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ZHANG Hao, FENG Jie, ZHANG Shi Yu, LIU Wen Jia, MA Lin. Predicting Acute Mountain Sickness by Using Sea-level Regional Cerebral Blood Flow[J]. Biomedical and Environmental Sciences. doi: 10.3967/bes2024.100
Citation: ZHANG Hao, FENG Jie, ZHANG Shi Yu, LIU Wen Jia, MA Lin. Predicting Acute Mountain Sickness by Using Sea-level Regional Cerebral Blood Flow[J]. Biomedical and Environmental Sciences. doi: 10.3967/bes2024.100

Predicting Acute Mountain Sickness by Using Sea-level Regional Cerebral Blood Flow

doi: 10.3967/bes2024.100
Funds:  This work was supported by the National Natural Science Foundation of China (No.81741115), Military Creative Project (No. 16CXZ014), and Military Healthcare Project (No. 16BJZ11).
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  • Author Bio:

    ZHANG Hao, female, born in 1994, PhD. student, majoring in radiology

    FENG Jie, male, born in 1984, PhD., majoring in radiology

  • Corresponding author: MA Lin, Chief Physician, MD., PhD., Email: cjr.malin@vip.163.com
  • MA Lin, FENG Jie and ZHANG Hao conceived and designed research. FENG Jie, ZHANG Shi Yu, and LIU Wen Jia recruited volunteers and performed experiments. ZHANG Hao, FENG Jie and ZHANG Shi Yu performed data analysis. ZHANG Hao and FENG Jie interpreted results of experiments. ZHANG Hao prepared figures and drafted manuscript. ZHANG Hao, FENG Jie and MA Lin edited and revised manuscript. MA Lin approved final version of manuscript. All the authors have read and approved the final version of the manuscript.
  • The authors declare that they have no conflict of interests.
  • &These authors contributed equally to this work.
  • Received Date: 2024-03-25
  • Accepted Date: 2024-05-27
  •   Objective   We aim to investigate the role of sea-level cerebral blood flow (CBF) in the prediction of acute mountain sickness (AMS) by using three-dimensional pseudo-continuous arterial spin labeling (3D-pCASL).  Methods   Forty-eight healthy volunteers reached an altitude of 3650 m by air after receiving head MR scan including 3D-pCASL at sea level. The CBF value of bilateral anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), and posterior inferior cerebellar artery (PICA) territories and laterality index (LI) of CBF were compared between AMS and non-AMS groups. Statistical analyses were applied to determine the relationship between CBF and AMS, and the predictive performance was assessed by receiver operating characteristic (ROC) curve.  Results   The mean cortical CBF in women (81.65±2.69 ml/100g/min) was higher than that in men (74.35±2.12 ml/100g/min) (P < 0.05). In men, cortical CBF values of bilateral ACA, PCA, PICA and right MCA were higher in AMS than in non-AMS. Cortical CBF of right PCA best predicted AMS (AUC = 0.818). In women, LI of CBF in ACA was different between AMS and non-AMS, and it predicted AMS with AUC of 0.753.  Conclusion   Although the mechanism and prediction of AMS are quite complicated, higher cortical CBF at sea level, especially the CBF of posterior circulation system, may be used for the prediction in male volunteers using non-invasive 3D-pCASL.
  • MA Lin, FENG Jie and ZHANG Hao conceived and designed research. FENG Jie, ZHANG Shi Yu, and LIU Wen Jia recruited volunteers and performed experiments. ZHANG Hao, FENG Jie and ZHANG Shi Yu performed data analysis. ZHANG Hao and FENG Jie interpreted results of experiments. ZHANG Hao prepared figures and drafted manuscript. ZHANG Hao, FENG Jie and MA Lin edited and revised manuscript. MA Lin approved final version of manuscript. All the authors have read and approved the final version of the manuscript.
    The authors declare that they have no conflict of interests.
    &These authors contributed equally to this work.
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Predicting Acute Mountain Sickness by Using Sea-level Regional Cerebral Blood Flow

doi: 10.3967/bes2024.100
Funds:  This work was supported by the National Natural Science Foundation of China (No.81741115), Military Creative Project (No. 16CXZ014), and Military Healthcare Project (No. 16BJZ11).
  • Author Bio:

