By using resting-state 3D ASL and BOLD techniques, CBF-DC coupling changes were investigated in patients with COPD. COPD patients showed decreased CBF in the bilateral DLPFC, ACG and left SMG, and increased DC in the left PreCG and left SMG. More importantly, COPD showed increased CBF/DC ratio in the bilateral medial frontal cortex, bilateral caudate nucleus, left temporal gyrus and left LNG, and CBF/DC ratio in several brain regions significantly correlated with MoCA, visuospatial/executive and delay recall scores.
The COPD showed decreased CBF in bilateral DLPFC, ACG and left SMG. The brain constitutes only about 2% of the body weight, but easily receives up to 15-20% of the total cardiac output as CBF. CBF changes may be ascribed to the following reasons. The hypothesis of neurovascular coupling suggested that CBF is governed by neural activity changes through complex coordinated mechanisms involving neurons, glial cells, and vascular components [16, 33]. Moreover, the neural stimuli may be involved in the control of the diameter of the cerebral vessel and brain blood supply, resulting to CBF changes. Finally, chemical mediators, such as neuroinflammation factors, adenosine, nitric oxide[8, 17], hydrogen, potassium, calcium and lactate, may trigger hemodynamic responses resulting in vasodilation/vasoconstriction and CBF changes.
Higher DC values were found in the left PreCG and left SMG in COPD. The higher DC represents more correlations between the given voxel and the rest voxels, indicating that neurons in this voxel is more important and active. Tomasi and Volkow  suggested that voxels with high DC serve as the interconnection hubs, meaning effective and fast brain communication with minimal cost of energy. Widespread evidences of increased functional activation have been reported in patients with COPD. Increased resting state connection could be interpreted as a reduction in precise control over functional networks that is not beneficial, indicating a disrupt network. Our study showed a significantly negative correlation between the mean DC value of the left supramarginal gyrus and the visuospatial/executive function score, suggesting that the left SMG may be associated with visuospatial/executive dysfunction in COPD patients.
Voxel-wise analyses revealed that COPD patients showed significantly higher CBF/DC ratio in several regions. Subsequent ROI-based analyses showed lower CBF and lower DC values in these regions in COPD group than those in healthy controls. However, by using voxel-wise analyses, there is no overlap between the merged regions generated in intergroup comparisons of CBF, DC and regions with intergroup different CBF/DC ratio, we speculated that CBF/DC ratio could enlarge the differences between the COPD and healthy group. Moreover, in some merged ROIs, COPD patients showed significant lower CBF/DC ratio. We demonstrated that combination of CBF, DC and CBF/DC ratio base on voxel-wise and ROI-wise analyses may be a comprehensive and reliable method to investigate underlying mechanisms of COPD patients.
COPD patients showed increased CBF/DC ratio in the left LNG. The increased CBF/DC ratio was driven by disproportionally attenuated CBF and DC. The LNG is involved in encoding of complex images, object discrimination and identification and recognition of words. Supporting this, the LNG is functionally associated with decreased naming performance and visual processing and visual hallucination. In the COPD group, the negative correlation between the higher CBF/DC ratio of the LNG and the naming score indicated that the attenuation degree of DC is greater than that of CBF in this region, resulting in decompensated increase of CBF per unit of functional connection in the left LNG and poor naming function.
In addition, COPD patients also showed higher CBF/DC ratio in the bilateral medial frontal cortex, bilateral caudate nucleus, and left middle temporal cortex. Several COPD studies on grey matter have provided evidences of reduced thickness and volume in these regions[3, 39]. And the frontal cortex is involved in processing of emotion information with visual input during the observation and execution tasks[10, 23]. Increased CBF/DC ratio of these regions may play a compensatory role for the reduced grey matter volume. In the present study, the increased CBF/DC ratio in bilateral medial frontal cortex and left middle temporal cortex is driven by decreased CBF and DC. And the CBF decline may be the cause of the decreased grey matter volume. Consist with our study, hypoperfusion in the frontal cortex and cognitive abnormalities has been found in COPD patients. The positive correlation between higher CBF/DC ratio in this region and MoCA, visuospatial/executive and delayed recall functions may suggest that the abnormal neurovascular changes in this region are related with dysfunctional visuospatial/executive and delayed recall in COPD patients.
In the ROI analyses, COPD patients exhibited decreased CBF/DC ratio in the left PreCG/DLPFC and left SMG, which are involved in somatic motor function and spatial working memory. Decreased grey matter density and neural activation in the left PreCG have been found in COPD patients [38–40]. The DLPFC is a key part of dorsal visual processing stream regions which are involved in visual reproduction impairment in COPD. Using surface-based morphometry, Chen et al.  provided evidence that the thinner DLPFC was predictive factor of poorer visual reproduction performance, they also found reduced cortical thickness and surface in the PreCG and SMG in COPD. In our study, these regions showed lower CBF and higher DC, suggesting that the decreased CBF/DC ratios in these regions were driven by the CBF decrease and DC increase, which might be attributed to reduced cortical thickness and surface, rendering to cognitive impairment in COPD.
In this study, significant correlations between CBF and DC were found in the four merged ROIs in both COPD and healthy groups. However, further comparison analyses showed no significant differences in the correlation coefficients between two groups which meant normal neurovascular coupling in all subjects and no significant differences in the four ROIs between the two groups. To minimize effects of interference factors, we excluded participants with other diseases or disorders which may affect the cerebral function and structure, such as cardiovascular, metabolic diseases, neurosis and psychosis. We speculated that this finding may be associated with current status of COPD patients in this study. More COPD patients with different stages may be needed to investigate in the further studies.
Unexpectedly, no associations between abnormal brain functions and pulmonary-specific disease markers were found, we speculate that the extrapulmonary manifestations of COPD may not be strongly related to pulmonary-specific disease markers. In addition, various studies provided evidences that cigarette smoking may involve in the cerebral functional or structural abnormalities in patients with COPD. However, no correlation between the duration or the amount of smoking and the cerebral abnormalities were found in all smokers.
Several limitations should be taken into account when interpret our findings. Firstly, relatively small sample size may influence our interpretations, more COPD patients are needed in the further investigations. Secondly, CBF and DC are indirect indices, preventing us from direct and more reliable measurements of cerebral perfusion and neural activity. Finally, COPD patients after oxygen therapy are not enrolled into this study, a follow-up study with longitudinal comparison is needed for validity of the present findings.