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Training-dependent cognitive advantage is suppressed at high altitude
Physiology & Behavior 106 (2012) 439–445
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Training-dependent cognitive advantage is suppressed at high altitude Peng Li a, d, e, Gang Zhang a, d, e, Hai-yan You b, d, e, Ran Zheng b, d, e,⁎, Yu-qi Gao c, d, e,⁎⁎ a
Department of High Altitude Military Hygiene, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China Department of Health Service, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China c Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China d Key Laboratory of High Altitude Medicine, Ministry of Education, Chongqing 400038, China e The Key Laboratory of High Altitude Medicine, PLA, Chongqing 400038, China b
a r t i c l e
i n f o
Article history: Received 23 December 2011 Received in revised form 22 February 2012 Accepted 2 March 2012 Keywords: High altitude Cognitive function Cognitive training Neural plasticity Hypoxia
a b s t r a c t Ascent to high altitude is associated with decreases in cognitive function and work performance as a result of hypoxia. Some workers with special jobs typically undergo intensive mental training because they are expected to be agile, stable and error-free in their job performance. The purpose of this study was to determine the risk to cognitive function acquired from training following hypoxic exposure. The results of WHO neurobehavioral core tests battery (WHO-NCTB) and Raven's standard progressive matrices (RSPM) tests of a group of 54 highly trained military operators were compared with those of 51 non-trained ordinary people and were investigated at sea level and on the fifth day after arrival at high altitudes (3900 m). Meanwhile, the plasma levels of brain-derived neurotrophic factor (BDNF), interleukin 1β (IL-1β) and vascular endothelial growth factor (VEGF) were examined. The result showed that at sea level, the trained group exhibited significantly better performance on neurobehavioral and RSPM tests. At high altitude, both groups had decreased accuracy in most cognitive tests and took longer to finish them. More importantly, the highly trained subjects showed more substantial declines than the non-trained subjects in visual reaction accuracy, auditory reaction speed, digit symbol scores, ability to report correct dots in a pursuit aiming test and total RSPM scores. This means that the training-dependent cognitive advantages in these areas were suppressed at high altitudes. The above phenomenon maybe associated with decreased BDNF and elevated inflammatory factor during hypoxia, and other mechanisms could not be excluded. © 2012 Elsevier Inc. All rights reserved.
1. Introduction At altitudes exceeding 3000 m, arterial oxyhemoglobin saturation (SaO2) decreases markedly and produces adverse changes in brain function [1–3]. These effects manifest as memory impairment [4], reduction in the speed and precision of reaction [5] and perception [6], inefficiency in learning [7] and information processing [8], and declined motor flexibility [9], etc. Worldwide, millions of people spend time at high altitudes each year for both tourist and work reasons (e.g., researchers, engineering builders, railway staff and military soldiers). One serious problem is that the work performance of these people can decline markedly at high altitude. Modern working concepts include technologically enabled individuals operating automated machinery and intelligence systems. ⁎ Correspondence to: R. Zheng, Department of Health Service, College of High Altitude Military Medicine, Third Military Medical University, No. 30 Gao Tan Yan Zheng Street, Sha Ping Ba District, Chongqing, China 400038. Fax: + 86 23 68752329. ⁎⁎ Correspondence to: Y.-Q. Gao, College of High Altitude Military Medicine, Third Military Medical University, No. 30 Gao Tan Yan Zheng Street, Sha Ping Ba District, Chongqing, China 400038. Fax: + 86 23 68752334. E-mail addresses: [email protected] (R. Zheng), [email protected] (Y. Gao). 0031-9384/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2012.03.002
People engaged in crucial technical or operational work (e.g., aircraft pilots, workers managing large machinery, drivers controlling modern trains) require much greater cognitive capabilities than other workers. At high altitudes, a small cognitive lapse by one of these critical personnel may cause failure of a mission or other catastrophic consequences. For example, impairment in the judgment and decision-making capacities of train drivers may increase the risk of an accident when operating trains in dangerous conditions. Typically, these workers have undergone a longer process of occupational training, which leads to operational proficiency, especially in agility, stability and accuracy. Studies in humans and in many animal species have shown that training can improve the performance of a wide range of cognitive functions [10,11] and that training-dependent cognitive enhancement is mainly due to taking advantage of neural plasticity [12–16]. However, due to a lack of studies specifically designed for these well-trained people at high altitudes, it has not been established whether the cognitive abilities acquired from training were affected by a hypoxic environment at high altitudes, and whether the extent of cognitive deficits of highly trained workers and nontrained people were similar at these altitudes. The present study aims to clarify the aforementioned problems and compared the cognitive impairment between specially trained
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military operators and ordinary soldiers in troops who were assigned to a high altitude area with an elevation of 3900 m. Because the influences of cognitive function are manifested behaviorally, neurobehavioral testing is commonly recognized as a sensitive and valid method for detecting cognitive dysfunction [17]. Previous studies have revealed that some high-load or difficult-task cognitive functions are more easily affected by hypoxic exposure [18,19], so the Raven's standard progressive matrices (RSPM) test was adopted to measure cognitive capacity for the encoding and analysis of complex information, such as comparisons and analogies [20]. Thus, in the present study, the neurobehavioral and RSPM tests were chosen to comprehensively evaluate the decline of cognitive efficiency resulting from high altitude hypoxia. Since brain function was easily damaged by hypoxia, we consider the hypothesis that hypoxic exposure could also reverse or disturb neural connections built depending upon training, which may be due to a decreased supply of oxygen and energy, changed neural structure and synapse-related cytokines, and thus attenuate training-dependent cognitive ability. The results of this study preliminarily demonstrated that the training-dependent advantage of cognition was really suppressed by exposure to hypoxia. The decreased brain-derived neurotrophic factor (BDNF) and the elevated inflammatory cytokines during hypoxia were likely involved in the mechanism. 2. Methods 2.1. Subjects There were 105 male soldiers who participated in this study, including 54 professionally trained operational personnel and 51 other soldiers. The subjects in the operational personnel group all served in the real-time monitoring, measuring and commandexecuting of an automatic control system. They all underwent strict training of auditory, visual and manual abilities for at least 6 months, resulting in efficient skills in reaction, memory and hand-eye coordination. Members of the other soldier group were selected from a pool of soldiers engaged in routine jobs, including stevedoring, repairing, secretarial work, cooking and medical care, and who had not received special cognitive training. The two groups were matched for age, height, weight and educational level (Table 1). The subjects all resided at altitudes that were lower than 500 m and had never traveled to altitudes of 2000 m or higher. The troops were transported by train from plains region (altitude b300 m) to a base camp on the Qinghai–Tibetan Plateau (altitude 3900 m) within 5 days (Fig. 1). When reaching above 2800 m, additional oxygen was supplied to the train coach, which increased the percentage of O2 from 21% to 24–25% by volume. All tests were administered to each individual 30 days prior to his departure from low land and 5 days after his arrival at the high altitude (3900 m) base camp (Fig. 1). No subjects had prior experience with neurobehavioral or RSPM tests. Subjects who showed signs of acute mountain sickness (The criterion was both a headache and a total Lake Louise symptom score of 3 or greater [21]) or who were using any medications or were using supplementary oxygen during investigation were excluded. All participants provided informed consent, and the study protocol was approved by the Ethics Committee of the Third Military Medical University.
