, equivalent to an altitude of 4,800 m), vagally-mediated HRV returned to its original levels within 20 minutes, and HR significantly decreased below baseline levels [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Interestingly, just 6 minutes after a 10-minute exposure to hypoxia (FIO\u003csub\u003e2\u003c/sub\u003e: 9.6%, equivalent to an altitude of 6,200 m), the global HRV (i.e., overall autonomic activity) rebounded above the baseline level, accompanied by bradycardia in females [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A series of previous studies suggest that acute, short-term inhalation of hypoxic gas may trigger cardiac parasympathetic overactivation, manifesting as bradycardia following hypoxic stress. However, these studies have so far primarily focused on severe hypoxia, so the proper hypoxic conditions to potentially improve CVA after acute hypoxia have not yet been clearly identified. According to the hormesis principle, low doses of a stressor typically induce a positive adaptive response with potential beneficial effects, whereas high doses generally result in detrimental effects [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This biological concept leads us to hypothesize that the hormetic region of hypoxia (i.e., supercompensation in CVA following acute hypoxic stress) is located at milder levels than in previous studies. Physical exercise, similar to the physiological stressor of hypoxia, has been widely demonstrated to support the hormesis principle [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Consistent with this, our accumulated findings strongly suggest that milder levels of exercise have beneficial effects on brain function [\u003cspan additionalcitationids=\"CR26 CR27 CR28\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], further supporting this hypothesis. Based on our empirical evidence, it is possible that levels of hypoxia milder than those previously studied may exist, which could act as hormetic stressors.\u003c/p\u003e \u003cp\u003eThe major physiological reason for the deterioration of vagal-mediated HRV under hypoxic conditions is decreased SpO\u003csub\u003e2\u003c/sub\u003e, which leads to cardiac vagal withdrawal. However, changes in psychological factors resulting from the acute fluctuation of CVA during hypoxia may also contribute to this effect. The acute deterioration in CVA that occurs during the initial stage of hypoxic stress can influence the psychological state, highlighting the importance of evaluating acute mountain-sickness symptoms in high-altitude areas after 6 hours of climbing to avoid potential confounding effects from initial vagal responses [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Several previous studies have consistently shown a strong association between suppressed CVA and negative psychological conditions, such as major depressive disorder, generalized anxiety disorder, and other forms of negative emotional states [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, it is interesting to note that significant rebounds in CVA occur during the initial recovery phase after a bout of psychological stress [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and this phenomenon is potentially associated with changes in pleasant mood following psychological stress [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This relationship implies that the rebound of CVA may indicate underlying emotional and psychological states associated with pleasant mood conditions following stress.\u003c/p\u003e \u003cp\u003eWhile various studies have indicated potential positive effects in CVA after the inhalation of hypoxic gas, the majority of these studies have concentrated on relatively severe and prolonged hypoxic conditions. It has been reported that an FIO\u003csub\u003e2\u003c/sub\u003e of 15% might not lead to changes in CVA [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], indicating the existence of a hormetic region above this level where benefits can be observed. Nonetheless, severe hypoxic conditions can evoke acute mountain sickness (e.g., headaches, nausea, dizziness) [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e] and can also cause cognitive fatigue characterized by impaired executive function in the prefrontal cortex, even during short-term hypoxia [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. This raises concerns regarding the safety of deliberately triggering acute hypoxia, despite its potential benefits. Furthermore, to the best of our knowledge, no prior study has explored the relationship between acute fluctuations in CVA and emotional states in relation to acute hypoxia. Therefore, in this study, our primary purposes were twofold: 1) to investigate whether short-term inhalation of acute low-dose hypoxia at an FIO\u003csub\u003e2\u003c/sub\u003e of 13.5% enhances CVA after hypoxic stress, and 2) to examine whether fluctuation of CVA is associated with mood changes, particularly pleasant states.