Disrupted neurovascular coupling in patients with lung cancer after chemotherapy

Introduction

With advancements in lung cancer therapeutics, there has been a considerable increase in the survival rate of patients with lung cancer (1-3), resulting in a growing population of individuals living with the long-term consequences of these treatments. Among them, chemotherapy-related cognitive impairment (CRCI) is the most frequently encountered (3). In fact, the majority of cancer survivors (>75%) experience CRCI (4-6), negatively affecting their occupational, familial, and social lives. Platinum-based chemotherapy is the mainstay treatment in the first-line therapy for advanced non-small cell lung cancer (NSCLC) and adjuvant therapy for patients with early-stage lung cancer (7). Research over the past several decades has demonstrated that platinum-based chemotherapeutics can trigger structural and functional abnormalities in several brain areas involved in processing speed, attention, executive function, and memory, which may be neurological biomarkers of CRCI in patients with lung cancer (5,8-13). Although incremental progress in the research on the related mechanisms has been made, the neuropathological mechanisms underlying these cognitive deficits among patients with lung cancer who have undergone platinum-based chemotherapy have not been sufficiently clarified. An in-depth investigation of the neural mechanisms related to CRCI in the context of lung cancer holds considerable clinical significance for the early prevention and intervention of this condition.

Emerging evidence suggests that optimal brain function is highly dependent on the close temporal and regional coupling between neural activity and cerebral blood flow (CBF), which is referred to as neurovascular coupling. More specifically, this refers to brain regions with higher spontaneous neural activity tending to have stronger connectivity, greater energy consumption, and increased perfusion (14,15). Resting-state functional magnetic resonance imaging (rs-fMRI) has been established as a robust approach for examining intrinsic regional brain activities (16,17). Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) analyses are two critical methods for depicting the various characteristics of the global rs-fMRI signal (18,19). You et al. (20) used fMRI to measure altered ALFF and ReHo values in multiple brain regions and found abnormal spontaneous neuronal activity in patients with lung cancer after chemotherapy, with significantly decreased rs-fMRI values in the default-mode network (DMN) region of the brain. A prospective study examining the trajectory of ALFF changes during neoadjuvant chemotherapy in patients with breast cancer (21). Following one cycle of chemotherapy, significant declines in ALFF values have been observed in certain brain regions, remaining stable until completion of treatment. Notably, the bulk of these ALFF changes were localized within the frontal lobe.

Arterial spin labeling (ASL) is a noninvasive MRI technique that can measure the CBF to assess the vascular supply to the brain and thus holds considerable potential in clarifying the pathophysiology underlying CRCI (22). Previous studies using ASL-MRI have reported changes in CBF in patients with cancer following chemotherapy, along with other key insights. For instance, patients with breast cancer were found to exhibit increased regional CBF in the right precentral gyrus and decreased regional CBF in both the parietal and frontal lobes following chemotherapy (23,24). In another study, patients with NSCLC treated with chemotherapy, as compared to prechemotherapy patients, exhibited increased CBF in the left insula, right caudate, left superior temporal gyrus (STG), right superior occipital gyrus (SOG), and right middle frontal gyrus (MFG), along with significantly aberrant CBF connectivity within the left STG, right MFG, and right caudate (25).

However, these aforementioned studies adopted a single neuroimaging technique to assess neuronal activity or cerebral perfusion in patients with cancer following chemotherapy, but no research has directly and comprehensively examined the effect of chemotherapeutic drugs on neurovascular coupling (NVC). An authoritative study did reveal that the correlations and ratios between CBF and functional connectivity could be analyzed to characterize the NVC between the cerebral perfusion and neuronal activity in the brain (26), which may provide insights into the underlying physiological of human brain. In recent years, alterations in NVC have been widely examined across neurological and psychiatric diseases and are considered to play an important role in neuropathological mechanisms of related cognitive disorders (27-31). Consequently, to better understand the brain changes in patients with lung cancer after platinum-based chemotherapy, a comprehensive exploration of NVC status is warranted.

