Resting-state functional MRI analysis of the brain’s adaptation to chronic hypoxia: disease and environment
Original Article

Resting-state functional MRI analysis of the brain’s adaptation to chronic hypoxia: disease and environment

Minzhi Zhong1#, Xuguang Duan2#, Zou Qiao3, Zhiping Liang1, Yuemin Weng1, Hui Luo1, Yiqin Du1, Jun Bu1, Huaqu Zeng4

1Department of Radiology, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, China; 2Department of Radiology, Nyingchi People’s Hospital, Nyingchi, China; 3Department of Radiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; 4Department of Radiotherapy Center, Gaozhou People’s Hospital, Maoming, China

Contributions: (I) Conception and design: M Zhong, X Duan, J Bu, H Zeng; (II) Administrative support: J Bu, H Zeng; (III) Provision of study materials or patients: X Duan, Z Qiao, Z Liang, Y Weng; (IV) Collection and assembly of data: M Zhong, X Duan, Z Qiao, Z Liang, Y Weng, H Luo, Y Du; (V) Data analysis and interpretation: M Zhong, X Duan, Z Qiao, J Bu, H Zeng; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Prof. Jun Bu, MD. Department of Radiology, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), No. 396 Tongfu Zhong Road, Guangzhou 510220, China. Email: jeanbujun@163.com; Prof. Huaqu Zeng, MD. Department of Radiotherapy Center, Gaozhou People’s Hospital, No. 89, Xiguan Road, Gaozhou, Maoming 525200, China. Email: 756660752@qq.com.

Background: The brain is highly sensitive to oxygen supply; however, it remains unclear whether chronic hypoxia resulting from disease or environmental exposure leads to similar or distinct patterns of brain adaptation. This study aimed to characterize and compare the structural and functional brain changes associated with chronic hypoxia induced by chronic obstructive pulmonary disease (COPD) and high-altitude residence.

Methods: A total of 110 participants were enrolled in the study, including 20 patients with COPD (aged 45–65 years) and 30 matched controls, as well as 30 high-altitude residents (aged 35–50 years, altitude >2,800 m for >30 years) and 30 matched low-altitude controls. Structural brain assessment was performed using three-dimensional (3D) T1-weighted imaging, with voxel-based morphometry (VBM) analysis conducted via statistical parametric mapping. Functional evaluation was performed using regional homogeneity (ReHo) analysis with the Data Processing and Analysis of Brain Imaging (DPABI) toolkit based on resting-state blood oxygen level-dependent (BOLD) data. Group comparisons were performed using two-sample t-tests, with statistical significance set at P<0.05.

Results: Patients with COPD exhibited reduced gray matter volume in eight regions, predominantly located in emotion- and cognition-related regions, including the Temporal_inf_R (cluster size =194, t=3.50), Rectus_R (cluster size =145, t=3.72), ParaHippocampal_L (cluster size =158, t=3.68), and Insula_R (cluster size =201, t=4.38). The high-altitude residents showed gray matter changes primarily in visual regions, including the Cuneus_L (cluster size =162, t=2.79) and Occipital_Mid_L (cluster size =140, t=−2.82). ReHo analysis revealed increased ReHo in the bilateral caudate (R: cluster size =125, t=2.99; L: cluster size =89, t=2.34) and decreased ReHo in the Lingual_R (cluster size =94, t=−4.93) and Precuneus_R (cluster size =92, t=−4.78) in the COPD patients, while the high-altitude residents showed increased ReHo in the bilateral supplementary motor area (R: cluster size =164, t=3.80; L: cluster size =144, t=3.48) and decreased ReHo in the Precuneus_R (cluster size =82, t=−4.08). No significant differences in age or education were observed between the groups; however, the hemoglobin and oxygen saturation (SpO2) levels differed significantly between the groups (P<0.01).

Conclusions: These findings indicate that COPD and high-altitude residence are associated with distinct structural brain changes, affecting emotion- and cognition-related regions in patients with COPD and visual regions in high-altitude residents, despite broadly similar functional (ReHo) alterations in motor and visual areas. These findings highlight the differential vulnerability of brain regions to distinct types of chronic hypoxia.