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eTwenty-one healthy, non-smoking young adults who had not been exposed to normobaric hypoxia or an altitude greater than 3,500 m within two years of their participation were included in this study. Because vagal-mediated HRV is vulnerable to adverse emotional arousal responses linked to psychological stress, depression, and sleep disorders, all participants underwent pre-screening with relevant self-report questionnaires [\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. The screening criteria included specific cutoff scores on the Beck Depression Inventory (BDI), the Center for Epidemiologic Studies Depression Scale (CESD), and the Pittsburgh Sleep Quality Index (PSQI). Through G*Power 3.1 analysis, we determined that a minimum of 18 participants were required to achieve a power of 0.80, a two-sided alpha of 0.05, and a medium effect size (Cohen's f\u0026thinsp;=\u0026thinsp;0.25) in this experiment. The Institutional Ethics Committee of Tsukuba University approved this study, and all participants provided written informed consent before the experiments. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents a detailed list of the characteristics of the participants.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnthropological characteristics and psychological states\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAnthropological Characteristics\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 / 6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (yr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e168.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePsychological States\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCESD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBDI-II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSQI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eValues are mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eBMI\u003c/em\u003e Body Mass Index, \u003cem\u003eCESD\u003c/em\u003e Center for Epidemiologic Studies Depression Scale, \u003cem\u003eBDI-II\u003c/em\u003e Beck Depression Inventory-II, \u003cem\u003ePSQI\u003c/em\u003e Pittsburgh Sleep Quality Index\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eExperimental protocol\u003c/h2\u003e \u003cp\u003eAll experiments were carried out between 9 am and 5 pm, and a consistent laboratory temperature of 22 to 24 degrees Celsius was ensured. Participants were instructed to abstain from consuming coffee, tea, or medications that could directly affect sympathovagal balance or engaging in exhaustive physical exercise 24 hours prior to the experiment. Each participant's psychophysiological condition (e.g., mental health and physical activity for the day) was checked prior to the experiment to ensure they were in an appropriate state. As recommended by Task Force [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], participants were directed to adopt a seated position with their eyes closed for 5 minutes in a quiet, noise-free environment prior to beginning the experiments, ensuring they reached a stable state. Each participant participated in both a normobaric hypoxia (NH) condition and a normobaric normoxia (NN) condition, with each condition taking place in random order on different days at the same time of day, employing a single-blind, counterbalanced design. All participants were seated at rest on an ergometer in normoxia for 5 minutes, followed by 10 minutes of exposure to either hypoxic gas (NH; FIO\u003csub\u003e2\u003c/sub\u003e: 13.5%, corresponding to an altitude of 3,500 m) or ambient air (NN; FIO\u003csub\u003e2\u003c/sub\u003e: 20.9%, sea level). After inhalation, participants rested for 20 minutes while inhaling ambient air. The hypoxic gas mixture was prepared in advance of the experiment and stored in a 250-liter Douglas bag generated through a hypoxicator (Everest Summit II, Will Co. Ltd., Tokyo, Japan). In the NH condition, gas inhalation was switched (either from normoxia to hypoxia or from hypoxia to normoxia) by attaching and detaching a gas hose connected to Douglas bags supplying hypoxic gas or ambient air to the mask. To account for the experimental design and control for the potential impact of the hose on psychophysiological factors, the NN condition was conducted in the same way as the NH condition, but with participants inhaling ambient air. The mood was assessed every 5 minutes. Throughout the experiment, SpO\u003csub\u003e2\u003c/sub\u003e, HR, and electrocardiogram (ECG) signals were monitored continuously, and the data were sampled as 5-minute averages for each of the seven sessions (Pre, Normoxia\u003csup\u003e1\u0026ndash;2\u003c/sup\u003e or Hypoxia\u003csup\u003e1\u0026ndash;2\u003c/sup\u003e, Post\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e). The summarized experimental design is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSpO\u003csub\u003e2\u003c/sub\u003e, ventilation, and respiratory rate\u003c/h2\u003e \u003cp\u003eThe SpO\u003csub\u003e2\u003c/sub\u003e levels were continuously monitored using a pulse oximeter (OLV-3100, Nihon Kohden, Japan) placed on the right index finger, and the data were recorded in real-time through an A/D converter (PowerLab, AD Instruments, Colorado Springs, CO, USA). Given the susceptibility of short-term HRV to ventilation and frequency of respiration [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e], we continuously monitored both indices using breath-by-breath methods with a gas analyzer (Aeromonitor AE300, Minato Medical Science, Osaka, Japan) throughout the experiments. Although the respiratory rate was not controlled during the experiment, participants were instructed to breathe normally and maintain a regular breathing pattern.