In our study, we examined NVC alterations by calculating a series of NVC patterns (including CBF-ALFF correlation coefficients, CBF-ReHo correlation coefficients, CBF:ALFF ratios, and CBF:ReHo ratios) in patients with NSCLC with or without exposure to platinum-based chemotherapy. Additionally, we performed correlation analyses to determine the associations between NVC parameters and cognitive performance domains. These analyses were designed to test the following hypotheses: (I) Chemotherapy-exposed patients exhibit neurovascular unit (NVU) decoupling at both the global gray-matter (GM) level and in certain regional levels of the brain. (II) The degree of neurovascular decoupling correlates with cognitive impairment outcomes. Using multimodal neuroimaging approaches, we sought to generate insights into the neurological mechanisms underlying CRCI. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1321/rc).

Methods

Participants

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Institutional Review Board of Nanjing Medical University (Approval No. KY2021000589YX). Before enrollment, all participants provided written informed consent in compliance with the study protocol.

This cross-sectional study recruited 43 patients diagnosed with lung cancer at the Department of Respiratory Medicine at Nanjing First Hospital from November 2022 to August 2023. The cohort comprised 20 patients undergoing adjuvant chemotherapy [CT(+)] and 23 age-, sex-, and education-matched patients not receiving chemotherapy [CT(−)]. All enrolled participants were right-handed individuals with a minimum educational attainment of a junior high school level. Patients with NSCLC (stage II–III) were pathologically confirmed via surgical resection, bronchoscopic biopsy, or percutaneous needle biopsy. Among the chemotherapy-treated cohort, 10 patients underwent cisplatin-based and 10 underwent carboplatin-based chemotherapy over a treatment duration of 3 to 6 months. None of the participants was excluded from the fMRI analysis due to excessive head movement during the scanning procedure. The following exclusion criteria were applied: a history of prophylactic cranial irradiation; the presence of brain metastases; a documented history of stroke, craniocerebral trauma, epilepsy, Parkinson disease, Alzheimer disease, or other acute psychiatric or neurological disorders; major medical comorbidities (e.g., anemia, thyroid dysfunction, severe cardiac disease, and abnormal renal and hepatic function); and severe visual or auditory deficits. The Mini-Mental State Examination (MMSE) was employed to assess the participants’ overall cognitive functioning (32). The neuropsychological status was measured via the Montreal Cognitive Assessment (MoCA) (33), which was applied to evaluate various cognitive functions such as visuospatial or execution ability, attention, language skills, abstract thinking, memory (both short-term immediate and delayed recall), and spatial orientation (34). All participants underwent standardized MRI scanning protocols and cognitive function evaluations.

Data acquisition

All enrolled participants underwent MRI with the same eight-channel 3.0-T magnetic resonance scanner (Ingenia, Philips Medical Systems, Best, Netherlands). To mitigate scanner noise and reduce head movement, participants were provided earplugs and positioned with snug but comfortable foam padding. During the scanning procedure, participants were directed to keep their eyes closed and assume a state of rest. Prior to functional and perfusion imaging, standard diagnostic MRI sequences—including thick-slice T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and T2-weighted fluid-attenuated inversion recovery (T2-FLAIR)—were performed for each participant to exclude organic brain lesions or metastatic involvement.

For anatomical characterization, three-dimensional high-resolution sagittal T1-weighted images were acquired via a 3D turbo fast echo (3D-TFE) sequence under the following parameters: echo time (TE) =3.7 ms, repetition time (TR) =8.1 ms, flip angle =8°, field of view (FOV) =256×256 mm², acquisition matrix =256×256, isotropic slice thickness (no gap) =1 mm, number of sagittal slices =172, and total scan duration =5 minutes and 29 seconds. Resting-state cerebral perfusion was assessed via a 2D pseudocontinuous arterial spin labeling (pCASL) sequence under the following parameters: TE =11 ms, TR =4,000 ms, label duration =1,650 ms, postlabel delay =1,600 ms, flip angle =90°, FOV =240×240 mm², slice thickness =4 mm (10% gap), matrix =64×64, number of axial slices =20, and scan duration =4 minutes and 8 seconds. The rs-fMRI data were collected with a gradient echo-planar imaging (GE-EPI) sequence under the following parameters: TE =30 ms, TR =2,000 ms, number of axial slices =36, slice thickness =4 mm (no gap), flip angle =90°, FOV =240×240 mm², acquisition matrix =64×64, and total scan duration =8 minutes and 8 seconds.