Table 1 Basic characteristics of the study population (mean ± SD).
Age Height (cm) Weight (kg) Years of education
Trained operational personnel group (n = 54)
Untrained ordinary soldiers group (n = 51)
26 ± 4 174 ± 5 72 ± 10 14 ± 2
26 ± 4 173 ± 4 70 ± 8 14 ± 2
2.2. Neurobehavioral test A selection of tests from the World Health Organization Neurobehavioral Core Test Battery (WHO-NCTB) was used, which access the following cognitive functions: auditory memory, manual dexterity, perceptual-motor speed, visual perception and motor steadiness. Additionally, the EP202 4-color choice reaction measurer (ECNU, Shanghai, China) and the DDX-200 auditory reaction measurer (BODA, Beijing, China) were used for visual and auditory reaction speeds. All cognitive tests were scheduled in the morning (between 9 a.m. and 11 a.m.) and were performed in a quiet and luminous room without interruptions by other people. The suitable tables and chairs were provided. All tests were administered by trained interviewers, and the methods have been described in detail elsewhere [22,23]. 2.3. The Raven's standard progressive matrices (RSPM) It was not applicable to compare RSPM scores of a group of subjects at high altitude with themselves at lowland due to possible retention of memory related to the test detail. Therefore, subjects from both the group of highly trained operators and the group of ordinary soldiers were randomly assigned to a pre-hypoxia or in-hypoxia subgroup to perform RSPM tests; each subgroup had 20 individuals. As previously reported [20], the test consists of 60 diagrammatic puzzles that are divided into five sets (A, B, C, D, and E) of 12 items each. A subject was given 30 min to complete all 60 questions, even if some of his answers were informed guesses. 2.4. Physiological Indices The resting arterial oxyhemoglobin saturation (SaO2) levels and heart rates (HRs) of all subjects were measured using a DatexOhmeda TuffSat portable instrument (SOMA, Connecticut, USA), before the cognitive tests. 2.5. Blood sampling and cytokine measurement Venous blood samples of each subject at low and high altitudes were obtained on the same days as cognitive tests. Cytokines in the plasma, including BDNF, interleukin 1β (IL-1β) and vascular endothelial growth factor (VEGF), were measured by the enzyme-linked immunosorbent assay (ELISA) using immunoassay kits (R&D Systems, Minneapolis, MN). 2.6. Pittsburgh Sleep Quality Index (PSQI) The PSQI consists of 18 questions that are designed to assess 7 components of sleep quality. The scores from each component can be summed to a total score that ranges from 0 to 21, where 0 indicates no difficulty and 21, severe difficulty. The details of the PSQI have been described elsewhere [24]. 2.7. Statistical analysis A statistical analysis was carried out using the SPSS 13.0 software. T-tests were used for normally distributed continuous variables and nonparametric rank-based analysis was used for non-normally distributed variables. The physiological and WHO-NCTB performances of each subject at high altitude were compared to baseline at lowland using tests for paired or related samples, and independent samples tests were used for comparisons between the two groups of subjects. For the RSPM performances of four independent groups, the between-group comparisons were performed using one-way analysis of variance (ANOVA) followed by a least significant difference (LSD) test. The criterion for significance was 0.05, and all p values were two-tailed.
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Fig. 1. Time course of the study: days of measurement and ascent by train.
3. Results 3.1. The physiological changes before and after hypoxic exposure As shown in Table 2, there were no differences between the highly trained operator group and the other soldier group in HR, SaO2 and sleep quality assessed with the PSQI at low altitude. At high altitude, almost all subjects showed increases in HR (approximately 20–25% higher), reductions in SaO2 (approximately 10% lower) and reduced sleep quality (PSQI scores were 1.3–1.5 points higher), but the extent of these changes (differences between pre-hypoxic and in-hypoxic conditions) was indistinguishable between the two cohorts of soldiers. 3.2. Neurobehavioral function changes The highly trained operational personnel group performed statistically better in some neurobehavioral tests than the other soldier group before high altitude living (reflected by p-value c in Table 3), including shorter reaction time and higher accuracy on the visual reaction test, better scores on the digit symbol test, and more correct dots and fewer wrong dots in pursuit aiming test. Almost all subjects exhibited significant declines of neurobehavioral function after arriving at the high altitude base camp. After 5 days living at 3900 m, both groups had reduced performance on most of the neurobehavioral tests (reflected by p-value a and pvalue b in Table 3, respectively), including lower visual reaction accuracy, longer auditory reaction time, and diminished performance on the digit span test, manual dexterity test (regardless of the hand that was tested), digit symbol test and pursuit aiming test. Visual reaction times and scores of Benton visual retention seemed to be unaffected by hypoxic exposure. Next, difference values of cognitive function between before and during high altitude living were calculated for each subject. Importantly, comparisons between the two groups indicated that the highly trained operational personnel exhibited more significant cognitive declines during hypoxia than the untrained soldiers, especially in visual
reaction accuracy and auditory reaction time (Fig. 2A–B). They also demonstrated more substantial declines in performance on the digit symbol test and the pursuit aiming test (as measured by reporting lower numbers of correct dots) (Fig. 2C–D). In other words, the initial advantage of highly trained operational personnel on these tests ceased at high altitude (reflected by p-valued in Table 3). 3.3. Changes of RSPM scores As shown in Table 4, at low altitude, the operational personnel demonstrated markedly higher cognitive capacity for complicated tasks, which was reflected by higher total RSPM scores (sum of scores for five subsets A–E) compared to those of ordinary soldiers (pvalue c). For each subset A–E, the scores of two groups did not differ. The RSPM scores for ordinary soldiers group did not change after 5 days of hypoxia (p-value b). However, the total RSPM scores and scores on subset E for trained operational personnel decreased significantly (p-value a). As a result, although the trained group had an advantage before hypoxia, the RSPM scores of the two groups were approximately equal at high altitude (p-value d). 3.4. Plasma cytokines respond to hypoxic exposure As shown in Fig. 3, no cytokine exhibit difference between trained group and untrained group either at lowland or at high altitude. There was a marked decrease of BDNF in plasma during hypoxia, and the decline was in essence the same between the trained and untrained group (Fig. 3A). Plasma IL-1β exhibited an increasing tendency at high altitude, and the two groups raised with similar extent (Fig. 3B). In addition, VEGF in plasma of both groups remained unaffected by hypoxic exposure (Fig. 3C). 4. Discussion Although there have been extensive reports of cognitive impairment at high altitude in recent years and similar results have been observed in the present study, the most significant finding of this paper
Table 2 Physiologic indices of the two groups measured at low and high altitudes (mean ± SD). Trained operational personnel group (n = 54)
SaO2 HR PSQI
Untrained ordinary soldiers group (n = 51)
Pre-hypoxia
In-hypoxia
Difference
Pre-hypoxia
In-hypoxia
Difference
97.54 ± 1.06 70.83 ± 11.6 5.15 ± 2.08
88.7 ± 2.63⁎ 89.98 ± 10.48⁎ 6.48 ± 2.88⁎
8.8 ± 2.88 19.15 ± 14.43 1.33 ± 2.63
97.61 ± 0.93 70.16 ± 9.73 4.84 ± 1.89
89.45 ± 1.97⁎ 88.96 ± 10⁎ 6.33 ± 2.2⁎
8.16 ± 2.27 18.8 ± 13.69 1.49 ± 1.96
⁎ P b 0.05; significantly different from corresponding values during pre-hypoxia using paired samples t-tests.