  • Corresponding author: MA Lin, Chief Physician, MD., PhD., Email: cjr.malin@vip.163.com
  • MA Lin, FENG Jie and ZHANG Hao conceived and designed research. FENG Jie, ZHANG Shi Yu, and LIU Wen Jia recruited volunteers and performed experiments. ZHANG Hao, FENG Jie and ZHANG Shi Yu performed data analysis. ZHANG Hao and FENG Jie interpreted results of experiments. ZHANG Hao prepared figures and drafted manuscript. ZHANG Hao, FENG Jie and MA Lin edited and revised manuscript. MA Lin approved final version of manuscript. All the authors have read and approved the final version of the manuscript.
  • The authors declare that they have no conflict of interests.
  • &These authors contributed equally to this work.

Abstract:   Objective   We aim to investigate the role of sea-level cerebral blood flow (CBF) in the prediction of acute mountain sickness (AMS) by using three-dimensional pseudo-continuous arterial spin labeling (3D-pCASL).  Methods   Forty-eight healthy volunteers reached an altitude of 3650 m by air after receiving head MR scan including 3D-pCASL at sea level. The CBF value of bilateral anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), and posterior inferior cerebellar artery (PICA) territories and laterality index (LI) of CBF were compared between AMS and non-AMS groups. Statistical analyses were applied to determine the relationship between CBF and AMS, and the predictive performance was assessed by receiver operating characteristic (ROC) curve.  Results   The mean cortical CBF in women (81.65±2.69 ml/100g/min) was higher than that in men (74.35±2.12 ml/100g/min) (P < 0.05). In men, cortical CBF values of bilateral ACA, PCA, PICA and right MCA were higher in AMS than in non-AMS. Cortical CBF of right PCA best predicted AMS (AUC = 0.818). In women, LI of CBF in ACA was different between AMS and non-AMS, and it predicted AMS with AUC of 0.753.  Conclusion   Although the mechanism and prediction of AMS are quite complicated, higher cortical CBF at sea level, especially the CBF of posterior circulation system, may be used for the prediction in male volunteers using non-invasive 3D-pCASL.

MA Lin, FENG Jie and ZHANG Hao conceived and designed research. FENG Jie, ZHANG Shi Yu, and LIU Wen Jia recruited volunteers and performed experiments. ZHANG Hao, FENG Jie and ZHANG Shi Yu performed data analysis. ZHANG Hao and FENG Jie interpreted results of experiments. ZHANG Hao prepared figures and drafted manuscript. ZHANG Hao, FENG Jie and MA Lin edited and revised manuscript. MA Lin approved final version of manuscript. All the authors have read and approved the final version of the manuscript.
The authors declare that they have no conflict of interests.
&These authors contributed equally to this work.
ZHANG Hao, FENG Jie, ZHANG Shi Yu, LIU Wen Jia, MA Lin. Predicting Acute Mountain Sickness by Using Sea-level Regional Cerebral Blood Flow[J]. Biomedical and Environmental Sciences. doi: 10.3967/bes2024.100
Citation: ZHANG Hao, FENG Jie, ZHANG Shi Yu, LIU Wen Jia, MA Lin. Predicting Acute Mountain Sickness by Using Sea-level Regional Cerebral Blood Flow[J]. Biomedical and Environmental Sciences. doi: 10.3967/bes2024.100
    • Nowadays, increasing numbers of people travel to high altitude. Incidence of acute mountain sickness (AMS) ranged from 25% to 94% according to the different ascent rates, altitudes reached and the individual susceptibilities[1]. AMS refers to the illness that usually occurs to unacclimatized individuals after rapid ascending to altitudes above 2500 m, and it characteristically comprises headache, fatigue, gastrointestinal symptoms, and dizziness according to Lake Louise Score (LLS) (2018)[2]. Previous investigations have paid much attention to the prevention and treatment of AMS, and a few studies also focused on the prediction of AMS. Appropriate and reliable prediction in advance would avoid many unnecessary risks. Previous studies for the predictions of AMS are through the application of the “tight-fit” hypothesis[3,4], baseline anxiety score[5], EEG-detected regional right temporal cerebral dysfunction[6], arterial oxygen saturation and breathing frequency with accuracy of 78%-80%[7], heart rate and pulse pressure and arterial elastance by ambulatory blood pressure device[8], physiological parameters by machine learning (accuracy of 0.886 - 0.996)[9], matrix metalloproteinase-9 and substance-P (AUC of 0.709)[10], uric acid (AUC of 0.817), platelet distribution width (AUC of 0.844)[11], genes (AUC of 0.833 - 0.989)[12], salivary and circulating miRNA (AUC of 0.811)[13,14], plasma samples (AUC of 0.704 - 0.908)[15] and so on.