Keywords: Resting-state functional magnetic resonance imaging (resting-state fMRI); chronic obstructive pulmonary disease (COPD); hypoxia; brain mapping; high-altitude

Submitted Feb 26, 2026. Accepted for publication Jun 26, 2026. Published online Jul 29, 2026.

doi: 10.21037/qims-2026-1-0438

Introduction

Hypoxia is a hallmark of various diseases, including respiratory, neurological, and hematological disorders, as well as high-altitude exposure (1). Chronic hypoxia is commonly observed in conditions such as neonatal asphyxia, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea-hypopnea syndrome (2,3). Patients with acute respiratory distress syndrome and high-altitude cerebral edema show significant brain changes, including atrophy and microhemorrhagic injury (4,5). The metabolic plasticity induced by hypoxia offers therapeutic potential for both chronic metabolic diseases and acute injuries (6). However, because chronic hypoxia often develops insidiously, its effects on brain structure and function are frequently overlooked.

Previous studies have shown that chronic hypoxia alters brain structure, function, and metabolism in affected individuals (7,8). Despite this knowledge, research on the effects of chronic hypoxia on the brain remains limited, and the exact pathological and physiological mechanisms underlying these changes remain unclear (9). Additionally, comparative analyses of brain damage resulting from disease-related versus environmental hypoxia are scarce. For example, COPD may lead to specific patterns of structural and functional brain abnormalities (10). Moreover, hypoxia in combination with cold or high temperatures may affect cerebral perfusion and oxygen supply differently. The mechanisms by which the brain adapts to these stressors remain unclear (11).

Functional magnetic resonance imaging (fMRI) allows clinicians to non-invasively explore changes in the brain (12,13), thereby enhancing our understanding of the complex patterns of various brain structures and neural functions (14,15). Among these approaches, voxel-based morphometry (VBM) and regional homogeneity (ReHo) are commonly used to characterize brain regions (16,17). VBM provides an automated, unbiased whole-brain assessment of gray matter volume without requiring a priori region selection, making it suitable for exploratory studies. ReHo measures the local synchronization of spontaneous blood oxygen level-dependent (BOLD) signals and reflects the coherence of neural activity within local circuits. Together, VBM and ReHo provide complementary structural and functional perspectives and are well suited for hypothesis-generating investigations of chronic hypoxia in which the affected brain regions cannot be predicted in advance.

Previous studies have examined VBM or ReHo alterations in COPD patients (18,19) or high-altitude residents (20,21) separately; however, no study has directly compared the patterns of structural and functional brain alterations associated with these two distinct causes of chronic hypoxia within a single analytical framework. The key knowledge gap is whether disease-induced (COPD) and environmental (high-altitude) chronic hypoxia produce similar or divergent patterns of brain adaptation.

Therefore, this study aimed to describe the structural differences between two chronic hypoxia models and extend our understanding of changes in local brain function at rest. This descriptive cross-sectional analysis aimed to characterize, rather than mechanistically explain, the patterns of brain changes associated with chronic hypoxia of different causes. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0438/rc).

Methods

Study population and design

A total of 110 participants were included in this two-center collaborative study, including 20 patients with COPD and 30 healthy controls (aged 45–65 years). Data were collected at the First Affiliated Hospital of Guangzhou Medical University. The environmental exposure group comprised 30 high-altitude residents and 30 low-altitude controls (aged 35–50 years). Data were collected at Nyingchi People’s Hospital in Xizang, China. The patients with COPD and corresponding healthy controls were matched for age (±3 years), sex, and education level (±2 years). Similarly, the high-altitude residents and low-altitude controls were matched for these demographic variables.

Inclusion criteria

The inclusion criteria for the COPD group were as follows: (I) compliance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 diagnostic criteria (https://www.goldcopd.org/); (II) post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <70% and FEV1 <80%; and (III) clinical stability.

The inclusion criteria for the high-altitude group were as follows: (I) residence at high altitude (>2,800 m; range: 2,800–3,650 m) for >30 years (mean duration, 42±11 years); (II) Tibetan residents; (III) oxygen saturation (SpO2) >90%; and (IV) Montreal Cognitive Assessment (MoCA) score ≥26.

The inclusion criteria for the control groups were as follows: (I) no history of psychiatric disorders; and (II) no systemic diseases.

Exclusion criteria

The exclusion criteria were as follows: (I) abnormal findings on routine brain magnetic resonance imaging (MRI); (II) a history of brain, cardiac, hepatic, or renal diseases; and/or (III) left-handedness.