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Table 3 Neurobehavioral function of the two groups measured at low and high altitudes (mean ± SD). Trained operational personnel group
Untrained ordinary soldiers group
(n = 54)
(n = 51)
Pre-hypoxia
Visual reaction time (s) Visual reaction error 0 time 1 time 2 times 3 times Audible reaction time (ms) Forward digit span Backward digit span Santa Ana (preferred) Santa Ana (nonpreferred) Digit symbol test Benton visual retention Pursuit Aiming (correct) Pursuit Aiming (wrong) Pursuit Aiming (total)
In-hypoxia
0.635 ± 0.068
0.649 ± 0.080
42 (77.8%) 12 (22.2%) 0 0 291.1 ± 69.3 12.22 ± 1.54 8.65 ± 2.59 26.36 ± 3.49 23.48 ± 3.35 76.50 ± 12.64 8.04 ± 1.16 153.24 ± 16.50 9.48 ± 3.85 162.72 ± 17.01
21(38.9%) 20(37%) 8 (14.8%) 4 (7.4%) 369.4 ± 92.1 11.74 ± 1.49 7.93 ± 2.27 24.55 ± 3.19 22.46 ± 3.25 71.37 ± 13.10 7.88 ± 1.06 141.85 ± 18.57 13.67 ± 4.44 156.07 ± 18.79
p-valuea ⁎
0.124 b 0.001
b 0.001 0.034 0.003 b 0.001 b 0.001 b 0.001 0.197 b 0.001 b 0.001 0.004
Pre-hypoxia
In-hypoxia
0.690 ± 0.072
0.700 ± 0.069
28 (54.9%) 18 (35.3%) 4 (7.8%) 1 (1.9%) 318.5 ± 97.1 12.18 ± 1.53 8.41 ± 2.28 25.80 ± 3.90 23.73 ± 3.11 71.33 ± 13.73 7.92 ± 1.26 145.22 ± 20.91 11.10 ± 4.08 156.31 ± 21.28
19 (37.3%) 20 (39.2%) 10 (19.6%) 2 (3.9%) 366.2 ± 100.64 11.75 ± 1.38 7.98 ± 2.21 24.30 ± 4.05 22.94 ± 2.87 69.31 ± 13.82 7.53 ± 1.22 140.88 ± 20.47 13.94 ± 5.95 154.82 ± 22.02
Between 2 groups
p-valueb ⁎
Pre-hypoxia
In-hypoxia
p-valuec
p-valued
#
0.237 0.001
b0.001 0.007
0.002 0.992
b 0.001 0.062 0.033 b 0.001 b 0.001 0.026 0.227 0.043 b 0.001 0.498
0.097 0.879 0.621 0.436 0.700 0.047 0.745 0.030 0.039 0.09
0.87 0.988 0.901 0.734 0.427 0.436 0.762 0.622 0.789 0.691
#
⁎ Comparisons were performed between pre-hypoxia and in-hypoxia using paired samples t-tests (except for visual reaction error, for which 2 related samples nonparametric rank-based tests were used). # Comparisons were performed between the two subject groups for scores during pre-hypoxia and in-hypoxia using independent samples t-tests (except for visual reaction error, for which 2 independent samples nonparametric rank-based tests were used).
is that well-trained operators demonstrate more severe cognitive deficits than untrained ordinary people at a high altitude. In other words, it has not previously been reported that the initial cognitive advantage that highly trained workers had over other people was lost during acute high altitude hypoxia. Under normal conditions, the performance of highly trained operators on several neurobehavioral tests and the RSPM test was significantly better than that of ordinary soldiers. This difference was due to extensive practice for targeted cognitive abilities. The contents of the
training program determined which aspects of cognitive abilities were enhanced. The great potential of the brain to develop, change and modify itself under the influence of training has been termed neural plasticity. Synapse was the cellular structure responsible for communication between neurons. It has been postulated that the short- and long-term modification of synapse efficacy played a primary role in training-dependent cognition improvement [25]. Other mechanisms of neural plasticity included intrinsic neuronal excitability, dendritic integration, neuron–glia signaling, and others [26].
Fig. 2. Difference values of neurobehavioral performances between pre-hypoxia and in-hypoxia. First, the pre-hypoxia/in-hypoxia difference value for each subject was calculated. Then, comparisons were performed between the two subject groups for the calculated difference values using 2 independent samples nonparametric tests. The medians were marked using horizontal lines and the cross-group comparisons were marked using connection lines.
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Table 4 RSPM scores measured at low and high altitude (mean ± SD). Set A
Set B
Set C
Set D
Set E
Total score
Trained operational personnel group Pre-hypoxia (n = 22) In-hypoxia (n = 21) p-valuea
11.09 ± 0.97 10.38 ± 1.36 0.091
10.41 ± 1.53 9.81 ± 1.89 0.272
8.86 ± 1.64 8.19 ± 1.99 0.231
8.31 ± 2.06 7.48 ± 1.75 0.155
7.82 ± 1.87 6.05 ± 2.09 0.007
46.5 ± 5.42 41.9 ± 5.49 0.002
Untrained ordinary soldiers group Pre-hypoxia (n = 21) In-hypoxia (n = 20) p-valueb p-valuec between groups during pre-hypoxia p-valued between groups during in-hypoxia
10.43 ± 1.5 10.3 ± 1.56 0.763 0.115 0.849
9.62 ± 1.75 9.60 ± 1.93 0.973 0.149 0.707
8.29 ± 1.87 7.90 ± 1.83 0.502 0.304 0.613
8.05 ± 2.09 7.50 ± 1.76 0.365 0.646 0.968
7.19 ± 2.38 6.1 ± 2.1 0.103 0.333 0.937
43.57 ± 4.04 41.4 ± 3.52 0.145 0.045 0.733
Between-group comparisons for RSPM scores of four subgroups were performed using one-way analysis of variance (ANOVA) followed by a least significant difference (LSD) test.