      As mentioned above, cardiovascular and respiratory indicators and gene expression level were mainly used for prediction in most of previous studies, while the AMS prediction with sea-level cerebral blood flow (CBF) has not been investigated so far.

      High-altitude headache (HAH) is the primary complaint of AMS at high altitude. Previous research demonstrated the associations between HAH and hemodynamics, and even indicated that CBF instead of systemic hemodynamics played a vital role and mattered more in HAH[16]. Bian et al specifically emphasized the potential significance of CBF in AMS, i.e. AMS was associated with alterations in cerebral hemodynamics in the posterior circulation and was characterized by higher blood velocity [17]. Our previous study also found different CBF variations at high altitude between AMS and non-AMS subjects by three-dimensional pseudo-continuous arterial spin labeling (3D-pCASL)[18]. All these studies suggest a possible correlation between AMS and cerebral hemodynamics, and we hypothesized that the baseline CBF at sea level may provide predictive information for AMS.

      3D-pCASL, which can be used for the quantitative measurement of CBF value without contrast media injection, has been widely applied in central nervous system diseases, including headache, vasculopathy and so on[19,20]. In this study, we aim to investigate the prediction efficiency for AMS based on CBF analysis at sea level by using 3D-pCASL in healthy volunteers.

    • This study was approved by the ethics committee of our hospital (S2015-014-02) and conformed to standards set by the Declaration of Helsinki. Written informed consents were acquired from all the participants.

    • Forty-eight potential travelers were recruited as participants. The inclusion criteria were as follows: healthy volunteers with age between 18 to 40 years (28.83 ± 4.85 years); no history of head trauma, mental or psychological illness, cerebrovascular disease, headaches, sleep disorders, diabetes, hypertension, etc; no alcohol or drug addiction; right-handedness; sea-level resident without high-altitude experience above 1500m within past 12 months; no intracranial and carotid artery stenosis examined by MR angiography. Exclusion criteria included MR claustrophobia, artifacts due to metal foreign body or head motion. Throughout the trial, any therapeutic or preventive drugs, alcohol, caffeine-containing food and drinks were avoided.

    • MR images including 3D-pCASL were acquired on a 3.0T MR scanner (Discovery MR 750, GE Healthcare, Milwaukee, WI, USA) with an 8-channel head coil (in vivo) at sea level (50 m). The subjects were required to lie in the scanner for 5 minutes before the scan. 3D-pCASL was performed in all subjects with following parameters: 512 sampling points on eight spirals, repetition time (TR) = 4844ms, echo time (TE) = 10.5ms, post-labeling delay (PLD) time = 2025 ms, bandwidth= ± 62.5 kHz, slice thickness = 4 mm, number of slices = 36, field of view (FOV) = 24 cm, number of excitations (NEX) = 3, acquisition time = 4 min 41 s.

    • MR data of the participants were acquired at sea level 36 hours prior to exposure to high altitude. Their physiological variables were also recorded including age, height, weight, systolic blood pressure, diastolic blood pressure, heart rate, blood oxygen saturation.

      The participants were taken to high altitude at 3650 m by air. 8 hours after their arrival at high altitude, the LLS were recorded. LLS consists of four parts including headache, gastrointestinal symptoms, fatigue, and dizziness. Each symptom is scored from 0 - 3 by the severity (none = 0, mild = 1, moderate = 2, and severe = 3)[2]. AMS is defined as a total score of at least three points with headache score of at least one point. The participants were then divided into AMS and non-AMS groups.