Image acquisition

Participants in the COPD group and the corresponding control group underwent MRI scanning using a 3.0 T scanner (Philips Healthcare, Best, Netherlands). Participants in the high-altitude group and the corresponding control group underwent MRI scanning using a 1.5 T scanner (GE HealthCare, Chicago, IL, USA). Structural imaging was performed using a high-resolution three-dimensional (3D) T1-weighted sequence with the following parameters: voxel size =1×1×1 mm3; slice number =160; field of view (FOV) =24 cm, and scan time =3 min 55 s. Resting-state fMRI data were acquired using a BOLD sequence with the following parameters: repetition time =3 s; number of time points =128; FOV =24 cm; and scan time =6 min 20 s. All participants were instructed to remain at rest with no external stimuli applied.

Data processing

VBM (https://neuro-jena.github.io/cat12-help/#version) and Data Processing and Analysis of Brain Imaging (DPABI) (http://rfmri.org/DPABI) software, both implemented on the MATLAB 2018a platform (MathWorks Inc., Natick, MA, USA) (22), were used for image processing. The preprocessing pipeline included conversion of Digital Imaging and Communications in Medicine (DICOM) images to Neuroimaging Informatics Technology Initiative (NIfTI) format, removal of the first 10 time points, head motion correction, spatial normalization, and linear drift removal.

Cognitive assessment

The MoCA has a total possible score of 30 points and assesses multiple cognitive domains, including orientation, memory, attention and calculation, recall ability, and language function. A MoCA score of <26 was considered indicative of cognitive impairment.

Statistical analysis

General demographic characteristics were analyzed using SPSS version 19.0 with independent-sample t-tests. Quantitative data are presented as mean ± standard deviation (SD). A P value <0.05 was considered statistically significant. Between-group comparisons of gray matter volume were performed using two-sample t-tests in statistical parametric mapping (http://www.fil.ion.ucl.ac.uk/spm). Differences in ReHo were analyzed using DPABI. A post hoc power analysis using G*Power 3.1 (two-sample t-test, α=0.05, effect size d=0.8) showed an achieved power of 0.72 for the COPD versus control comparison, which was considered acceptable for the exploratory analyses. Image results were corrected using AlphaSim correction (cluster-level P<0.05, 1,000 Monte Carlo simulations, individual voxel-level threshold P<0.01, and minimum cluster size >100 voxels).

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Medical Ethics Committee of Nyingchi People’s Hospital, Xizang, China. The requirement for written informed consent was waived because this retrospective study involved secondary analysis of previously collected and de-identified data.

Results

Demographics and baseline characteristics

No significant differences in age or education level were observed among the groups (Figure 1A,1B). However, hemoglobin and SpO2 levels differed significantly among the high-altitude residents, COPD patients, and healthy controls (P<0.01) (Figure 1C,1D).

Figure 1 Boxplots of demographic and clinical characteristics of the four study groups. COPD, chronic obstructive pulmonary disease; SpO2, oxygen saturation.

Gray matter structure

Patients with COPD exhibited decreased gray matter volume in multiple regions, including the cortex of the Temporal_inf_R, Rectus_R, ParaHippocampal_L, Temporal_Pole_Sup_L, Caudate_R, Postcentral_R, Parietal_inf_L, and Insula_R (Figure 2A, Table 1). The high-altitude group exhibited cortical changes, including in the Cuneus_L and Occipital_Mid_L cortex (Figure 2B, Table 2).

Figure 2 Clusters showing decreased gray matter volume on the coordinate view in patients with COPD (A) and the high-altitude group (B). COPD, chronic obstructive pulmonary disease.

Table 1

VBM results for patients with COPD

Brain area BA Cluster size (voxels) t Peak voxel MNI coordinates
X Y Z
Temporal_inf_R 20 194 3.50 45 −11 −30
Rectus_R 11 145 3.72 9 41 −26
ParaHippocampal_L 35 158 3.68 −24 5 −21
Temporal_Pole_Sup_L 28 141 3.77 46 3 −11
Caudate_R – 218 3.28 12 16.5 −1.5
Postcentral_R 4 279 3.76 59 −18 36
Parietal_inf_L 40 239 −3.53 −46.5 −36 52.5
Insula_R 38 201 4.38 46 3 −10

The caudate nucleus was not included in the Brodmann area partition. The caudate nucleus is not assigned to a Brodmann area. BA, Brodmann area; COPD, chronic obstructive pulmonary disease; L, left; MNI, Montreal Neurological Institute; R, right; VBM, voxel-based morphometry.

Table 2

VBM results for high-altitude residents

Brain area BA Cluster size (voxels) t Peak voxel Peak voxel MNI coordinates
X Y Z
Cuneus_L 18 162 2.79 −5 −96 −2.71
Occipital_Mid_L 18 140 –2.82 −30 −90.9 6

BA, Brodmann area; L, left; MNI, Montreal Neurological Institute; VBM, voxel-based morphometry.