The present study was specifically designed to test whether the cognitive superiority that resulted from intensive training had been influenced by acute hypoxic exposure. The results clearly demonstrated that some aspects of cognitive function that had been superior in the highly trained group at low altitude exhibited more vulnerable at high altitude. These aspects included reaction, perception and motor stability, as well as cognitive capacity for processing complex information. The cause of cognitive impairment at high altitude was known to be reduced cerebral oxygen supply and consequent brain damage [27]. In addition, poor sleep quality at high altitude may disturb cognitive function [28]. However, there were no differences between the two cohorts of soldiers in either oxyhemoglobin saturation or sleep quality. Perhaps the primary explanation was that hypoxic exposure damaged the relevant structures or functions underlying trainingdependent neural plasticity. Anatomically, the brain regions that happened to be most vulnerable to hypoxic damage, such as the cortical layers and the hippocampus, are also closely related to neural plasticity [16,29]. Changes that occurred in these areas following hypobaric
hypoxia included morphological alteration [30], neuronal apoptosis [31], neurotransmitter disorder [32] and abnormal electrical activity [33]. Moreover, synapses, which are key cellular structures in trainingdependent neural plasticity, were easily damaged under hypoxic conditions. Several studies have already demonstrated that hypoxia had a direct influence on the synaptic release of neurotransmitters [34–36] and the expression of genes involved in synaptic function [37], In addition, hypoxia-inducible factor 1α (HIF-1α), a transcription factor that is upregulated during hypoxia, may play an important role in affecting genes expression relevant to synapse [38]. We consider some cytokines may participate in the reversal or disturb of synaptic plasticity that was built during training. It was reported that the level of VEGF in the hippocampus can dynamically modulate neuronal plasticity [39]. In addition, BDNF plays an essential role in plastic changes of synapse, including enhancing hippocampal long-term potentiation (LTP) and attenuating long-term depression (LTD) [40,41]. Some inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) could also cause synaptic dysfunction through
Fig. 3. Plasma BDNF, IL-1β and VEGF cytokine concentrations at low and high altitudes (n = 40). Venous blood samples of each subject at low and high altitudes were obtained and plasma cytokines were measured. The comparisons were performed between pre-hypoxia/in-hypoxia using 2 related samples nonparametric tests. The median concentrations were marked using horizontal lines and the pre-hypoxia/in-hypoxia differences were marked using connection lines.
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affecting synaptic transmission and synaptic proteins [42,43]. Moreover, the fact of increasing IL-6 at high altitude has been observed [44]. In the present study, except for VEGF, the drop of protective cytokine BDNF and the elevation of damaging inflammatory cytokine IL-1β did occur during hypoxia. We noticed that these changed cytokines exhibited no difference between trained and untrained groups, but it did not contradict to the opinion that these altered cytokines may suppress training-dependent cognitive advantage much more. The reason was that the newly built neurons connection benefiting from recent training may be easily affected than stable basic cognition. Meanwhile, the synaptic plasticity that training-dependent advantage depends upon was more susceptible by these changed cytokines. Further research is required to determine the exact cause–effect relationship. We had to admit that, for methodological reason, the specific ability that the operators have been trained for cannot be tackled exactly and can only be indirectly and partly reflected by NCTB and RSPM tests in the present study. Thus except for examined general cognitive functions, we cannot exclude that the trained soldiers would still be able to perform the trained tasks better than untrained people. Some important questions also remain for future research. First, it is necessary to approach how training-dependent neural plasticity is easily affected by hypoxia exposure, especially to define the brain regions related to this study using fMRI or similar techniques and to explore key functional molecule in the brain tissue by simulating animal experiments. Second, it is important to identify whether the deficits of training-dependent cognition in hypoxia are transient or permanent because cognitive deficits may recover after acclimatization to hypoxia. Finally, it is valuable to know which anti-hypoxic drugs or means could minimize losses of cognitive advantage built upon training at high altitude. 5. Conclusions In summary, the present study confirmed that cognitive advantage of highly trained workers was easily suppressed by hypoxia at high altitude although exact mechanisms were not yet clear. Therefore, close attention should be paid to these personnel, and effective measures, including but not limited to providing workers with a reasonable oxygen supply and powerful anti-hypoxic drugs, should be taken to ensure that good performance of various job tasks is sustained at high altitudes. Acknowledgments The work was supported by the 973 Project of China (No. 2012CB518201) and the Science Foundation of the Third Military Medical University (No. 2010XQN18). References [1] Hornbein TF, Townes BD, Schoene RB, Sutton JR, Houston CS. The cost to the central nervous system of climbing to extremely high altitude. N Engl J Med 1989;321:1714–9. [2] Virues-Ortega J, Buela-Casal G, Garrido E, Alcazar B. Neuropsychological functioning associated with high-altitude exposure. Neuropsychol Rev 2004;14:197–224. [3] Bjursten H, Ederoth P, Sigurdsson E, Gottfredsson M, Syk I, Einarsson O, et al. S100B profiles and cognitive function at high altitude. High Alt Med Biol 2010;11:31–8. [4] Shukitt-Hale B, Stillman MJ, Welch DI, Levy A, Devine JA, Lieberman HR. Hypobaric hypoxia impairs spatial memory in an elevation-dependent fashion. Behav Neural Biol 1994;62:244–52. [5] Wesensten NJ, Crowley J, Balkin T, Kamimori G, Iwanyk E, Pearson N, et al. Effects of simulated high altitude exposure on long-latency event-related brain potentials and performance. Aviat Space Environ Med 1993;64:30–6. [6] Bouquet C, Gardette B, Gortan C, Therme P, Abraini JH. Color discrimination under chronic hypoxic conditions (simulated climb “Everest-Comex 97”). Percept Mot Skills 2000;90:169–79. [7] Bouquet CA, Gardette B, Gortan C, Abraini JH. Psychomotor skills learning under chronic hypoxia. Neuroreport 1999;10:3093–9. [8] Singh SB, Thakur L, Anand JP, Yadav D, Amitabh, Banerjee PK. Effect of chronic hypobaric hypoxia on components of the human event related potential. Indian J Med Res 2004;120:94–9.