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eHeart rate variability\u003c/h2\u003e \u003cp\u003eThe ECG signal was recorded continuously using an A/D converter at a sampling rate of 1,000 Hz throughout the experiment. After removing abnormal beats, the HRV analysis was computed based on 256 NN interval segments within the 300 s recorded during the Pre, Hypoxia\u003csup\u003e1\u0026ndash;2\u003c/sup\u003e, and Post\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e periods to ensure data stability. The time-domain analysis of HRV was chosen for the current study because it is appropriate for short-term analysis and is resilient to variations in respiratory rate, offering a reliable assessment of cardiac autonomic modulation [\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. The standard deviation of normal-to-normal intervals (SDNN) was evaluated as a measure of the global HRV activity and the root mean square of successive differences (RMSSD) were evaluated as a measure of parasympathetic nervous activity, specifically reflecting CVA. The SDNN/RMSSD ratio was used to calculate the sympathovagal balance, which is a measure of the interaction between sympathetic and parasympathetic nervous activity [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Additionally, we employed the square root of the Baevsky stress index (SI), a geometric indicator of HRV, to assess the psychophysiological stress induced by hypoxia [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The SI was normalized and calculated using the following equation: SI\u0026thinsp;=\u0026thinsp;AM\u003csub\u003eo\u003c/sub\u003e/2M\u003csub\u003eo\u003c/sub\u003e*M\u003csub\u003ex\u003c/sub\u003eDM\u003csub\u003en\u003c/sub\u003e [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The mode (M\u003csub\u003eo\u003c/sub\u003e) indicates the most frequently observed value in the dynamic sequence of cardiac intervals, indicating the most common HR interval during a given measurement period. The amplitude of the mode (AM\u003csub\u003eo\u003c/sub\u003e) quantifies the proportion of cardiac intervals that correspond to the mode value, expressed as a percentage. The variation scope (M\u003csub\u003ex\u003c/sub\u003eDM\u003csub\u003en\u003c/sub\u003e) represents the range of variability among cardiac interval values within the dynamic sequence, offering a gauge of the heart rate's fluctuation range. These parameters are calculated using data from variational pulsometry, a technique for assessing the variability and dynamics of pulse rate. These data were then analyzed for HRV with the Kubios HRV software (Kubios Oy, Kuopio, Finland), using 5-minute segments for short-term analysis. Since the indices of SDNN and RMSSD were not normally distributed according to the Kolmogorov-Smirnov test, all analyses were conducted on the natural logarithm (ln) transformed values to ensure the data met the assumptions of parametric statistical tests.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMood change\u003c/h2\u003e \u003cp\u003eTwo-dimensional mood scale (TDMS) questionnaires were used to assess psychological states before, during, and after the acute inhilation of hypoxic gas. This scale is employed for the assessment of individual self-monitoring and self-regulation of mood states [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. The TDMS is a psychometric scale comprising eight self-assessment items that measure mood using descriptive words such as energetic, lively, lethargic, listless, relaxed, calm, irritated, and nervous. Participants were asked to rate their current mood on a 6-point Likert scale ranging from 0 (\"Not at all\") to 5 (\"Extremely\"). The recorded TDMS score was used to calculate the pleasure level of each participant at that specific point in time, which is determined by adding the vitality and stability levels, which range from \u0026minus;\u0026thinsp;20 to +\u0026thinsp;20.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eRepeated measures analyses of variance (ANOVA) were performed using R Studio software (ver. 4.3.1) to assess variations in the data based on two within-subject factors: two Conditions (NH and NN) and seven Sessions (Pre, Hypoxia\u003csup\u003e1\u0026ndash;2\u003c/sup\u003e, and Post\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e). In cases where the assumption of sphericity was violated (as indicated by Mauchly's test statistic with a significance level of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), a Greenhouse-Geisser correction was applied. When the ANOVA showed a significant effect, the Bonferroni post-hoc test was used for multiple comparisons. To explore how changes in pleasant mood synchronize with both CVA and psychophysiological stress, induced by hypoxia, we employed the lnRMSSD and the SI for analysis. We conducted repeated measures correlation analysis using R Studio software, equipped with the 'rmcorr' package [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. The significance level for all tests was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eChanges in SpO\u003csub\u003e2\u003c/sub\u003e in response to hypoxia and corresponding dynamics in HR and HRV\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the