Jiaxing Zhang

High altitude hypoxia is known to induce both physiological and neural alterations, however, the dynamics of brain functional changes following short-term exposure remain unclear. This study aimed to investigate the physiological and neural effects of short-term high altitude exposure and subsequent recovery at low altitude. We assessed hematological parameters and brain functional activity at three time points: one week before ascent, on day 30 of high altitude exposure, and two months after returning to sea level. After 30 days at high altitude, red blood cell count and hemoglobin increased, with the SpO₂ decreased; the regional homogeneity (ReHo) were significant differences in the cerebellum posterior lobe, brainstem, fusiform, lingual gyrus, and precentral gyrus. The voxel-mirrored homotopic connectivity (VMHC) were significant differences in the occipital and postcentral cortices. Edge-level functional connectivity (FC) analysis revealed reduced connectivity within the visual network (VN), sensorimotor network (SMN), subcortical network (SCN), and frontoparietal network (FPN), as well as between the SMN and ventral attention network (VAN), and between the FPN and default mode network (DMN). Our findings revealed that both physiological indices and brain functional measures (ReHo, VMHC, and FC) showed a similar pattern of recovery, returning to baseline levels after returning to low altitude for two months. These results provide new evidence for the reversibility of brain functional alterations following short-term high altitude exposure.

Gender differences in adaptation to high-altitude environments are evident, but the specific patterns in Tibetan brains remain unclear. We analyzed T1-weighted magnetic resonance imaging scans and neuropsychological test results from 61 male and 68 female Tibetans, with lowland Han participants as controls. Tibetan females had poorer performance than males in digit serial accumulation and forward digit span. Both Tibetan and Han males had significantly larger global gray matter volume and white matter volume than females, only Tibetan female brains contained a larger proportion of gray matter than male brains. Tibetan females (vs. males) had smaller regional gray matter volume in the left rostral middle frontal gyrus and pars opercularis and right caudal middle frontal gyrus, and gray matter volume in the left pars opercularis in all Tibetans had a significant positive correlation with forward digit span. Conversely, Tibetan females had greater cortical thickness in these regions, which negatively correlated with altitude. Han populations exhibited different gender-based patterns in gray matter volume and cortical thickness compared to Tibetans. These findings suggest that Tibetan female brains are more susceptible to high-altitude, and the observed gender differences in brain volume may relate to distinct neuropsychological performances.

High altitude (HA) exposure induces impairments in visual function. This study was designed to dynamically observe visual function after returning to lowland and elucidate the underlying mechanism by examining the structure and function of retina and visual pathway. Twenty-three subjects were recruited before (Test 1), and one week (Test 2) and three months (Test 3) after their return from HA (4300 m) where they resided for 30 days. The clock task was used to assess visual cognition; and pattern-reversal visual evoked potential (p-VEP) and full-field electroretinogram (ff-ERG) were employed to record electrophysiological responses of retinal cells; optical coherence tomography (OCT), color doppler imaging (CDI) and magnetic resonance imaging(MRI) were used to measure structures of retina and visual pathway. In Test 2 vs. Test 1, there was increased reaction time during angle task; the amplitudes of scotopic 3.0 cd·s/m² and scotopic 10.0 cd·s/m² ERG a-wave and scotopic 3.0 cd·s/m² oscillatory potential in the right eye were significantly decreased, all of which were negatively correlated with the increased reaction time during the angle task. In Test 3 vs. Test 1, there were decreased amplitude of scotopic 10.0 cd·s/m² a-wave in the right eye and increased velocity of ophthalmic artery and ocular perfusion pressure in bilateral eyes. The VEP and visual pathway structures remained normal throughout the entire test. HA exposure caused damage to rod and cone responses in both outer and inner retina. After returning to sea level, the damaged visual cell functions gradually recovered over time, coinciding with an increase in the ocular perfusion.