Data processing

For the spatial normalization of T1 images to Montreal Neurological Institute (MNI) space, high-resolution 3D T1-weighted magnetic resonance (MR) data were analyzed with the Voxel-Based Morphometry 8 (VBM8) toolbox (http://dbm.neuro.uni-jena.de/vbm/) within Statistical Parametric Mapping 12 (SPM12; http://www.fil.ion.ucl.ac.uk/spm). The Brain Extraction Tool (BET) was used to produce T1-weighted brain images through the elimination of nonbrain tissues (35).

The ASL data were analyzed to generate CBF maps through use of SPM8 and ASLtbx (https://cfn.upenn.edu/~zewan) (36). The specific steps were as follows: (I) SPM8 software was employed to perform gradient nonlinearity correction in all directions, realignment, and segmentation of the CBF images for all participants, with the CBF images of CT(−) patients coregistered to the positron emission tomography (PET) perfusion template in MNI space. (II) The MNI-standard CBF template was defined as the average coregistered CBF images of the CT(−) patients. The CBF images of all participants were then coregistered to the MNI-standard CBF template. (III) Nonbrain tissue was removed from coregistered CBF images via automated segmentation, followed by spatial smoothing with an 8 mm × 8 mm full-width at half-maximum (FWHM) Gaussian kernel to enhance signal consistency. (IV) Voxel-wise normalization was performed by dividing individual CBF values by the global mean CBF of the whole brain, yielding standardized CBF maps for group-level analysis. The procedures have been described in another study (25).

The rs-fMRI data were preprocessed via the RESTplus v. 1.21 software package (http://www.restfmri.net/forum/restplus). The preprocessing workflow consisted of discarding of the initial 10 volumes, slice timing correction, motion realignment, nuisance signal regression, spatial normalization to the MNI template, and application of spatial smoothing with an 8-mm FWHM Gaussian kernel. If the maximum displacement or rotation of head movement in a participant exceeded 3.0 mm (3.0°), this participant would be excluded.

The ALFF and ReHo values were both calculated via RESTplus v. 1.21. First, we transformed the time courses into frequency domain using the fast Fourier transform. The ALFF value was calculated as the mean square root of the power spectrum from 0.01 to 0.08 Hz for each voxel. For standardization purposes, we divided the whole-brain mean ALFF to generate the ALFF map of every standardized voxel. For ReHo analysis, the normalized images underwent bandpass filtering within the frequency range of 0.01 to 0.08 Hz before computation. ReHo values were quantified via the Kendall coefficient of concordance between a given voxel and its neighboring voxels in a voxel-wise manner. Individual ReHo maps were normalized by dividing the value of each voxel by the global mean ReHo to minimize intersubject variability. Finally, spatial smoothing was applied with an 8-mm FWHM Gaussian kernel to enhance the signal-to-noise ratio.