alterations in SpO\u003csub\u003e2\u003c/sub\u003e in reaction to low-dose hypoxic stress, accompanied by the corresponding variations in HR and HRV indices. First, SpO\u003csub\u003e2\u003c/sub\u003e, which triggers physiological and autonomical responses as well as representing the severity of hypoxia, showed a significant interaction (\u003cem\u003eF\u003c/em\u003e (1.61, 32.14)\u0026thinsp;=\u0026thinsp;186.06, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.903). In the NH condition, SpO\u003csub\u003e2\u003c/sub\u003e levels decreased to approximately 90% during hypoxia, significantly lower than those in the NN condition for both segments: Hypoxia\u003csup\u003e1\u003c/sup\u003e (\u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;250.59, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.926), Hypoxia\u003csup\u003e2\u003c/sup\u003e (\u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;252.54, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.927). These levels subsequently returned to their baseline state by the Post\u003csup\u003e2\u003c/sup\u003e segment (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The corresponding fluctuation of HR and HRV indices are shown Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb-f. HR, which reflects cardiac function in response to hypoxia, revealed a significant interaction (\u003cem\u003eF\u003c/em\u003e (3.50, 69.91)\u0026thinsp;=\u0026thinsp;48.25, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.707). Post-hoc comparisons using the Bonferroni correction showed that HR in the NH condition was significantly higher during hypoxia (Hypoxia\u003csup\u003e1\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;8.01, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.286; Hypoxia\u003csup\u003e2\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;16.22, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.448) and lower post-hypoxia until Post\u003csup\u003e3\u003c/sup\u003e (\u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;4.87, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.196) compared to the NN condition, remaining low below their Pre levels up to Post\u003csup\u003e2\u003c/sup\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Figures c and d (lnSDNN and lnRMSSD) illustrate the fluctuations in cardiac autonomic activity in response to hypoxia. Significant interactions were found for both HRV indices: lnSDNN (\u003cem\u003eF\u003c/em\u003e (3.52, 70.37)\u0026thinsp;=\u0026thinsp;6.28, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.239) and lnRMSSD (\u003cem\u003eF\u003c/em\u003e (3.42, 68.44)\u0026thinsp;=\u0026thinsp;20.03, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.500). Bonferroni corrected post-hoc analysis revealed that lnSDNN in the NH condition was lower during hypoxia (Hypoxia\u003csup\u003e2\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;4.48, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.183), significantly rebounded during post-hypoxia (Post\u003csup\u003e1\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;8.58, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.300) compared to the NN condition, and remained higher than their Pre levels up to Post\u003csup\u003e4\u003c/sup\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Similarly, lnRMSSD in the NH condition was lower during hypoxia (Hypoxia\u003csup\u003e1\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;4.64, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.188; Hypoxia\u003csup\u003e2\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;18.71, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.483) and significantly rebounded in post-hypoxia (Post\u003csup\u003e1\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;6.75, \u003cem\u003ep\u003c/em\u003e = 0.017, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.252) than in the NN condition, remaining elevated above their Pre levels up to Post\u003csup\u003e2\u003c/sup\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). These results indicated supercompensation in CVA immediately following hypoxic stress. Figures e and f (lnSDNN/lnRMSSD ratio and SI) illustrate the changes in stress levels triggered by hypoxia. The lnSDNN/lnRMSSD ratio exhibited a significant interaction (\u003cem\u003eF\u003c/em\u003e (6, 120)\u0026thinsp;=\u0026thinsp;5.98, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.230). Post-hoc analysis with Bonferroni correction revealed that the lnSDNN/lnRMSSD ratio in the NH condition was significantly higher during hypoxia (Hypoxia\u003csup\u003e1\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;6.98, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.259; Hypoxia\u003csup\u003e2\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;13.11, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.396) compared to the NN condition (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee). SI revealed a significant interaction (\u003cem\u003eF\u003c/em\u003e (2.65, 33.96)\u0026thinsp;=\u0026thinsp;6.24, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.238). Post-hoc analysis with Bonferroni correction showed that during hypoxia, the SI in the NH condition was significantly higher (Hypoxia\u003csup\u003e2\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;10.52, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.345) than in the NN condition, and subsequently decreased below Pre levels up to Post\u003csup\u003e2\u003c/sup\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ef). These results show that stress levels temporarily increased during hypoxia, followed by a significant decrease below baseline after the hypoxic stress. There were no significant differences observed between the Pre-session values in either condition for all parameters (\u003cem\u003ep\u003c/em\u003e \u0026gt; 0.5).