Brain function with ReHo

The patients with COPD showed increased ReHo in the bilateral caudate regions and decreased ReHo in the Lingual_R and Precuneus_R (Figure 3A, Table 3). In the COPD group, no significant correlations were observed between the SpO2 levels and ReHo values in the caudate, lingual, or precuneus regions (Pearson’s r range: −0.21 to 0.18; all P>0.05). In the high-altitude residents, ReHo was increased in the bilateral Supp_Motor_Area and decreased in the precuneus_R (Figure 3B, Table 4).

Figure 3 ReHo alterations in patients with COPD and high-altitude residents. (A) COPD patients versus corresponding controls. (B) High-altitude residents versus low-altitude controls. Warm colors (positive) indicate increased ReHo values, while cool colors (negative) indicate decreased ReHo values. COPD, chronic obstructive pulmonary disease; ReHo, regional homogeneity.

Table 3

ReHo results for patients with COPD

Area BA Cluster size (voxels) t Peak voxel MNI coordinates
X Y Z
Caudate_R – 125 2.99 15 17 9
Caudate_L – 89 2.34 −12 11 9
Lingual_R 18 94 −4.93 23 −74 −20
Precuneus_R 23 92 −4.78 5 −54 29

BA, Brodmann area; COPD, chronic obstructive pulmonary disease; L, left; MNI, Montreal Neurological Institute; R, right; ReHo, regional homogeneity.

Table 4

ReHo results for high-altitude residents

Area BA Cluster size (voxels) t Peak voxel MNI coordinates
X Y Z
Supp_Motor_Area_R 6 164 3.80 8 13 62
Supp_Motor_Area_L 8 144 3.48 −3 18 60
   Precuneus_R 29 82 −4.08 13 −47 15

BA, Brodmann area; L, left; MNI, Montreal Neurological Institute; R, right; ReHo, regional homogeneity.

Discussion

Exposure to low-oxygen conditions (hypoxia) triggers various acute and chronic physiological adaptations, among which sympathetic nervous system activation is crucial for endothelial regulation (23). Environmental hypoxia primarily results from hypoxemia caused by reduced barometric pressure and thus a lower inspired partial pressure of oxygen (24-26). In contrast, patients with COPD primarily experience tissue hypoxia resulting from ventilation–perfusion mismatch (27).

VBM neuroimaging studies have revealed distinct patterns of cortical structural changes under chronic hypoxic conditions. Patients with COPD exhibit significant reductions in gray matter volume in emotion-related brain regions such as the Temporal_inf_R, Temporal_Pole_Sup_L, Insula_R, Parietal_inf_L, and ParaHippocampal_L. These neuroanatomical alterations have been associated with impaired emotional regulation (28,29). The dyspnea-related discomfort and anxiety often lead to activity avoidance behaviors in this population. The insula mediates respiratory interoception and fear processing (30). The parahippocampal gyrus regulates emotional and memory functions (31). The inferior parietal lobule integrates multisensory information for body representation and cognitive-emotional processing (32,33).

These structural alterations may have important clinical implications. Emerging evidence suggests that frailty in patients with COPD is associated with reduced cortical thickness, particularly in the superior frontal gyrus (34). Although frailty was not directly assessed in the present study, the observed gray matter reductions in emotion- and cognition-related regions (including the insula, parahippocampal gyrus, and inferior parietal lobule) may represent a potential pathway linking chronic hypoxia, brain structural changes, and adverse clinical outcomes such as cognitive decline and physical frailty.

In contrast, the high-altitude residents exhibited a different pattern of gray matter reductions, primarily involving visual processing areas such as the Cuneus_L and Occipital_Mid_L. The cuneus plays an essential role in visual information processing by modulating the transmission of signals along the primary visual pathway to extrastriate cortical areas and also contributes to working memory regulation (35,36). Emerging evidence suggests a potential link between cuneus dysfunction and depressive disorders; however, further research is necessary to clarify this relationship (37).

Functional neuroimaging studies have identified distinct ReHo alterations in patients with COPD, characterized by increased ReHo in the bilateral caudate nucleus and decreased ReHo in the Lingual_R and precuneus_R regions. These areas are crucial for emotional regulation, memory processing, and self-referential cognition (38). Although some individuals may exhibit anxiety symptoms, overt cognitive deficits are often not detectable at this stage of disease progression, potentially reflecting variations in disease severity or duration. Notably, under hypoxic conditions, a positive correlation has been reported between respiratory intensity scores and increased neural activity in the lingual and fusiform gyri in individuals with more severe symptoms (39).

