A Neuroimaging Study Of Chronic Hypoxia Induced Cognitive Impairment

In recent years,encouraged by series of new policies,more and more Chinese people from less developed rural areas have immigrated to Tibet for business,education or service.Health maintenance of the high-altitude immigrant population has become a major focus for public health departments in the Chinese government.In high-altitude,hypoxia combined with other physiological stress,such as hypobaria,cold,ultraviolet rays and dehydration,contributes to a decline in cognitive function.According to previous studies,acute hypobaric hypoxia exposure for several weeks during short-term expedition to extremely high-altitude areas causes decline in working memory,learning ability,attention and concentration.Compared to the number of studies on cognitive changes after acute high-altitude exposure,there are fewer studies on cognitive impairments associated with chronic exposure to hypobaric hypoxia.Besides,these studies commonly compared high-altitude indigenous residents or immigrants with age matched sea level residents;in this case,when assessing neuropsychological/cognitive differences,the demographic,cultural and socioeconomic differences between the populations may lead to significant bias.The influence of chronic high-altitude exposure on cognitive function in high-altitude immigrants has yet to be dynamically assessed and fully confirmed.Furthermore,although several neuropsychological alterations under hypoxia have been observed with neurobehavioral and neurobiological methods in previous studies,the key position and mechanism of hypoxia related cognitive impairment have not yet been revealed,which may cast negative influence on the cognitive function maintenance at high altitude.ObjectiveHerein in this study,we carried out a panel study in a young healthy high-altitude immigrant population and addressed the cumulative impact of chronic high-altitude exposure on cognitive function,including working memory,.In addition,brain structural and functional alterations during chronic high-altitude exposure,together with cognitive changes were followed,to ascertain the neural structural and functional basis of cognitive impairment during chronic high-altitude exposure.Methods1.Subject enrollment and following-upOn July 2014,69 high school graduates admitted to Tibet University for in Lhasa were enrolled into this panel study and followed up for two years.The subjects were instructed to complete a set of questionnaires comprising high-altitude exposure history,and sociodemographic information including parental education,vocation and socioeconomic status.2.Physiological and neuropsychologic measurementsDuring the baseline and follow-up investigation,physical examinations were performed to assess the subjects' health condition.The clinical tests consisted of basic physiological measurement,blood biochemical tests,hematologic tests,heart function tests and pulmonary function tests.A neuropsychological test battery consisted of immediate verbal memory(IVBM),delayed verbal memory(DVBM),immediate visual memory(IVIM),delayed visual memory(DVIM),Stroop test(ST),visual simple reaction time(VSRT),audial simple reaction time(ASRT),visual recognition reaction time(VRRT)and audial recognition reaction time(ARRT)was performed to measure the working memory,executive control and psychomotor function of the subjects.3.MRI data acquisitionOn July 2014 and May 2016,magnetic resonance imaging(MRI)data,including standard T1-weighted 3D anatomical data,diffusion tensor imaging(DTI)and resting state functional magenatic resonance imaging(rs-f MRI)data were acquired using the General Electric Discovery MR750 3.0T systems in Xijing Hospital of Fourth Military Medical University and General Hospital of Tibet Military Region,respectively.4.MRI data analysisStructural MRI data was analyzed by VBM to reveal the alteration of regional grey matter(GM)volume after exposure,while DTI data was analyzed by tract based spatial statistics(TBSS)to reveal the changes of fractional anisotropy(FA),axial diffusivity(AD),radial diffusivity(RD)and mean diffusivity(MD).Simultaneously,functional imaging analysis based on rs-fMRI was performed to investigate the regional homogeneity(ReHo)and functional connectivity(FC)differences between before and after exposure.Finally,independent component analysis(ICA)and dual regression was implemented to perform the before-after comparison of regional brain function within resting state networks(RSNs).Results1.Demographic information and high-altitude exposureAccording to the investigation,All the subjects enrolled in this study aged below 20.Most subjects came from less developed rural areas and immigrated to Tibet to acquire higher education.Furthermore,the cumulative high exposure time per 12 months of the subjects(301.6±9.1d)approximated the average level of the whole immigrant population investigated in our previous cross-sectional survey.Taken together,since the current follow-up study was based on the typical Chinese high-altitude immigrant population,the cognitive and