    • The original images transferred to the workstation were processed into CBF mappings by Functool 3D-ASL. The arterial territories as ROI were sketched by a blinded observer (blinded to the symptoms) with 7-year experience in neuroradiology with ITK-SNAP software in terms of the definition in previous study[21,22]. ROI measurement consisted of cortical CBF value in anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), and posterior inferior cerebellar artery (PICA) territories. The CBF value of each ROI was auto-extracted in the software. The laterality index (LI) of CBF was calculated in different arterial territories by the equation[23]: LI = (LCBF - RCBF)/(LCBF + RCBF). In this study LI was presented by multiplying 1,000. 3 months later, the ROI sketching procedures were repeated by the same observer, and also performed by another blinded observer with 2-year experience in neuroradiology.

    • Statistical analyses and demonstration were performed using SPSS (version 26.0), Medcalc and Graphpad Prism (version 10.1.2). Normality tests were performed in all the continuous quantitative variables. All the variables were with normal distribution except LI of CBF in MCA in men and LI of CBF in PICA in women. T-test and nonparametric test were used for difference assessment of CBF or LI score in CBF in two groups. Spearman correlation analysis was used. Univariable logistic regression analysis was applied for selection of AMS predictor. The predictive ability was assessed by receiver operating characteristic (ROC) curve. P value of less than 0.05 was regarded as a statistically significant difference. Intraclass correlation coefficient (ICC) analysis was used to evaluate the interobserver and intraobserver agreement levels for sketching the ROI of different arterial territories.

    • Forty-eight volunteers (23 males and 25 females, age ranged from 19 to 39 years) were enrolled in the study. The age (31.36 ± 4.59 years vs 28.36 ± 4.05 years, P = 0.096) and the incidence (47.83% vs 56.00%, P = 0.773) of AMS showed no significant difference between men and women. The detailed information was demonstrated in Table 1. The Spearman correlation coefficient between HAH severity and LLS was 0.662 (P < 0.01) in men and 0.626 (P < 0.01) in women.

      Men (n = 23)     Women (n = 25)  
      Parameters Non-AMS AMS P Non-AMS AMS P
      Number (%) 12 (52.17) 11 (47.83)     11 (44.00) 14 (56.00)  
      Age (year) 29.17 ± 4.80 31.36 ± 4.59 0.276   26.55 ± 5.45 28.36 ± 4.05 0.350
      SaO2 (%) 97.17 ± 0.58 97.36 ± 0.67 0.459   97.82 ± 0.98 97.79 ± 0.43 0.912
      Height (cm) 176.42 ± 4.87 173.18 ± 5.17 0.137   162.73 ± 4.50 162.21 ± 4.89 0.790
      Weight (kg) 73.17 ± 10.47 74.23 ± 9.03 0.798   60.45 ± 14.07 55.71 ± 6.62 0.275
      BMI (kg/m2) 23.53 ± 3.41 24.74 ± 2.70 0.361   22.95 ± 6.16 21.15 ± 2.07 0.315
      Systolic blood pressure (mmHg) 117.67 ± 10.16 120.36 ± 13.05 0.584   107.09 ± 12.31 107.07 ± 7.57 0.996
      Diastolic blood pressure (mmHg) 80.67 ± 6.89 78.91 ± 8.60 0.593   71.27 ± 7.81 72.79 ± 7.15 0.619
      Heart rate (beats/min) 75.08 ± 6.67 77.73 ± 8.14 0.402   75.27 ± 10.68 70.36 ± 8.32 0.208
      Mean CBF (ml/100g/min) 69.67 ± 9.40 79.47 ± 8.73 0.017*   82.89 ± 17.43 80.68 ± 9.95 0.692
        Note. Data are mean ± SD. AMS, acute mountain sickness; BMI, body mass index; SaO2, blood oxygen saturation; CBF, cerebral blood flow. *Statistical significance was attributed as P < 0.05.

      Table 1.  Demographics and physiological indicators in Men and Women

    • The mean cortical CBF in women (81.65±2.69 ml/100g/min) was higher than that in men (74.35 ± 2.12 ml/100g/min) (P < 0.05).

      CBF features between groups in men and women were shown in Figure 1.

      Figure 1.  Cortical CBF values in different arterial territories between non-AMS and AMS in men (A) and in women (B).