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComparison of respiratory rate and ventilation\u003c/h2\u003e \u003cp\u003eWe evaluated whether participants maintained consistent respiratory rate and ventilation volume across different conditions and sessions throughout the experiment. A repeated measures two-way ANOVA with experimental conditions (NH, NN) and sessions (Pre, Hypoxia\u003csup\u003e1\u0026ndash;2\u003c/sup\u003e, Post\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e) revealed no significant interaction for either respiratory rate (\u003cem\u003eF\u003c/em\u003e (2.68, 53.52)\u0026thinsp;=\u0026thinsp;0.66, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.566, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.032) or ventilation (\u003cem\u003eF\u003c/em\u003e (2.37, 47.32)\u0026thinsp;=\u0026thinsp;0.58, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.590, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.028).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eVariations in pleasant mood with respect to CVA and SI\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e indicates the alternations in pleasure level triggered by low-dose hypoxia and their synchronization with CVA and SI. Repeated measures two-way ANOVA for pleasure level indicated a significant interaction (\u003cem\u003eF\u003c/em\u003e (3.38, 67.55)\u0026thinsp;=\u0026thinsp;11.02, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.355). Bonferroni-corrected post hoc comparisons revealed that pleasure levels in the NH condition significantly decreased during hypoxia (Hypoxia\u003csup\u003e1\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;9.16, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.314; Hypoxia\u003csup\u003e2\u003c/sup\u003e: \u003cem\u003eF\u003c/em\u003e (1, 20)\u0026thinsp;=\u0026thinsp;18.54, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u0026#120578;\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.481) and subsequently rebounded to levels higher than their Pre levels at Post\u003csup\u003e1\u003c/sup\u003e (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). No significant differences were observed in the pre-session values between either condition (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Furthermore, there was a significant correlation between pleasure level and lnRMSSD fluctuation (\u003cem\u003er\u003c/em\u003e\u003csub\u003e\u003cem\u003erm\u003c/em\u003e\u003c/sub\u003e (294)\u0026thinsp;=\u0026thinsp;0.21, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb) as well as SI changes (\u003cem\u003er\u003c/em\u003e\u003csub\u003e\u003cem\u003erm\u003c/em\u003e\u003c/sub\u003e (294) = -0.13, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe primary purpose of the present study was to investigate whether inhaling acute short-term and low-dose hypoxic gas enhances both CVA and related positive mood after transitory hypoxic stress. We observed a supercompensation phenomenon in CVA immediately following the cessation of hypoxic gas inhalation. Moreover, pleasure levels rebounded above the baseline post-hypoxia, correlating with fluctuations in CVA and SI. These results provide practical evidence, for the first time, that briefly inhaling low-dose hypoxic gas as a hormetic stress inducer can improve both CVA and mood following the cessation of inhalation.\u003c/p\u003e \u003cp\u003eDuring acute low-dose hypoxic gas inhalation, we observed significant cardiac vagal withdrawal accompanied by an increase in HR, indicative of heightened sympathetic activation; interestingly, upon cessation of hypoxic gas inhalation, the sympathovagal balance quickly shifted toward more vagal activity dominance, resulting in a decreased HR (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb, d). This vagal rebound phenomenon following relative sympathetic dominance has been well-documented in animal studies involving stimulation of specific regions of the hypothalamus, demonstrating that the sympathovagal balance functions reciprocally [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Similarly, it is widely recognized that acute physical exercise increases sympathetic activity and inhibits vagal tone, but immediately following exercise, the sympathovagal balance reverses, shifting toward vagal dominance [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The findings of this study indicate that a similar reciprocal pattern of sympathovagal balance occurs in response to hypoxic stress.