Global CBF-ALFF and CBF-ReHo coupling analysis

The Fisher z transformation was applied to CBF, ALFF, and ReHo images in each participant to improve the normality of the data distribution. To quantitatively evaluate the global coupling between CBF and ALFF and between CBF and ReHo, voxel-wise correlation analyses were performed for each participant. Due to spatial preprocessing procedures, including registration and spatial smoothing, neighboring voxels demonstrate significant statistical dependence, resulting in the effective degrees of freedom in cross-voxel correlation analyses being considerably lower than the total voxel count within the GM mask. Using the 3dFWHMx program within the Analysis of Functional NeuroImages (AFNI) software package (http://afni.nimh.nih.gov), we quantified the spatial smoothness to 12×14×17 mm³, significantly surpassing the voxel dimensions of 3×3×3 mm³, which indicated that spatial correlations were primarily influenced by smoothing effects (26). To address the voxel-voxel dependence induced by spatial smoothing, the effective degrees of freedom for cross-voxel correlations were estimated with the approximation formula proposed by Liang et al. (26), resulting in a value of 1,350. This method was employed to calculate the adjusted P values for statistical inference. For each participant, a CBF-ALFF correlation coefficient was calculated to quantify the spatial correspondence between CBF and ALFF distributions. Furthermore, the correlation coefficient values between CBF and ReHo were calculated for each participant to evaluate the synchronization of neural activity. Two-sample t-tests were used to examine the intergroup differences in the CBF-ALFF and CBF-ReHo correlation coefficients between the CT(−) group and the CT(+) group.

Regional CBF:ALFF ratio and CBF/ReHo ratio analysis

To use AFNI software to assess regional NVC—defined as the ratio of CBF to neuronal activity (quantified by ALFF or ReHo)—voxel-wise CBF:ALFF ratios and CBF:ReHo ratios were computed for each participant. Group differences in these ratios between CT(−) and CT(+) cohorts were evaluated via two-sample t tests, with age and gender included as covariates. Voxel-wise false-discovery rate (FDR) correction was used to address multiple comparisons, with statistical significance defined as a corrected P value less than 0.05.

Statistical analysis

Group differences in age and cognitive scores between the CT(−) and CT(+) groups were evaluated using two-sample t tests, whereas gender distribution was compared via chi-squared tests. For neuroimaging metrics—including CBF-ALFF correlation coefficients, CBF-ReHo correlation coefficients, CBF:ALFF ratios, and CBF:ReHo ratios—voxel-wise two-sample t-tests were conducted via SPM12 software. Statistical significance was determined via an uncorrected voxel-wise threshold of P<0.001, which was followed by FDR correction at the cluster level (P<0.05).

The values of clusters (regional CBF:ALFF ratio and CBF:ReHo ratio) exhibiting significant intergroup differences in CBF:ALFF and CBF:ReHo ratios were extracted. Pearson correlation analyses were subsequently conducted to examine potential relationships between the values of these clusters and the cognitive assessment scores within the CT(+) group. Statistical association analyses were performed via SPSS 19.0 software (IBM Corp., Armonk, NY, USA). Statistical significance was set at P value <0.05.

Results

Demographic and clinical characteristics

The demographic and clinical characteristics of the study participants are summarized in Table 1. No statistically significant differences were observed in age, gender, or educational attainment between the two groups. However, compared to patients in the CT(−) group, those in the CT(+) group exhibited significantly lower MoCA scores.

Alterations in the global CBF-ALFF and CBF-ReHo correlation coefficients

Group-level comparisons revealed significant differences in the whole-brain CBF-ALFF correlation coefficients and CBF-ReHo correlation coefficients. The mean global CBF-ALFF coupling values were 0.163±0.455 in the CT(+) group and 0.199±0.458 in the CT(−) group. CT(+) patients exhibited significantly reduced global CBF-ALFF coupling compared to CT(−) patients (t=−2.590; P=0.013) (Figure 1A). Similarly, the global CBF-ReHo coupling values in the CT(+) group and CT(−) group were 0.229±0.449 and 0.258±0.401, respectively. At the group level, CT(+) patients exhibited a significant reduction in CBF-ReHo coupling compared to CT(−) patients at the group level (t=−2.285; P=0.028) (Figure 1B).

Figure 1 Global neurovascular coupling alterations in CBF-ALFF and CBF-ReHo correlation coefficients. (A) The CT(+) group exhibited decreased CBF-ALFF correlation coefficients and (B) decreased CBF-ReHo correlation coefficients. *, statistically significant. ALFF, amplitude of low-frequency fluctuation; CBF, cerebral blood flow; CT(+), patients treated with chemotherapy; CT(−), patients not treated with chemotherapy; ReHo, regional homogeneity.