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Training-dependent cognitive advantage is suppressed at high altitude Peng Li a, d, e, Gang Zhang a, d, e, Hai-yan You b, d, e, Ran Zheng b, d, e,⁎, Yu-qi Gao c, d, e,⁎⁎ a
Department of High Altitude Military Hygiene, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China Department of Health Service, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China c Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China d Key Laboratory of High Altitude Medicine, Ministry of Education, Chongqing 400038, China e The Key Laboratory of High Altitude Medicine, PLA, Chongqing 400038, China b
a r t i c l e
i n f o
Article history: Received 23 December 2011 Received in revised form 22 February 2012 Accepted 2 March 2012 Keywords: High altitude Cognitive function Cognitive training Neural plasticity Hypoxia
a b s t r a c t Ascent to high altitude is associated with decreases in cognitive function and work performance as a result of hypoxia. Some workers with special jobs typically undergo intensive mental training because they are expected to be agile, stable and error-free in their job performance. The purpose of this study was to determine the risk to cognitive function acquired from training following hypoxic exposure. The results of WHO neurobehavioral core tests battery (WHO-NCTB) and Raven's standard progressive matrices (RSPM) tests of a group of 54 highly trained military operators were compared with those of 51 non-trained ordinary people and were investigated at sea level and on the fifth day after arrival at high altitudes (3900 m). Meanwhile, the plasma levels of brain-derived neurotrophic factor (BDNF), interleukin 1β (IL-1β) and vascular endothelial growth factor (VEGF) were examined. The result showed that at sea level, the trained group exhibited significantly better performance on neurobehavioral and RSPM tests. At high altitude, both groups had decreased accuracy in most cognitive tests and took longer to finish them. More importantly, the highly trained subjects showed more substantial declines than the non-trained subjects in visual reaction accuracy, auditory reaction speed, digit symbol scores, ability to report correct dots in a pursuit aiming test and total RSPM scores. This means that the training-dependent cognitive advantages in these areas were suppressed at high altitudes. The above phenomenon maybe associated with decreased BDNF and elevated inflammatory factor during hypoxia, and other mechanisms could not be excluded. © 2012 Elsevier Inc. All rights reserved.
1. Introduction At altitudes exceeding 3000 m, arterial oxyhemoglobin saturation (SaO2) decreases markedly and produces adverse changes in brain function [1–3]. These effects manifest as memory impairment [4], reduction in the speed and precision of reaction [5] and perception [6], inefficiency in learning [7] and information processing [8], and declined motor flexibility [9], etc. Worldwide, millions of people spend time at high altitudes each year for both tourist and work reasons (e.g., researchers, engineering builders, railway staff and military soldiers). One serious problem is that the work performance of these people can decline markedly at high altitude. Modern working concepts include technologically enabled individuals operating automated machinery and intelligence systems. ⁎ Correspondence to: R. Zheng, Department of Health Service, College of High Altitude Military Medicine, Third Military Medical University, No. 30 Gao Tan Yan Zheng Street, Sha Ping Ba District, Chongqing, China 400038. Fax: + 86 23 68752329. ⁎⁎ Correspondence to: Y.-Q. Gao, College of High Altitude Military Medicine, Third Military Medical University, No. 30 Gao Tan Yan Zheng Street, Sha Ping Ba District, Chongqing, China 400038. Fax: + 86 23 68752334. E-mail addresses: [email protected] (R. Zheng), [email protected] (Y. Gao). 0031-9384/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2012.03.002
People engaged in crucial technical or operational work (e.g., aircraft pilots, workers managing large machinery, drivers controlling modern trains) require much greater cognitive capabilities than other workers. At high altitudes, a small cognitive lapse by one of these critical personnel may cause failure of a mission or other catastrophic consequences. For example, impairment in the judgment and decision-making capacities of train drivers may increase the risk of an accident when operating trains in dangerous conditions. Typically, these workers have undergone a longer process of occupational training, which leads to operational proficiency, especially in agility, stability and accuracy. Studies in humans and in many animal species have shown that training can improve the performance of a wide range of cognitive functions [10,11] and that training-dependent cognitive enhancement is mainly due to taking advantage of neural plasticity [12–16]. However, due to a lack of studies specifically designed for these well-trained people at high altitudes, it has not been established whether the cognitive abilities acquired from training were affected by a hypoxic environment at high altitudes, and whether the extent of cognitive deficits of highly trained workers and nontrained people were similar at these altitudes. The present study aims to clarify the aforementioned problems and compared the cognitive impairment between specially trained
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military operators and ordinary soldiers in troops who were assigned to a high altitude area with an elevation of 3900 m. Because the influences of cognitive function are manifested behaviorally, neurobehavioral testing is commonly recognized as a sensitive and valid method for detecting cognitive dysfunction [17]. Previous studies have revealed that some high-load or difficult-task cognitive functions are more easily affected by hypoxic exposure [18,19], so the Raven's standard progressive matrices (RSPM) test was adopted to measure cognitive capacity for the encoding and analysis of complex information, such as comparisons and analogies [20]. Thus, in the present study, the neurobehavioral and RSPM tests were chosen to comprehensively evaluate the decline of cognitive efficiency resulting from high altitude hypoxia. Since brain function was easily damaged by hypoxia, we consider the hypothesis that hypoxic exposure could also reverse or disturb neural connections built depending upon training, which may be due to a decreased supply of oxygen and energy, changed neural structure and synapse-related cytokines, and thus attenuate training-dependent cognitive ability. The results of this study preliminarily demonstrated that the training-dependent advantage of cognition was really suppressed by exposure to hypoxia. The decreased brain-derived neurotrophic factor (BDNF) and the elevated inflammatory cytokines during hypoxia were likely involved in the mechanism. 2. Methods 2.1. Subjects There were 105 male soldiers who participated in this study, including 54 professionally trained operational personnel and 51 other soldiers. The subjects in the operational personnel group all served in the real-time monitoring, measuring and commandexecuting of an automatic control system. They all underwent strict training of auditory, visual and manual abilities for at least 6 months, resulting in efficient skills in reaction, memory and hand-eye coordination. Members of the other soldier group were selected from a pool of soldiers engaged in routine jobs, including stevedoring, repairing, secretarial work, cooking and medical care, and who had not received special cognitive training. The two groups were matched for age, height, weight and educational level (Table 1). The subjects all resided at altitudes that were lower than 500 m and had never traveled to altitudes of 2000 m or higher. The troops were transported by train from plains region (altitude b300 m) to a base camp on the Qinghai–Tibetan Plateau (altitude 3900 m) within 5 days (Fig. 1). When reaching above 2800 m, additional oxygen was supplied to the train coach, which increased the percentage of O2 from 21% to 24–25% by volume. All tests were administered to each individual 30 days prior to his departure from low land and 5 days after his arrival at the high altitude (3900 m) base camp (Fig. 1). No subjects had prior experience with neurobehavioral or RSPM tests. Subjects who showed signs of acute mountain sickness (The criterion was both a headache and a total Lake Louise symptom score of 3 or greater [21]) or who were using any medications or were using supplementary oxygen during investigation were excluded. All participants provided informed consent, and the study protocol was approved by the Ethics Committee of the Third Military Medical University.