neuroimaging assessment acquired in this study may be representative and valuable as a reference for health maintenance in Chinese Tibet immigrants.2.Alteration of physiological parameters under chronic hypoxia exposureAmong the hematologic parameters,RBC,HGB and HCT displayed a compensatory lift at the end of the 1st year and then maintained the high level(p=0.000,p=0.000,p=0.000),indicating an improvement of blood oxygen carrying capacity.Among the heart function parameters,LVEF,LVSF and LVEDD displayed a compensatory improvement in the 1st year and then stayed at the high level(p=0.000,p=0.000,p=0.000),while E/A ratio decreased simultaneously(p=0.000),indicating an improvement of left ventricular systolic function.However,although compensatory physiological changes were significantly identified in various aspects,SpO2 of the subjects were still at a low level during the long term exposure,indicating that hypoxia persisted within the subjects.3.Cognitive impairment under chronic hypoxia exposureIn the DVBM and DVIM test,the subjects' performance significantly varied over exposing time(p=0.000;p=0.000),indicating the impaired function of working memory.The first part of ST indicated,the subjects' number of correct response varied over exposing time(p=0.000),while the responding time has been prolonged(p=0.004).Similarly,in the second part of ST,the accuracy and resonding time both varied over exposing time(p=0.001;p=0.015),indicating the impaired function of executive function.In the reaction time tests,VSRT,ASRT,VRRT and ARRT have been prolonged under hypoxia(p=0.000;p=0.000;p=0.000;p=0.000),indicating the impaired psychomotor function.Notably,all the above mentioned cognitive impairments occurred in the early stages of exposure(before 1 y)with no amelioration during the over time,indicating that the cognitive changes are irreversible under chronic high-altitude exposure.4.Alteration of GM/WM structure under chronic hypoxia exposureStructural imaging analysis using VBM revealed brain structural alterations after chronic high-altitude exposure.Decreased GM volume was found in the left putamen by before-after comparison,suggesting loss of neurons in this region(|t| > 4.90,p < 0.05,FDR correction).Besides,TBSS analysis found diffusion disturbance in WM microstructure,including elevated FA in left anterior corona radiate(p < 0.05,TFCE correction)and elevated AD in bilateral superior corona radiate,sagittal stratum,external capsule,superior fronto-occipital fasciculus and fornix stria(p < 0.05,TFCE correction),which may suggest compensatory reorganization of WM microstructure.Furthermore,we also found elevated RD in right internal capsule(p < 0.05,TFCE correction),which may be related to hypoxia caused demyelination.5.Alteration of resting-state brain function under chronic hypoxia exposureFunctional imaging analysis based on rs-fMRI was performed to investigate the ReHo differences between before and after high-altitude exposure.Compared to pre-exposure,the subjects' after exposure showed a significant decrease in ReHo in bilateral putamen,bilateral superior temporal gyri,bilateral superior parietal lobule,anterior cingulate gyri,medial frontal gyri and anterior cerebellum lobe(|t| > 2.70,p < 0.01,AlphaSim correction).A region in the anterior left putamen where both GM volume and ReHo were significantly decreased,was used as the seed to study alterations in FCs with other brain regions.Subjects after-exposures were characterized by decreased FC in the bilateral superior temporal gyri,bilateral striatum,bilateral postcentral gyri,anterior/middle cingulate gyri,medial frontal gyri,right cerebellum,right hippocampi and right brainstem(p < 0.01,FDR correction).Statistics analysis supported the significant correlation between the alteration of ReHo/FCs and the changing value of neuropsychological measurements(p < 0.05).Dual regression analysis reported disrupted captivation with default mode network and executive control network(p < 0.05,FDR correction).Taken together,the decreased neural activity,functional relationship and networks as revealed by ReHo,FC and RSN analysis may be the brain functional basis of the chronic hypoxia related cognitive impairment.ConclusionWe carried out a panel study based on young healthy high-altitude immigrant population in order to assess the cognitive and neuroimaging changes of the immigrants associated with chronic high-altitude exposure.A series of cognitive functions were identified to be impaired during high-altitude exposure,such as working memory and psychomotor function.Structural MRI and rs-fMRI analysis provide direct evidence of neuron loss,WM reorganization,decreased neural activity,weakened functional connectivities and altered brain networks,which may jointly constitute the brain structural and functional basis of the chronic hypoxia related cognitive impairment.Putamen was found with both GM loss and ReHo decrease.It may be inferred that this region is more sensitive to chronic hypoxia exposure and should be highlighted in the future researches of cognitive function maintenance at high altitude.