Alterations in the regional CBF:ALFF ratios and CBF:ReHo ratios

There were significant differences in CBF:ALFF ratio between the two groups (Table 2 and Figure 2A). In contrast to the CT(−) group, the CT(+) group exhibited decreased CBF:ALFF ratios in the left MFG and right middle temporal gyrus (MTG), with higher CBF:ALFF ratios observed in the left parahippocampal gyrus, left thalamus, right MFG, and right STG. Moreover, the CBF:ReHo ratios were significantly different (Table 3 and Figure 2B). In comparison to the CT(−) group, the CT(+) group demonstrated lower CBF:ReHo ratios in the right SOG, right rolandic operculum, and right inferior parietal lobule (IPL), and left precuneus. Conversely, the CT(+) group exhibited higher CBF:ReHo ratios in the right MFG and left inferior frontal gyrus (IFG).

Figure 2 Regional neurovascular coupling alterations in the CBF:ALFF ratio and CBF:ReHo ratio. (A) The distribution of brain regions with significant intergroup differences in CBF:ALFF ratio. (B) The distribution of brain regions with significant intergroup differences in CBF:ReHo ratio. A significantly increased value in the group is shown with a warm color, while a significantly decreased value in the group is shown with a cold color. ALFF, amplitude of low-frequency fluctuations; CBF, cerebral blood flow; IFG, inferior frontal gyrus; IPL, inferior parietal lobule; L, left; MFG, middle frontal gyrus; MTG, middle temporal gyrus; R, right; ReHo, regional homogeneity; ROL, rolandic operculum; SOG, superior occipital gyrus; STG, superior temporal gyrus.

Correlations between regional CBF:ALFF ratios and neurocognitive outcomes

Significant correlations were observed between changes in the mean CBF:ALFF ratio and neurocognitive outcomes (Figure 3). Specifically, the CBF:ALFF ratio in the right MFG was negatively correlated with MoCA score (r=–0.261; P=0.021) and memory score (r=–0.231; P=0.032). Meanwhile, CBF:ALFF ratio in the left parahippocampal region was significantly associated with MoCA scores (r=–0.252; P=0.024) and memory scores (r=–0.316; P=0.009). No other regional CBF:ALFF ratio values demonstrated significant correlations with the MoCA scores or its subcategories, including visuospatial/executive function, naming ability, attention, language proficiency, abstract reasoning, and orientation.

Figure 3 The associations between NVC changes and the risk of adverse neurocognitive outcomes. (A,B) The CBF:ALFF ratio in the right MFG exhibited a negative correlation with the MoCA scores and memory scores. (C,D) The CBF:ALFF ratio in the left parahippocampal gyrus exhibited a negative correlation with the MoCA scores and memory scores. ALFF, amplitude of low-frequency fluctuations; CBF, cerebral blood flow; L, left; MFG, middle frontal gyrus; MoCA, Montreal Cognitive Assessment; NVC, neurovascular coupling; R, right.

Correlations between regional CBF:ReHo ratios and neurocognitive outcomes

No regional CBF:ReHo ratio values were found to be correlated with the MoCA scores, including subcategories such as visuospatial/executive function, naming ability, attention, language proficiency, abstract reasoning, and orientation.

Discussion

To the best of our knowledge, this study is the first to examine NVC alterations in patients with platinum-based chemotherapy through the integration of ASL and rs-fMRI techniques. In our study, we performed global and regional multimodal NVC analysis of patients with lung cancer treated or untreated by chemotherapy. We found that the CT(+) group had a lower across-voxel correlation between CBF and ALFF and between CBF and ReHo, suggesting the decoupling of the NVU at the whole-brain GM level. Another intriguing finding of this study is that the CT(+) group had regional disturbances in cognition-related cortical areas compared with the CT(−) group. Moreover, the regional neurovascular decoupling (the CBF:ALFF ratio of the right MFG and left parahippocampal region) were negatively correlated with cognitive performances (MoCA scores and memory scores). Our findings contribute significantly to the understanding of cognitive impairment and its underlying neuropathologic mechanism in patients with lung cancer who have undergone platinum-based chemotherapy.