Table 1 Basic characteristics of the study population (mean ± SD).
Age Height (cm) Weight (kg) Years of education
Trained operational personnel group (n = 54)
Untrained ordinary soldiers group (n = 51)
26 ± 4 174 ± 5 72 ± 10 14 ± 2
26 ± 4 173 ± 4 70 ± 8 14 ± 2
2.2. Neurobehavioral test A selection of tests from the World Health Organization Neurobehavioral Core Test Battery (WHO-NCTB) was used, which access the following cognitive functions: auditory memory, manual dexterity, perceptual-motor speed, visual perception and motor steadiness. Additionally, the EP202 4-color choice reaction measurer (ECNU, Shanghai, China) and the DDX-200 auditory reaction measurer (BODA, Beijing, China) were used for visual and auditory reaction speeds. All cognitive tests were scheduled in the morning (between 9 a.m. and 11 a.m.) and were performed in a quiet and luminous room without interruptions by other people. The suitable tables and chairs were provided. All tests were administered by trained interviewers, and the methods have been described in detail elsewhere [22,23]. 2.3. The Raven's standard progressive matrices (RSPM) It was not applicable to compare RSPM scores of a group of subjects at high altitude with themselves at lowland due to possible retention of memory related to the test detail. Therefore, subjects from both the group of highly trained operators and the group of ordinary soldiers were randomly assigned to a pre-hypoxia or in-hypoxia subgroup to perform RSPM tests; each subgroup had 20 individuals. As previously reported [20], the test consists of 60 diagrammatic puzzles that are divided into five sets (A, B, C, D, and E) of 12 items each. A subject was given 30 min to complete all 60 questions, even if some of his answers were informed guesses. 2.4. Physiological Indices The resting arterial oxyhemoglobin saturation (SaO2) levels and heart rates (HRs) of all subjects were measured using a DatexOhmeda TuffSat portable instrument (SOMA, Connecticut, USA), before the cognitive tests. 2.5. Blood sampling and cytokine measurement Venous blood samples of each subject at low and high altitudes were obtained on the same days as cognitive tests. Cytokines in the plasma, including BDNF, interleukin 1β (IL-1β) and vascular endothelial growth factor (VEGF), were measured by the enzyme-linked immunosorbent assay (ELISA) using immunoassay kits (R&D Systems, Minneapolis, MN). 2.6. Pittsburgh Sleep Quality Index (PSQI) The PSQI consists of 18 questions that are designed to assess 7 components of sleep quality. The scores from each component can be summed to a total score that ranges from 0 to 21, where 0 indicates no difficulty and 21, severe difficulty. The details of the PSQI have been described elsewhere [24]. 2.7. Statistical analysis A statistical analysis was carried out using the SPSS 13.0 software. T-tests were used for normally distributed continuous variables and nonparametric rank-based analysis was used for non-normally distributed variables. The physiological and WHO-NCTB performances of each subject at high altitude were compared to baseline at lowland using tests for paired or related samples, and independent samples tests were used for comparisons between the two groups of subjects. For the RSPM performances of four independent groups, the between-group comparisons were performed using one-way analysis of variance (ANOVA) followed by a least significant difference (LSD) test. The criterion for significance was 0.05, and all p values were two-tailed.
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Fig. 1. Time course of the study: days of measurement and ascent by train.
3. Results 3.1. The physiological changes before and after hypoxic exposure As shown in Table 2, there were no differences between the highly trained operator group and the other soldier group in HR, SaO2 and sleep quality assessed with the PSQI at low altitude. At high altitude, almost all subjects showed increases in HR (approximately 20–25% higher), reductions in SaO2 (approximately 10% lower) and reduced sleep quality (PSQI scores were 1.3–1.5 points higher), but the extent of these changes (differences between pre-hypoxic and in-hypoxic conditions) was indistinguishable between the two cohorts of soldiers. 3.2. Neurobehavioral function changes The highly trained operational personnel group performed statistically better in some neurobehavioral tests than the other soldier group before high altitude living (reflected by p-value c in Table 3), including shorter reaction time and higher accuracy on the visual reaction test, better scores on the digit symbol test, and more correct dots and fewer wrong dots in pursuit aiming test. Almost all subjects exhibited significant declines of neurobehavioral function after arriving at the high altitude base camp. After 5 days living at 3900 m, both groups had reduced performance on most of the neurobehavioral tests (reflected by p-value a and pvalue b in Table 3, respectively), including lower visual reaction accuracy, longer auditory reaction time, and diminished performance on the digit span test, manual dexterity test (regardless of the hand that was tested), digit symbol test and pursuit aiming test. Visual reaction times and scores of Benton visual retention seemed to be unaffected by hypoxic exposure. Next, difference values of cognitive function between before and during high altitude living were calculated for each subject. Importantly, comparisons between the two groups indicated that the highly trained operational personnel exhibited more significant cognitive declines during hypoxia than the untrained soldiers, especially in visual
reaction accuracy and auditory reaction time (Fig. 2A–B). They also demonstrated more substantial declines in performance on the digit symbol test and the pursuit aiming test (as measured by reporting lower numbers of correct dots) (Fig. 2C–D). In other words, the initial advantage of highly trained operational personnel on these tests ceased at high altitude (reflected by p-valued in Table 3). 3.3. Changes of RSPM scores As shown in Table 4, at low altitude, the operational personnel demonstrated markedly higher cognitive capacity for complicated tasks, which was reflected by higher total RSPM scores (sum of scores for five subsets A–E) compared to those of ordinary soldiers (pvalue c). For each subset A–E, the scores of two groups did not differ. The RSPM scores for ordinary soldiers group did not change after 5 days of hypoxia (p-value b). However, the total RSPM scores and scores on subset E for trained operational personnel decreased significantly (p-value a). As a result, although the trained group had an advantage before hypoxia, the RSPM scores of the two groups were approximately equal at high altitude (p-value d). 3.4. Plasma cytokines respond to hypoxic exposure As shown in Fig. 3, no cytokine exhibit difference between trained group and untrained group either at lowland or at high altitude. There was a marked decrease of BDNF in plasma during hypoxia, and the decline was in essence the same between the trained and untrained group (Fig. 3A). Plasma IL-1β exhibited an increasing tendency at high altitude, and the two groups raised with similar extent (Fig. 3B). In addition, VEGF in plasma of both groups remained unaffected by hypoxic exposure (Fig. 3C). 4. Discussion Although there have been extensive reports of cognitive impairment at high altitude in recent years and similar results have been observed in the present study, the most significant finding of this paper
Table 2 Physiologic indices of the two groups measured at low and high altitudes (mean ± SD). Trained operational personnel group (n = 54)
SaO2 HR PSQI
Untrained ordinary soldiers group (n = 51)
Pre-hypoxia
In-hypoxia
Difference
Pre-hypoxia
In-hypoxia
Difference
97.54 ± 1.06 70.83 ± 11.6 5.15 ± 2.08
88.7 ± 2.63⁎ 89.98 ± 10.48⁎ 6.48 ± 2.88⁎
8.8 ± 2.88 19.15 ± 14.43 1.33 ± 2.63
97.61 ± 0.93 70.16 ± 9.73 4.84 ± 1.89
89.45 ± 1.97⁎ 88.96 ± 10⁎ 6.33 ± 2.2⁎
8.16 ± 2.27 18.8 ± 13.69 1.49 ± 1.96
⁎ P b 0.05; significantly different from corresponding values during pre-hypoxia using paired samples t-tests.