      In men, the mean cortical CBF was significantly higher in AMS than non-AMS (Table 1), and the regional CBF was significantly higher in AMS group in most arterial territories (Table 2).

        Men (n = 23)     Women (n = 25)  
      Variables  Non−AMS AMS P   Non−AMS AMS P
      R ACA 71.55±9.95 81.80±10.47 0.025*   90.98±20.71 94.25±11.55 0.620
      L ACA 75.15±8.85 84.05±9.86 0.033*   93.69±19.78 91.12±9.98 0.676
      R MCA 64.39±9.28 73.92±10.24 0.029*   83.56±16.94 79.87±10.20 0.506
      L MCA 63.75±8.45 70.25±7.02 0.059   82.16±14.91 79.01±8.12 0.506
      R PCA 60.58±9.68 70.86±8.58 0.014*   82.91±19.29 79.76±14.46 0.645
      L PCA 61.89±10.69 71.13±8.42 0.033*   86.16±19.95 81.55±14.70 0.512
      R PICA 53.65±8.45 61.76±8.84 0.035*   72.40±17.82 69.93±10.73 0.672
      L PICA 52.73±8.91 60.21±7.47 0.042*   71.29±14.50 69.91±8.81 0.772
      LI ACA 25.52±37.44 13.88±31.56 0.431   15.45±32.47 −16.14±27.10 0.014*
      LI MCA −15.09 (−20.54,13.44) −25.64 (−64.00,13.51) 0.288   −6.84±31.23 −4.07±24.62 0.807
      LI PCA 7.30±26.29 1.85±27.26 0.630   17.01±24.71 9.10±26.41 0.449
      LI PICA −9.71±34.95 −11.53±30.09 0.895   1.31 (22.08, −23.37) −3.10 (−20.27,12.29) 0.936
        Note. Data are mean ± SD, and median (interquartile range); Unit of CBF: ml/100g/min; R, right; L, left; CBF, cerebral blood flow; ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; LI, laterality index; AMS, acute mountain sickness. *Statistical significance was attributed as P < 0.05.

      Table 2.  CBF Features among Non-AMS and AMS

      In women, no significant mean cortical CBF difference was found between AMS and non-AMS, but LI of CBF in ACA was significantly different between AMS and non-AMS (Table 2).

      R, right; L, left; ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; AMS, acute mountain sickness; CBF, cerebral blood flow.

    • All the variables with statistically significant difference (P < 0.05) in t-test and nonparametric test were selected for univariable logistic regression analysis (Table 3).

      Gender Variables   OR P 95% CI
      Men R ACA 1.127 0.051 1.000–1.270
        L ACA 1.129 0.059 0.996–1.281
        R MCA 1.108 0.045* 1.002–1.224
        R PCA 1.135 0.031* 1.012–1.272
        L PCA 1.115 0.056 0.997–1.247
        R PICA 1.129 0.057 0.996–1.279
        L PICA 1.132 0.066 0.992–1.291
      Women LI ACA 0.965 0.027* 0.935–0.996
        Note. R, right; L, left; CI, confidence interval; OR, odds ratio; ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; LI, laterality index. *Statistical significance was attributed as P < 0.05.

      Table 3.  The Univariable Logistic Regression Analysis in Men and Women

    • After predictor selection by univariable logistic regression analysis, the predictive ability assessment of the variables (if P < 0.05 in univariable logistic regression analysis) was performed, and the variable with biggest area under the ROC curve (AUC) was considered as the best predictor for AMS (Table 4 and Figure 2). In men, CBF of right PCA in AMS prediction (AUC = 0.818, accuracy = 86.96%). In women, the performance of LI in ACA was good in AMS prediction with AUC of 0.753 and accuracy of 76.00%.

      GenderVariables  AUC
      (95% CI)
      Se
      (%)
      Sp
      (%)
      PPV
      (%)
      NPV
      (%)
      YICutoffAccuracy
      (%)
      MenR MCA0.750
      (0.542−0.958)
      63.6483.3377.7871.430.470> 71.10673.91
       R PCA0.818
      (0.619−1)
      81.8291.6790.0084.620.735> 66.46886.96
      WomenLI ACA0.753
      (0.558−0.948)
      85.7163.6475.0077.780.494≤ 6.75176.00
        Note. Unit of CBF in Cutoff: ml/100g/min; AUC, area under the curve; CI, confidence interval; PPV, positive predictive value; NPV, negative predictive value; YI, Youden index; R, right; ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; LI, laterality index; AMS, acute mountain sickness. *Statistical significance was attributed as P < 0.05.