\u003c/p\u003e \u003cp\u003eDespite the importance of identifying the potential mechanisms that may play a crucial role in the supercompensation of CVA following acute hypoxic stress, these remain largely unexplored. SpO\u003csub\u003e2\u003c/sub\u003e is an acknowledged physiological indicator that influences the rebalancing of sympathovagal activity in response to hypoxia [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In the NH condition, we observed a positive correlation between the degree of desaturation and the cardiac vagal withdrawal during hypoxia (Hypoxia\u003csup\u003e2\u003c/sup\u003e \u0026ndash; Pre; \u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.473, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030), as well as a similar correlation between oxygen restoration and CVA recovery post-hypoxia (Post\u003csup\u003e1\u003c/sup\u003e \u0026ndash; Hypoxia\u003csup\u003e2\u003c/sup\u003e; \u003cem\u003er\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.625, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002). However, these alternations in SpO\u003csub\u003e2\u003c/sub\u003e levels did not directly correlate with the amount of CVA rebound (Post\u003csup\u003e1\u003c/sup\u003e \u0026ndash; Pre), suggesting the possibility of an unidentified mechanism involving overactivation in CVA after acute hypoxia. Classically, baroreceptor activation has been described as initiating a switch from sympathetic dominance to augmented vagal activity [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]. Within this framework, physical exercise may provide valuable insights into the potential mechanisms by which changes in post-exercise cardiac baroreflex sensitivity (BRS) contribute to the rebound of CVA after acute physiological stress. Moderate-intensity exercise has been reported to improve cardiac BRS and CVA one hour post-exercise [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Additionally, vagally mediated cardiac BRS increased three hours after the cessation of graded exercise to exhaustion [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Considering that the recovery of cardiac BRS post-exercise is modulated by exercise intensity [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e], this suggests that the degree of physiological stress may determine the timing of CVA rebound post-stress. Interestingly, one previous study reported a rapid increase in BRS associated with bradycardia following 15 minutes of acute hypoxia (FIO\u003csub\u003e2\u003c/sub\u003e: 11%) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Based on this evidence, it is postulated that post-inhibitory rebound potentiation of CVA could occur immediately after the acute inhalation of low-dose hypoxic gas, particularly in relation to BRS. Further studies are required to investigate and elucidate the relationship and mechanisms underlying this phenomenon.\u003c/p\u003e \u003cp\u003eThe additional purpose of this study was to identify the proper hypoxic condition that can trigger a CVA rebound while also remaining safe. Consequently, we adopted a specific hypoxic condition (FIO\u003csub\u003e2\u003c/sub\u003e: 13.5%, 10 minutes). A prior study suggested that CVA might not be significantly changed with 10 minutes of exposure to normobaric hypoxia with an FIO\u003csub\u003e2\u003c/sub\u003e of 15% (SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;92.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5% under hypoxia) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], suggesting that more severe hypoxic conditions, with lower oxygen levels, might be required to trigger significant fluctuations in CVA. In the present study, we observed that during the initial 5 minutes of hypoxia inhalation (Hypoxia\u003csup\u003e1\u003c/sup\u003e), lnRMSSD decreased and the lnSDNN/lnRMSSD ratio increased in the NH condition compared to the NN condition (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed, e). A previous study supports our findings, demonstrating a slight shift in the sympathovagal balance towards sympathetic dominance when participants were exposed to 5 minutes of an initial hypoxic condition of FIO\u003csub\u003e2\u003c/sub\u003e of 11.5% (arterial hemoglobin oxygen saturation [SaO\u003csub\u003e2\u003c/sub\u003e]\u0026thinsp;=\u0026thinsp;86.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4% under hypoxia) [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. Subsequently, in our experiment, in the NH condition, there was a significant decrease in SpO\u003csub\u003e2\u003c/sub\u003e levels to 88.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6% in the Hypoxia\u003csup\u003e2\u003c/sup\u003e segment, which was markedly lower than both the Pre-session and the NN condition (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). This decrease in SpO\u003csub\u003e2\u003c/sub\u003e levels resulted in a significant cardiac vagal withdrawal, when compared to both the Pre-session and the NN condition. Additionally, our supplementary experiments revealed CVA suppression in a dose-response manner to hypoxia. At an FIO\u003csub\u003e2\u003c/sub\u003e of 16% (equivalent to an altitude of 2,000 m), there was no fluctuation in CVA during and after hypoxia (SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;93.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4% in Hypoxia\u003csup\u003e2\u003c/sup\u003e). However, at an FIO\u003csub\u003e2\u003c/sub\u003e of 9.6% (equivalent to an altitude of 6,200 m), significant suppression of CVA was observed during hypoxia (SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;87.