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Table 3 Neurobehavioral function of the two groups measured at low and high altitudes (mean ± SD). Trained operational personnel group
Untrained ordinary soldiers group
(n = 54)
(n = 51)
Pre-hypoxia
Visual reaction time (s) Visual reaction error 0 time 1 time 2 times 3 times Audible reaction time (ms) Forward digit span Backward digit span Santa Ana (preferred) Santa Ana (nonpreferred) Digit symbol test Benton visual retention Pursuit Aiming (correct) Pursuit Aiming (wrong) Pursuit Aiming (total)
In-hypoxia
0.635 ± 0.068
0.649 ± 0.080
42 (77.8%) 12 (22.2%) 0 0 291.1 ± 69.3 12.22 ± 1.54 8.65 ± 2.59 26.36 ± 3.49 23.48 ± 3.35 76.50 ± 12.64 8.04 ± 1.16 153.24 ± 16.50 9.48 ± 3.85 162.72 ± 17.01
21(38.9%) 20(37%) 8 (14.8%) 4 (7.4%) 369.4 ± 92.1 11.74 ± 1.49 7.93 ± 2.27 24.55 ± 3.19 22.46 ± 3.25 71.37 ± 13.10 7.88 ± 1.06 141.85 ± 18.57 13.67 ± 4.44 156.07 ± 18.79
p-valuea ⁎
0.124 b 0.001
b 0.001 0.034 0.003 b 0.001 b 0.001 b 0.001 0.197 b 0.001 b 0.001 0.004
Pre-hypoxia
In-hypoxia
0.690 ± 0.072
0.700 ± 0.069
28 (54.9%) 18 (35.3%) 4 (7.8%) 1 (1.9%) 318.5 ± 97.1 12.18 ± 1.53 8.41 ± 2.28 25.80 ± 3.90 23.73 ± 3.11 71.33 ± 13.73 7.92 ± 1.26 145.22 ± 20.91 11.10 ± 4.08 156.31 ± 21.28
19 (37.3%) 20 (39.2%) 10 (19.6%) 2 (3.9%) 366.2 ± 100.64 11.75 ± 1.38 7.98 ± 2.21 24.30 ± 4.05 22.94 ± 2.87 69.31 ± 13.82 7.53 ± 1.22 140.88 ± 20.47 13.94 ± 5.95 154.82 ± 22.02
Between 2 groups
p-valueb ⁎
Pre-hypoxia
In-hypoxia
p-valuec
p-valued
#
0.237 0.001
b0.001 0.007
0.002 0.992
b 0.001 0.062 0.033 b 0.001 b 0.001 0.026 0.227 0.043 b 0.001 0.498
0.097 0.879 0.621 0.436 0.700 0.047 0.745 0.030 0.039 0.09
0.87 0.988 0.901 0.734 0.427 0.436 0.762 0.622 0.789 0.691
#
⁎ Comparisons were performed between pre-hypoxia and in-hypoxia using paired samples t-tests (except for visual reaction error, for which 2 related samples nonparametric rank-based tests were used). # Comparisons were performed between the two subject groups for scores during pre-hypoxia and in-hypoxia using independent samples t-tests (except for visual reaction error, for which 2 independent samples nonparametric rank-based tests were used).
is that well-trained operators demonstrate more severe cognitive deficits than untrained ordinary people at a high altitude. In other words, it has not previously been reported that the initial cognitive advantage that highly trained workers had over other people was lost during acute high altitude hypoxia. Under normal conditions, the performance of highly trained operators on several neurobehavioral tests and the RSPM test was significantly better than that of ordinary soldiers. This difference was due to extensive practice for targeted cognitive abilities. The contents of the
training program determined which aspects of cognitive abilities were enhanced. The great potential of the brain to develop, change and modify itself under the influence of training has been termed neural plasticity. Synapse was the cellular structure responsible for communication between neurons. It has been postulated that the short- and long-term modification of synapse efficacy played a primary role in training-dependent cognition improvement [25]. Other mechanisms of neural plasticity included intrinsic neuronal excitability, dendritic integration, neuron–glia signaling, and others [26].
Fig. 2. Difference values of neurobehavioral performances between pre-hypoxia and in-hypoxia. First, the pre-hypoxia/in-hypoxia difference value for each subject was calculated. Then, comparisons were performed between the two subject groups for the calculated difference values using 2 independent samples nonparametric tests. The medians were marked using horizontal lines and the cross-group comparisons were marked using connection lines.
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Table 4 RSPM scores measured at low and high altitude (mean ± SD). Set A
Set B
Set C
Set D
Set E
Total score
Trained operational personnel group Pre-hypoxia (n = 22) In-hypoxia (n = 21) p-valuea
11.09 ± 0.97 10.38 ± 1.36 0.091
10.41 ± 1.53 9.81 ± 1.89 0.272
8.86 ± 1.64 8.19 ± 1.99 0.231
8.31 ± 2.06 7.48 ± 1.75 0.155
7.82 ± 1.87 6.05 ± 2.09 0.007
46.5 ± 5.42 41.9 ± 5.49 0.002
Untrained ordinary soldiers group Pre-hypoxia (n = 21) In-hypoxia (n = 20) p-valueb p-valuec between groups during pre-hypoxia p-valued between groups during in-hypoxia
10.43 ± 1.5 10.3 ± 1.56 0.763 0.115 0.849
9.62 ± 1.75 9.60 ± 1.93 0.973 0.149 0.707
8.29 ± 1.87 7.90 ± 1.83 0.502 0.304 0.613
8.05 ± 2.09 7.50 ± 1.76 0.365 0.646 0.968
7.19 ± 2.38 6.1 ± 2.1 0.103 0.333 0.937
43.57 ± 4.04 41.4 ± 3.52 0.145 0.045 0.733
Between-group comparisons for RSPM scores of four subgroups were performed using one-way analysis of variance (ANOVA) followed by a least significant difference (LSD) test.