Altitude training has been widely adopted. This study aimed to establish a mice model to determine the time point for achieving the best endurance at the lowland. C57BL/6 and BALB/c male mice were used to establish a mice model of hypoxic training with normoxic training mice, hypoxic mice, and normoxic mice as controls. All hypoxic mice were placed in a chamber filled with 16% O₂ and N₂, and hypoxic training mice were trained for two weeks. Then mice were removed from the chamber and tested at normoxic conditions weekly at the beginning of the experiment and the second, third, fourth, and sixth weeks. The tests for endurance ability include maximal aerobic speed (MAS), Rota-rod, and grip strength. In addition, the open field, visual cliff, and Y maze were used to test cognitive abilities. Body composition and lactic acid tolerance level were also measured. For BALB/c but not C57BL/6 mice were evaluated for effectively training. Based on the average MAS of all mice, mice successfully passed the training according to the procedure: the first week (32%MAS/10min, 48%MAS/10min, and 64%MAS/10min) and second week (40%MAS/10min, 56%MAS/10min, and 72%MAS/10min). Hypoxic training mice reached peak rotarod performance on the 7th day post-training (Test 3), with significant improvements compared to Test 1, 2, 4, and 5. At Test 3, their rotarod scores significantly differed from both H and N groups, and showing a trend towards difference from NT group. Meanwhile, hypoxic mice showed significant cognitive impairment, anxiety, depression, muscle loss, and fat gain compared with hypoxic training mice after hypoxia intervation. Two consecutive weeks of 16% O2 training followed by one week of reoxygenation may be the best for endurance competition. Thus, we think a mouse model for hypoxic training was built, with Rota-rod testing as a detection indicator. Moreover, hypoxic training may alleviate the damage of hypoxia to the body.

The effects of hypoxia on brain function remain largely unknown. This study aimed to clarify this issue by visual-stimulated functional magnetic resonance imaging design. Twenty-three college students with a 30-d high-altitude exposure were tested before, 1 week and 3 months after returning to sea level. Brain functional magnetic resonance imaging and retinal electroretinogram were acquired. One week after returning to sea level, decreased blood oxygenation level dependent in the right lingual gyrus accompanied with increased blood oxygenation level dependent in the frontal cortex and insular cortex, and decreased amplitude of electroretinogram a-wave in right eye; moreover, the bilateral lingual gyri showed increased functional connectivity within the dorsal visual stream pathway, and the blood oxygenation level dependent signals in the right lingual gyrus showed positive correlation with right retinal electroretinogram a-wave. Three months after returning to sea level, the blood oxygenation level dependent signals recovered to normal level, while intensively increased blood oxygenation level dependent signals in a broad of brain regions and decreased retinal electroretinogram were also existed. In conclusion, hypoxic exposure has long-term effects on visual cortex, and the impaired retinal electroretinogram may contribute to it. The increased functional connectivity of dorsal stream may compensate for the decreased function of retinal photoreceptor cells to maintain normal visual function.

世居高原藏族已形成独特的适应低氧环境的机制，低氧诱导因子（hypoxia-inducible factor，HIF）通路基因内皮PAS结构域蛋白1（endothelial PAS domain protein 1，EPAS1）的遗传变异已被阐明与其低氧适应密切相关。脑耗氧量高，因此最容易受到高原低氧的影响。本研究旨在探讨HIF通路基因遗传变异与世居高原藏族脑结构和功能网络的关系。本研究招募了135名世居高原藏族人（19.9 ± 1.1岁）作为研究对象，匹配的65名平原汉族人作为基因遗传变异的对照人群。首先，根据文献选择EPAS1基因中12个单核苷酸多态性（single nucleotide polymorphism，SNP）位点进行基因分型。其次，通过脑磁共振成像（magnetic resonance imaging，MRI）扫描获得藏族脑T1结构像和静息态功能MRI（functional MRI，fMRI）。藏族人群中单倍型GA和CAAA的频率显著高于平原汉族，具有这些高频率单倍型的适应较好藏族人群的脑皮层表面积在左中央后回、右距状旁回、右额中回和右后扣带回显著增加，皮层体积在左距状旁回和右颞上回显著增加，脑功能连接主要在躯体运动、腹侧注意、视觉和默认模式网络上显著增加。总之，本研究揭示了EPAS1基因适应性遗传变异与世居高原藏族脑结构和功能网络的关系，发现基因上适应较好的藏族人群脑的变化集中在功能活跃的视觉感知和运动控制脑区及其相关功能神经网络以及默认模式网络。脑的这些变化有助于调节藏族的高原活动。