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7% in Hypoxia\u003csup\u003e1\u003c/sup\u003e, SpO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;77.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1% in Hypoxia\u003csup\u003e2\u003c/sup\u003e). Despite this, there was no supercompensation in CVA following hypoxia under this severe hypoxic condition (refer to Supplementary Information for detailed results). It has been reported that a condition with a FIO\u003csub\u003e2\u003c/sub\u003e at 13.5% does not lead to cognitive fatigue during 10 minutes of hypoxia, whereas a condition with an FIO\u003csub\u003e2\u003c/sub\u003e of 10.5% is associated with a decrease in executive function [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Furthermore, symptoms of acute mountain sickness typically manifest within 6 to 12 hours after ascent [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. Taken together, a series of results support our hypothesis that inhaling short-term and low-dose hypoxia (FIO\u003csub\u003e2\u003c/sub\u003e: 13.5% for 10 minutes) has the potential to act as a hormetic stressor that could enhance CVA post-hypoxia while ensuring safety.\u003c/p\u003e \u003cp\u003eWe found that pleasure levels rebounded immediately following acute hypoxia, and repeated-measures correlation results showed that this psychological fluctuation was significantly correlated with CVA and SI in both conditions (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea-c). It has been suggested that dynamic fluctuations in CVA predict instantaneous changes in psychological mood states, encompassing both negative mental states and emotional reactivity to mental stress [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. Our present results are consistent with previous findings that significant rebounds in CVA occur during the initial recovery phase after a bout of psychological stress [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Interestingly, this phenomenon of enhanced recovery following stress may be related to a sense of pleasure experienced post-stress [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Taken together, these findings suggest that the rebound in CVA following acute hypoxic stress is associated with an improved mood, potentially resulting from reduced psychophysiological stress during recovery from hypoxia.\u003c/p\u003e \u003cp\u003eThe present study was unable to directly compare diverse hypoxic conditions using a within-subject design, considering it is plausible that prior hypoxic exposures might influence CVA responses in terms of acclimatization. Nevertheless, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e provides a rough comparison of CVA rebound across three distinct hypoxic conditions compared to sea level. To investigate whether an FIO\u003csub\u003e2\u003c/sub\u003e of 13.5% is the proper condition for inducing CVA rebound, we monitored changes in CVA and SpO\u003csub\u003e2\u003c/sub\u003e with two other distinct hypoxic conditions: a milder hypoxic condition (FIO\u003csub\u003e2\u003c/sub\u003e: 16.0%) and a more severe hypoxic condition (FIO\u003csub\u003e2\u003c/sub\u003e: 9.6%). Based on our results, an FIO\u003csub\u003e2\u003c/sub\u003e of 13.5% appears to be the proper hypoxic condition for promptly enhancing CVA rebound post-hypoxia, acting as a form of hormetic stress (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). For detailed results, please refer to the Supplementary Information.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHere, we present the clinical evidence of the facilitative effects on both CVA and mood following low-dose hypoxic gas inhalation. Enhanced CVA, typically assessed through HRV, is recognized as a biomarker of improved stress resilience [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Therefore, short-term and low-dose hypoxia inhalation (e.g., inhaling hypoxic gas with an FIO\u003csub\u003e2\u003c/sub\u003e of 13.5% for 10 minutes) may develop into a feasible approach for resilience-building interventions, serving as a simple and time-efficient method to manage psychophysiological stress in modern society. This proposal is supported by a body of research on intermittent hypoxia, which suggests that modest hypoxia and low-cycle conditions offer substantial therapeutic potential characterized by both safety and efficacy [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Significantly, the CVA measured by HRV has been linked to the top-down regulation originating from the prefrontal cortex, which governs self-regulatory processes, including cognitive function and emotional regulation [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Considering that vagally-mediated HRV has been shown to be strongly associated with executive functions, in comparison with other cognitive domains [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e], the increased CVA following hypoxia could have potential clinical implications in this context. Further studies are needed to investigate whether enhanced CVA after short-term and low-dose hypoxia inhalation indeed influences self-regulatory processes in individuals.