Proper brain neural activity critically depends on the adequate regulation of CBF through NVC to ensure the sufficient energetic supply of active brain regions (28). The NVC depends on the integrity of NVU, which is composed of neurons, astrocytes, the blood-brain barrier, and the extracellular matrix (37). Recent studies have documented that various antineoplastic platinum drugs induce a variety of molecular mechanisms that result in impaired neurogenesis, blood-brain barrier disruption, reduced hippocampal neurogenesis, secondary neuroinflammatory/immune responses, and white-matter abnormalities (2,38-41), all of which potentially disrupt the equilibrium between neuronal activity and blood supply. The correlation coefficients between blood supply and neural activity in our study roughly suggest a whole-brain NVC profile from a global perspective. Our findings of reduced CBF-ALFF coefficients and CBF-ReHo coefficients in the CT(+) group provide supporting evidence of neurovascular decoupling in patients with lung cancer after platinum-based chemotherapy. Previous studies have suggested that neurovascular decoupling is related to poorer cognitive function (28,42-44). Therefore, it is reasonable to speculate that it may be a neural mechanism underlying CRCI.

As a complement to the correlation coefficients between blood supply and neural activity, the ratio of blood supply to neuronal activity reflects detailed information on the regional NVC. It has also been introduced as a quantitative imaging marker for assessing cognitive dysfunction (31,45,46). In our study, the abnormal CBF:ALFF ratios and CBF:ReHo ratios in patients after platinum-based chemotherapy were mainly concentrated in the frontal lobe and temporal lobe. The frontal lobes are the largest lobes of the brain and play an integral role in higher-level cognitive processes and executive functions, such as attention and working memory (47). One animal study (48) reported that cisplatin can reduce the expression of presynaptic marker synaptophysin and glutamate marker vGlut-2, induce neuroinflammation, and reduce synaptic plasticity in the frontal cortex, resulting in long-term attention deficits. In their study, Chen et al. (49) observed a significant increase in CBF in the IFG, superior frontal gyrus, and temporal gyrus among patients with breast cancer following chemotherapy. Additionally, their findings revealed a notable correlation between the elevated CBF changes in certain brain regions and the decreased performance in alerting and executive control attention networks among these patients. Another brain activity-based study (50) on patients with gastric cancer treated with chemotherapy reported poor performance in verbal memory and executive function and decreased rs-fMRI values in the frontal areas of these patients. Moreover, among rs-fMRI values, lower ALFF in the left IFG was significantly associated with poor performance on the executive function test. These findings partially align with our results. We further identified an increased CBF:ReHo ratio in the left IFG of the CT(+) group. Notably, the IFG has been identified as a brain region whose metabolism is strongly correlated with cognitive performance in chemotherapy recipients (51). This observation further supports the hypothesis that chemotherapy-related alterations in NVC within this region are associated with cognitive deficits in treated patients.

Neuroimaging research has established the presence of reduced neural activity and increased cerebral perfusion in the MFG of patients with lung cancer following platinum-based chemotherapy (20,25). Our study further supports and extends upon this research by calculating the ratio of neural activity and blood perfusion and provides a comprehensive reflection of the neurophysiologic effects of platinum drugs in patients with lung cancer. Specifically, reduced CBF:ALFF ratio of the right MFG was significantly negatively correlated with MoCA scores and memory scores in the chemotherapy group. The MFG is critical for complex behavior and registers cognitive conflict, errors, and choice outcomes (52). These results support our hypothesis that disruption of the NVC is associated with the neurocognitive problems observed in survivors of lung cancer.