The present study was specifically designed to test whether the cognitive superiority that resulted from intensive training had been influenced by acute hypoxic exposure. The results clearly demonstrated that some aspects of cognitive function that had been superior in the highly trained group at low altitude exhibited more vulnerable at high altitude. These aspects included reaction, perception and motor stability, as well as cognitive capacity for processing complex information. The cause of cognitive impairment at high altitude was known to be reduced cerebral oxygen supply and consequent brain damage [27]. In addition, poor sleep quality at high altitude may disturb cognitive function [28]. However, there were no differences between the two cohorts of soldiers in either oxyhemoglobin saturation or sleep quality. Perhaps the primary explanation was that hypoxic exposure damaged the relevant structures or functions underlying trainingdependent neural plasticity. Anatomically, the brain regions that happened to be most vulnerable to hypoxic damage, such as the cortical layers and the hippocampus, are also closely related to neural plasticity [16,29]. Changes that occurred in these areas following hypobaric
hypoxia included morphological alteration [30], neuronal apoptosis [31], neurotransmitter disorder [32] and abnormal electrical activity [33]. Moreover, synapses, which are key cellular structures in trainingdependent neural plasticity, were easily damaged under hypoxic conditions. Several studies have already demonstrated that hypoxia had a direct influence on the synaptic release of neurotransmitters [34–36] and the expression of genes involved in synaptic function [37], In addition, hypoxia-inducible factor 1α (HIF-1α), a transcription factor that is upregulated during hypoxia, may play an important role in affecting genes expression relevant to synapse [38]. We consider some cytokines may participate in the reversal or disturb of synaptic plasticity that was built during training. It was reported that the level of VEGF in the hippocampus can dynamically modulate neuronal plasticity [39]. In addition, BDNF plays an essential role in plastic changes of synapse, including enhancing hippocampal long-term potentiation (LTP) and attenuating long-term depression (LTD) [40,41]. Some inflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) could also cause synaptic dysfunction through
Fig. 3. Plasma BDNF, IL-1β and VEGF cytokine concentrations at low and high altitudes (n = 40). Venous blood samples of each subject at low and high altitudes were obtained and plasma cytokines were measured. The comparisons were performed between pre-hypoxia/in-hypoxia using 2 related samples nonparametric tests. The median concentrations were marked using horizontal lines and the pre-hypoxia/in-hypoxia differences were marked using connection lines.
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affecting synaptic transmission and synaptic proteins [42,43]. Moreover, the fact of increasing IL-6 at high altitude has been observed [44]. In the present study, except for VEGF, the drop of protective cytokine BDNF and the elevation of damaging inflammatory cytokine IL-1β did occur during hypoxia. We noticed that these changed cytokines exhibited no difference between trained and untrained groups, but it did not contradict to the opinion that these altered cytokines may suppress training-dependent cognitive advantage much more. The reason was that the newly built neurons connection benefiting from recent training may be easily affected than stable basic cognition. Meanwhile, the synaptic plasticity that training-dependent advantage depends upon was more susceptible by these changed cytokines. Further research is required to determine the exact cause–effect relationship. We had to admit that, for methodological reason, the specific ability that the operators have been trained for cannot be tackled exactly and can only be indirectly and partly reflected by NCTB and RSPM tests in the present study. Thus except for examined general cognitive functions, we cannot exclude that the trained soldiers would still be able to perform the trained tasks better than untrained people. Some important questions also remain for future research. First, it is necessary to approach how training-dependent neural plasticity is easily affected by hypoxia exposure, especially to define the brain regions related to this study using fMRI or similar techniques and to explore key functional molecule in the brain tissue by simulating animal experiments. Second, it is important to identify whether the deficits of training-dependent cognition in hypoxia are transient or permanent because cognitive deficits may recover after acclimatization to hypoxia. Finally, it is valuable to know which anti-hypoxic drugs or means could minimize losses of cognitive advantage built upon training at high altitude. 5. Conclusions In summary, the present study confirmed that cognitive advantage of highly trained workers was easily suppressed by hypoxia at high altitude although exact mechanisms were not yet clear. Therefore, close attention should be paid to these personnel, and effective measures, including but not limited to providing workers with a reasonable oxygen supply and powerful anti-hypoxic drugs, should be taken to ensure that good performance of various job tasks is sustained at high altitudes. Acknowledgments The work was supported by the 973 Project of China (No. 2012CB518201) and the Science Foundation of the Third Military Medical University (No. 2010XQN18). References [1] Hornbein TF, Townes BD, Schoene RB, Sutton JR, Houston CS. The cost to the central nervous system of climbing to extremely high altitude. N Engl J Med 1989;321:1714–9. [2] Virues-Ortega J, Buela-Casal G, Garrido E, Alcazar B. Neuropsychological functioning associated with high-altitude exposure. Neuropsychol Rev 2004;14:197–224. [3] Bjursten H, Ederoth P, Sigurdsson E, Gottfredsson M, Syk I, Einarsson O, et al. S100B profiles and cognitive function at high altitude. High Alt Med Biol 2010;11:31–8. [4] Shukitt-Hale B, Stillman MJ, Welch DI, Levy A, Devine JA, Lieberman HR. Hypobaric hypoxia impairs spatial memory in an elevation-dependent fashion. Behav Neural Biol 1994;62:244–52. [5] Wesensten NJ, Crowley J, Balkin T, Kamimori G, Iwanyk E, Pearson N, et al. Effects of simulated high altitude exposure on long-latency event-related brain potentials and performance. Aviat Space Environ Med 1993;64:30–6. [6] Bouquet C, Gardette B, Gortan C, Therme P, Abraini JH. Color discrimination under chronic hypoxic conditions (simulated climb “Everest-Comex 97”). Percept Mot Skills 2000;90:169–79. [7] Bouquet CA, Gardette B, Gortan C, Abraini JH. Psychomotor skills learning under chronic hypoxia. Neuroreport 1999;10:3093–9. [8] Singh SB, Thakur L, Anand JP, Yadav D, Amitabh, Banerjee PK. Effect of chronic hypobaric hypoxia on components of the human event related potential. Indian J Med Res 2004;120:94–9.
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