Changes in cerebral blood flow (CBF) and regulation of cerebral circulation occur at high altitude (HA). However, the changes in CBF and their associations with neurological syndrome sequelae and blood pressure after subjects return to the lowlands remain unclear. In this study, the subjects were 23 college students who were teaching at an altitude of 4300 m for 30 days. These subjects were studied before reaching the HA (Test 1), one week after returning to the lowlands (Test 2), and three months after returning to the lowlands (Test 3). Symptom scores for de-acclimatization syndrome were evaluated. Changes in CBF were measured using the magnetic resonance imaging arterial spin labeling (ASL) technique. Additionally, the velocity of CBF in the cerebral arteries was measured using a transcranial doppler (TCD). In Test 2 vs. Test 1, the peak systolic velocity and mean velocity in the basilar artery were significantly decreased. CBF exhibited significant decreases in the left putamen/cerebellum crus1/vermis and right thalamus/inferior temporal gyrus, while significant increases were observed in the left postcentral gyrus/precuneus and right middle cingulate gyrus/superior frontal gyrus. In Test 3 vs. Test 1, the basilar artery velocity returned to the baseline level, while CBF continued to decrease. The mean global CBF showed a decreasing trend from Test 1 to Test 3. Furthermore, the mean global CBF had a negative correlation with the systolic pressure, pulse pressure, and mean arterial pressure. The decrease in CBF after reoxygenation may underlie the neurological symptoms in subjects returning to the lowlands. Increased blood pressure could serve as a predictor of a decrease in CBF.

It has been well-established that high-altitude (HA) environments affect the human brain; however, the differences in brain structural and functional networks between HA natives and acclimatized immigrants have not been well clarified. In this study, native HA Tibetans were recruited for comparison with Han immigrants (average of 2.3 ± 0.3 years at HA), with lowland residents recruited as controls. Cortical gray matter volume, thickness, and functional connectivity were investigated using magnetic resonance imaging data. In addition, reaction time and correct score in the visual movement task, hematology, and SpO₂ were measured. In both Tibetans and HA immigrants vs. lowlanders, decreased SpO₂, increased hematocrit and hemoglobin, and increased reaction time and correct score in the visual movement task were detected. In both Tibetans and HA immigrants vs. lowlanders, gray matter volumes and cortical thickness were increased in the left somatosensory and motor cortex, and functional connectivity was decreased in the visual, default mode, subcortical, somatosensory-motor, ventral attention, and subcortical networks. Furthermore, SpO₂ increased, hematocrit and hemoglobin decreased, and gray matter volumes and cortical thickness increased in the visual cortex, left motor cortex, and right auditory cortex in native Tibetans compared to immigrants. Movement time and correct score in task were positively correlated with the thickness of the visual cortex. In conclusion, brain structural and functional network difference in both Tibetan natives and HA immigrants were largely consistent, with native Tibetans only showing more intense brain modulation. Different populations acclimatized to HA develop similar brain mechanisms to cope with hostile HA environmental factors.

Cognitive dysfunction and brain white matter (WM) injury have been found in adults exposed to hypoxia. However, the mechanisms underlying these impairments remain unclear, and moreover, it is also unclear whether these impairments are reversible after reoxygenation. In this study, adult male mice were exposed to hypoxia for 15 days at a simulated altitude of 4300 m and then reoxygenated for 2 months. Control mice were raised under normoxic conditions. Mice showed a significant decrease in arterial oxygen saturation (SaO₂) and an increase in heart rate and breath rate after hypoxic exposure, and they displayed anxiety-like emotion and impaired cognitions. Hypoxic mice showed decreased brain WM fractional anisotropy (FA) and increased mean diffusion (MD) mainly in the corpus callosum and internal capsule. The reason for the adult brain WM injury was myelin rather than axon. Further, the myelin injury was due to the obstruction of oligodendrocyte precursor cells (OPCs) differentiation and eventually led to behavioral deficits. More importantly, the changes in physiological indicators, behavioral disorders, and WM injury caused by hypoxia can be recovered after reoxygenation. Taken together, our data indicate that adult brain WM injury caused by hypoxia is reversible after reoxygenation and enhancing OPCs differentiation may be a promising therapy for clinical hypoxic diseases associated with brain injury. Graphical Abstract Schematic diagram of brain WM and behavioral changes induced by hypoxia/reoxygenation in adult mice