The parahippocampal cortex, a part of the limbic system, located medial to the inferior occipital and temporal lobes surrounding the hippocampus, participates in modulating distinct emotions and memory encoding as the main cortical input to the hippocampus (53). The hippocampus acts as a key emotional regulator and memory center and is often the focus of neurological and psychiatric research (54,55). The parahippocampal cortex is an important hub of the hippocampal circuit, and damage to it can cause emotional and cognitive behavior abnormalities. Both clinical (51) and animal (56) research has established that chemotherapy reduces CBF and disrupts cerebral glucose metabolism, notably decreasing blood vessel density and impairing neurogenesis in the hippocampus (57,58). We found a higher CBF:ALFF ratio in the left parahippocampal gyrus and further identified significant negative associations between the CBF:ALFF ratio in the parahippocampus and MoCA and memory scores. These findings are in line with a 2020 study (59) that demonstrated chemotherapy induced anterior hippocampal functional connectivity abnormality, which is associated with depressive symptoms and estradiol and triglycerides disorders. We speculate that chemotherapy causes a reduction in hippocampal blood vessel density and a subsequent compensatory increase in parahippocampal blood flow and a decrease in neurogenesis; in turn, this dysregulates the CBF:ALFF ratio and ultimately causes a series of cognitive disorders. Unfortunately, we did not directly capture the altered NVC in the hippocampus.

The thalamus is a critical center for sensation, is the most significant relay station and integration center for sensory conduction, and serves as the gateway to the telencephalon (60). The conduction pathways from various sensations throughout the body (except for olfactory sensation) are replaced by neurons in the thalamus and then projected to the cerebral cortex. We observed higher CBF:ALFF ratios in the left thalamus, which is consistent with a previous morphological analysis which reported a significant reduction in GM volume in the bilateral thalamus of pediatric patients treated by chemotherapy (61). These findings suggest that thalamic damage may be a key process in the mechanism of CRCI, with brain neurotoxicity and neuroinflammation causing dysfunction in large-scale brain networks in several brain regions, including the thalamus. We did not obtain any significant correlation between the NVC in the thalamus and cognitive scores, and further studies are needed to examine this relationship.

This study involved certain limitations that should be addressed. First, relatively small sample might have biased the statistical results. Further studies, therefore, with more participants and fewer confounding factors would help verify our findings. Second, due to the cross-sectional design and lack of a healthy control group, we were only able to assess the effect of chemotherapy on NVC and could not adequately identify the impact of cancer itself or other factors on NVC. Prospective longitudinal studies including matched healthy controls are needed to confirm our conclusions. Third, our findings revealed neurovascular decoupling within certain regions of the limbic system following platinum-based chemotherapy. However, it is worth noting that we did not assess patients’ mood in this study. Consequently, in our subsequent investigation, we will implement scales related to depression and anxiety. Finally, we acknowledge that the duration of chemotherapy and the specific type of chemotherapy drugs used may potentially influence NVC and cognitive function. However, our study did not observe any significant differences between the groups, likely due to the small sample size. We plan to conduct further research with a larger sample size and employ more detailed grouping based on the duration of chemotherapy and the specific chemotherapy drugs administered. This will allow us to further characterize the potential effects of these factors on NVC and cognitive function.

Conclusions

In summary, our study revealed neurovascular decoupling in patients with NSCLC pre- and postchemotherapy through an integrated rs-fMRI and ASL assessment. More specifically, the neurovascular decoupling in the prefrontal and parahippocampal gyrus was associated with the cognitive function of these patients. Our findings indicated that platinum-based chemotherapy agents can disrupt NVC, which ultimately manifests as cognitive impairment. Our study highlights the importance of the NVU’s integrity and provides insights into investigating the neural mechanism underlying CRCI. Additionally, neurovascular decoupling might be a potential therapeutic target for preventing CRCI.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1321/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1321/dss

Funding: This work was supported by the Natural Science Foundation of Jiangsu Province (No. BK20211008).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1321/coif). The 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Institutional Review Board of Nanjing Medical University (Approval No. KY2021000589YX). Before enrollment, all participants provided written informed consent in compliance with the study protocol.

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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