      Table 4.  The Predictive Capacity Assessment in AMS in Men and Women

      Figure 2.  ROC curve of cortical CBF in right MCA (AUC = 0.750) and right PCA (AUC = 0.818) in predicting AMS in men (A), and LI of cortical CBF in ACA (AUC = 0.753) in predicting AMS in women (B).

    • The intraobserver and interobserver agreement for ROI sketching of different arterial territories were excellent (ICCs, 0.939 - 0.990, 0.951 - 0.985, respectively).

    • In this study, significantly higher sea-level CBF values were revealed in most arterial territories in AMS group in men, and LI of the isonym artery could matter in AMS prediction in women. As we know, hormone is an important factor affecting CBF between genders, as studies have shown that estrogen has a neuroprotective effect by stabilizing energy metabolism in vascular endothelium[24,25]. It could protect against reperfusion injury and ameliorate CBF during ischemia[26]. It could also relieve the vasospasm and help reduce the fluctuation of hemodynamics[27]. Since the CBF in women is relatively stable and not easily affected by the changes of external environment, that may explain why CBF does not work for AMS prediction in women, and that may be the reason for different prediction indices in men and women.

      Compared with previous studies, the advantages of our approach are as follows: MRI-based ASL scan is non-invasive without any intravenous injection of contrast media, and MRI has been clinically applied for many years and it is widely accessible in major cities in China. Furthermore, our experiment has been designed with following specific aspects: 1. Ascent rate: Rapid ascent by air instead of by car, train, or even on foot[5,6,10,11,14,15] was conducted in our study so as to avoid the gradual acclimatization to the hypoxia and ensure the evaluation of AMS by LLS. 2. Subjects: In our study, potential tourists with inclusion and exclusion criteria were selected as volunteers instead of professional mountaineers or random subjects without controlling the influencing factors[6,10,12,28]. 3. Real high altitude: LLS was evaluated at 3650 m instead of simulation chamber with normobaric hypoxia[3,7,13]. 4. Data acquisition: In order to predict AMS in advance, our data were collected at sea level before exposure to hypoxia compared with some studies[6,7,9,10].

      To the best of our knowledge, only few studies demonstrated associations between sea-level CBF and AMS, and some of our findings were consistent with the previous results indicating that sea-level velocities of left VA and right MCA in HAH group were higher than non-HAH group[16]. It is known that arterial velocities or diameters were usually regarded as the demonstration of cerebral blood flow[29-31]. In addition, Feddersen et al measured baseline CBF velocity of MCA, and though they did not perform a statistical analysis, the data indicated that the CBF velocities were indeed higher in the AMS group[6], and similar results at sea level were reported in good-performance climbers and bad-performance climbers[32].

      In spite of accumulative evidence on AMS and its relative factors, the mechanisms remain elusive[33]. As well known, CBF is dynamically regulated by many factors, including changes in cerebral metabolic activity, sympathetic nerve activity and so on[34].

      Considering the brain’s limited oxygen storage capacity, its already inordinate metabolism would no doubt exacerbate during hypoxia[35], which indicates the high demand for oxygen in the brain to maintain normal work due to insufficient partial pressure of oxygen. The cerebral oxygen delivery hinges on the combined effect of CBF and arterial oxygen content (CaO2), and the reduction of CaO2 causes CBF increase[36]. Classically, CBF was considered to be adjusted to the metabolic demands of the brain[37]. Therefore, higher sea-level CBF indicates higher metabolic demand or relative lower CaO2. The increased oxygen consumption during hypoxia stimulus[16] and insufficient oxygen necessitate compensatory adaptations in physiological functioning, including the initial quicker increase of CBF and subsequent slower increase of hemoglobin mass and concentration[35]. Therefore, CBF surges occur to compensate after acute ascent to high altitude. According to the evidence above, we considered that individuals with higher sea-level CBF might desire more oxygen, thus more CBF increase to provide sufficient oxygen and nutrient in brain at hypoxia. That might cause the increase of cerebral blood volume and subsequent increase of intracranial pressure, leading to headache and AMS in terms of the “tight-fit” hypothesis[29-31]. Just as Cochand revealed that individuals with AMS might be inherently more vulnerable to higher intracranial pressure[38].