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study demonstrates the facilitation of CVA and associated positive mood changes during periods following hypoxia. These findings highlight the potential of inhaling short-term and low-dose hypoxic gas as a novel approach for rapidly boosting parasympathetic activity and brightening the mood, distinguishing it as a unique and valuable addition to the current array of mindfulness-based interventions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to D. H. Lee (University of Anyang) for analysis support and discussion. We also extend our gratitude to Ms. Melissa Noguchi (ELCS English Language Consultation Services) for her assistance in proofreading the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data supporting the findings of this study are available upon request from the corresponding author, subject to the constraints imposed by the Institutional Ethics Committee of the University of Tsukuba, which safeguards against the disclosure of personal information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis work was supported in part by the Japan Society for the Promotion of Science (JSPS) 16H06405 (H.S.), 18H04081 (H.S.), 21H04858 (H.S.), and 23KJ0248 (D.L.); the Japan Science and Technology Agency (JST) Grant JPMJMI19D5 (H.S.), PMJSP2124 (D.L.). This work was partly supported by the Inviting Overseas Educational Research Units at the University of Tsukuba (2016\u0026ndash;2023) (to H.S.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eD.L. and H.S. are named as inventors on patent applications filed both domestically and internationally.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWeber CS, Thayer JF, Rudat M, Wirtz PH, Zimmermann-Viehoff F, Thomas A, Perschel FH, Arck PC, Deter HC (2010) Low vagal tone is associated with impaired post stress recovery of cardiovascular, endocrine, and immune markers. 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Front Neurosci 13:436204. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fnins.2019.00710\u003c/span\u003e\u003cspan address=\"10.3389/fnins.2019.00710\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Low-dose hypoxia, Autonomic nervous system, Cardiac vagal activity, Supercompensation, Pleasant mood","lastPublishedDoi":"10.21203/rs.3.rs-4609378/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4609378/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eDeveloping mindfulness-based strategies to efficiently improve cardiac vagal activity (CVA) is crucial for enhancing mood and managing stress. Recent studies have suggested that inhaling hypoxic gas could enhance CVA. However, the dynamics of CVA in response to acute hypoxia remain unelucidated, indicating that the proper hypoxic conditions expected to trigger the hormetic stress effect on CVA are unknown. Therefore, we aimed to achieve a comprehensive understanding of the hypoxic conditions required to improve CVA and mood following hypoxia.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTwenty-one healthy adults were assigned to participate in both hypoxic (NH) and normoxic (NN) conditions. Heart rate variability, saturation of percutaneous oxygen (SpO\u003csub\u003e2\u003c/sub\u003e), and mood were monitored across the following sessions: Pre (5 min), Hypoxia\u003csup\u003e1\u0026ndash;2\u003c/sup\u003e (10 min; NH, fraction of inspiratory oxygen (FIO\u003csub\u003e2\u003c/sub\u003e): 13.5% or NN, FIO\u003csub\u003e2\u003c/sub\u003e: 20.9%), and Post\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e (20 min). The Baevsky stress index (SI) was incorporated into the square root. For time domain analysis of CVA, both the standard deviation of NN intervals (SDNN) and the root mean square of successive differences (RMSSD) were utilized.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn the NH condition, SpO\u003csub\u003e2\u003c/sub\u003e decreased to 88.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6 during hypoxia, accompanied by reductions in log transformed (ln) SDNN and lnRMSSD. After hypoxia, both indicators rebounded, exhibiting a supercompensation phenomenon. Pleasure levels declined during hypoxia but rapidly rebounded afterward, which was linked to fluctuations in lnRMSSD and SI.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eWe discovered that acute short-term inhalation of low-dose hypoxic gas with an FIO\u003csub\u003e2\u003c/sub\u003e of 13.5% enhances both CVA and mood following hypoxia. This strategy could provide a practical resilience-building method.\u003c/p\u003e","manuscriptTitle":"Enhanced Cardiac Vagal Activity and Mood After Low-Dose Hypoxic Gas Inhalation in Healthy Young Adults","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-12 11:58:44","doi":"10.21203/rs.3.rs-4609378/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-06-25T23:54:15+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-21T14:53:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-21T13:52:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Autonomic Research","date":"2024-06-20T01:49:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9e7bcc02-29c5-44ac-8c63-aa5aa9cd0595","owner":[],"postedDate":"July 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-09-03T00:08:44+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-12 11:58:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4609378","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4609378","identity":"rs-4609378","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}