In contrast, the high-altitude residents demonstrated increased ReHo in the supplementary motor area (SMA), alongside decreased ReHo in the right precuneus. This reduced functional activity in the precuneus may be associated with impaired visual processing. These findings suggest that SMA-related compensatory mechanisms may not fully compensate for visual impairments, potentially indicating deficiencies in motor coordination.

This study revealed distinct gray matter changes along with convergent functional alterations in visual cortical regions across two models of chronic hypoxia. These findings underscore the heightened sensitivity of the visual cortex to systemic oxygen deprivation. Mild hypoxia primarily disrupts visual function through retinal oxygen deficiency, resulting in reduced photoreceptor sensitivity and impaired integration of visual information (40), while COPD-related hypoxia appears to exert greater effects on cognitive and emotional functions than on visual functions. Notably, patients with COPD exhibit rod cell atrophy as a consequence of chronic hypoxemia (41,42), while high-altitude exposure may additionally involve effects related to ultraviolet radiation (43). Further, lens epithelial cells have been reported to exhibit a 10-fold increase in erythropoietin expression following episodes of hypoxia (44).

This study had several limitations. First, different scanner field strengths were used, which may have significantly affected the MRI metrics. Previous studies have shown that field strength can introduce regional biases in VBM results and may yield larger estimates of atrophy at 3 T compared with those at 1.5 T (45,46). Additionally, the BOLD contrast-to-noise ratio is 2.3-fold higher at 3 T (47), and field strength can modulate resting-state network detection using independent component analysis (48). Thus, any apparent differences between the COPD and high-altitude groups may reflect scanner-related effects rather than biological differences; consequently, direct statistical comparisons between these two groups were not performed. Second, the relatively small COPD sample size (n=20) limited the statistical power of the study. Further, the lack of GOLD staging and the limited variability in SpO2 levels precluded the detection of severity-related brain changes. Unassessed confounders (including smoking status, inflammation, and depression/anxiety symptoms) may have biased brain findings. Third, visual acuity was not assessed, limiting the interpretation of hypoxia-related visual effects. Future studies with larger sample sizes and ancillary testing are needed to enable further correlation analyses.

Conclusions

This study described structural and regional functional brain changes associated with two models of chronic hypoxia: COPD-related hypoxia and high-altitude residence. To our knowledge, this is the first study to describe differences between disease-related and environmentally induced chronic hypoxia models. Functional alterations showed partial convergence across the two hypoxia models, with increased ReHo observed in motor-related regions (the bilateral caudate in COPD and the bilateral supplementary motor area in high-altitude residents) and decreased ReHo in the right precuneus shared by both groups; however, differences were observed in structural changes. COPD-related hypoxia was associated with gray matter alterations in emotion- and cognition-related regions, whereas high-altitude exposure was associated with structural changes primarily involving visual regions. Due to the differences in MRI scanner field strength and geographical conditions, direct statistical comparisons between the two hypoxia groups were not performed. Future studies need to be conducted to enhance the robustness of the study findings. Additionally, more in-depth clinical trials need to be conducted to explore whether compensatory mechanisms for chronic hypoxia extend to extracranial organs.

Acknowledgments

We sincerely thank the contributions of all study participants for their voluntary participation.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0438/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0438/dss

Funding: This study was supported by the Traditional Chinese Medicine Bureau of Guangdong Province (No. 20232132) and the Guangzhou Municipal Science and Technology Bureau (Nos. 2023A03J0989 and 2024A03J599).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0438/coif). H.Z. reports that the study was supported by Traditional Chinese Medicine Bureau of Guangdong Province (No. 20232132 awarded to the institutional research team) and Guangzhou Municipal Science and Technology Bureau (Nos. 2023A03J0989 and 2024A03J599 awarded to the institutional research team). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Medical Ethics Committee of Nyingchi People’s Hospital, Xizang, China. The requirement for written informed consent was waived because this retrospective study involved secondary analysis of previously collected and de-identified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Zhong M, Duan X, Qiao Z, Liang Z, Weng Y, Luo H, Du Y, Bu J, Zeng H. Resting-state functional MRI analysis of the brain’s adaptation to chronic hypoxia: disease and environment. Quant Imaging Med Surg 2026;16(9):688. doi: 10.21037/qims-2026-1-0438

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