      There is a traditional hypothesis that the sparse sympathetic innervation in the posterior fossa may lead to the inclination of high perfusion[39,40]. Sympathoexcitation at hypoxia[41,42] may lead to higher perfusion in those with higher sea-level CBF in cerebellum, consequent higher intracranial pressure, and susceptibility to headache and AMS at plateau as the above content mentioned.

      Considering the relation between CBF increase and functional activation. It was suggested that HAH might potentially share similar mechanisms with migraine[16] in which headache was closely correlated with the function interference of occipital cortex and cerebellum[43]. What is more, previous studies have demonstrated the close correlations between brain regions and the corresponding function, including the relationship between cerebellum and pain-perception regulation[44,45], anterior frontal and temporal cortex and pain processing[46,47], cingulate and pain stimulus[48,49], medial temporal gyrus and sensitivity to chronic hypoxia[50], frontal island and dyspnea and homeostasis maintenance at high altitude, frontal insular cortex and aerobic capacity[51-54]. As was suggested that cerebral metabolism rate was coupled with cerebral blood flow[55], we considered the hyperperfusion in above-mentioned regions might indicate hypermetabolism and thus higher sensitivity to pain perception and hypoxia.

      Based on the aforementioned explanation, we assumed that AMS were associated with higher CBF value which was in concordance with the previous studies[16,30,56]. Our result showed great agreements with Jansen et al that cerebellar CBF in bad-performance climbers was consistently higher than that in good-performance climbers[32], and was also consistent with their conclusion that CBF of people with AMS was higher than those without AMS[57].

      In this study, CBF of right PCA were demonstrated as the best predictor for AMS in men, with AUC of 0.818. As our results showed, posterior circulation system played a significant role in AMS prediction. That was consistent with Bian’s finding on close correlation in posterior circulation system and AMS score[17]. Also, it was demonstrated that both higher baseline bilateral VA velocities in HAH and increased VA and BA velocities at hypoxia[16] implied strong associations between posterior circulation system and HAH. And in our study, correlation of HAH and AMS was found which suggested that our results were consistent with Bian’s. In addition, previous study has indicated that after arrival and short stay at high altitude, CBF was inclined to increase in the posterior arterial territories[58], and a “tight” posterior fossa was more vulnerable to headache syndrome[29,30], thus causing higher susceptibility of AMS.

      Our results showed no cortical CBF difference between groups in women. That may be due to the fact that women normally possess significantly higher CBF than men[59]. Unlike the results in men, the best predictor for AMS in women was related with ACA instead of posterior circulation system in present study. Though our study revealed different results with Bian et al, previous findings on frontal headache at hypoxia[60,61] and increased velocity of ACA at high altitude might indicate the role of ACA and its asymmetry in AMS in women[16].

      In this study, only LI of CBF in ACA showed good predictive ability for AMS with AUC of 0.753 in women. The asymmetry of isonym artery may be of great importance in predicting AMS in women, which was probably caused by the amplified effects of the anatomical asymmetry of arteries during the CBF regulation at hypoxia as previously speculated[16]. Our results indicated that women might be more sensitive to the effects resulted from the arterial asymmetry, and the specific mechanism warrants further investigations.

      Though this study is the first to predict AMS by ASL, it has some potential limitations. Firstly, the sample size is relatively small, future study with larger sample size is needed although logistically challenging. Secondly, only young participants were investigated. Thirdly, only one PLD (2025 ms) was applied, and multi-PLD should be used in future study to acquire more CBF data for analysis.

    • Sea-level cortical CBF acquired by 3D-pCASL could be used for the prediction of AMS. Higher CBF in specific regions of posterior circulation system would herald higher possibility of AMS in men. The asymmetry of isonym artery may play a particular role in predicting AMS in women.

    • This study was approved by the medical ethics committee of our hospital (S2015-014-02) and conformed to standards set by the Declaration of Helsinki. Written informed consents were acquired from all the participants.

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