Our results demonstrated the radiation-induced brain functional connectivity abnormalities of NPC patients. The captured deficit pattern of functional connectivity was reliable in identifying the RT− from RT+ with 81.36% accuracy. The 45 consensus connections were mainly the mutual connections between the cerebellum, sensorimotor, and cingulo-opercular networks. In addition, 5 consensus functional connections were significantly correlated with the MoCA scores, among which 1 connection was significantly correlated to the attention score. Together, these findings suggested that the altered functional connectivity pattern might serve as a potential biomarker of the radiation-induced brain dysfunctions in NPC patients.
The 45 consensus connections were associated with all of the 6 networks previously defined, especially the mutual connections between the cerebellum, sensorimotor, and cingulo-opercular networks. The cerebellum is close to the tumor proximity, which is inevitably included in the radiation volume target, suffering a high irradiation dose. Anatomical surveys indicated that the cerebellum is extensively interconnected with the cerebral cortex via thalamus in the output circuit, and via the pons in the input circuit, which forms a contralateral circuit. Besides, it was demonstrated that the cerebellum is not only associated with motor control function, as traditionally considered, but is also involved in cognitive function. In our exploration, though we chose the patients with normal appearing white matter and gray matter in the brain, the cerebellum was still strongly involved in the abnormal functional connectivity pattern. We speculated that the cerebellum function may be altered during the RT process in the RT+ NPC patients comparing to the RT− group, and the cerebellar–cerebral circuits may be damaged.
Our results found that the cerebellum network was abnormally connected with sensorimotor and cingulo-opercular network. The sensorimotor network is the coupling of sensory and motor functions, and the cingulo-opercular functional network is associated with controlling goal-directed behaviors. We proposed that the functional connectivity alterations between the cerebellum and sensorimotor network might imply the radiation-induced motor deficits in NPC patients, while the functional connectivity alterations between the cerebellum and cingulo-opercular network may involve in the cognitive functional abnormalities. Indeed, the motor ability deficit was previously demonstrated in the NPC RT+ patient. In some clinical reports, the RT+ NPC patients exhibited swallowing impairment and bulbar palsy, which were involved in the sensorimotor function deficits.
The correlation analysis showed that 5 consensus functional connections were significantly correlated with the MoCA scores, which included the functional connections between the vermis and hippocampus, cerebellum lobule VI and dlPFC, precuneus and dorsal frontal lobe, cuneus and middle occipital lobe, and insula and cuneus.
Hippocampus plays an important role in the information consolidation and spatial navigation, and is also known to be involved in attention processes such as visuospatial working memory and modulating executive functions. Studies have reported that the RT would induce the hippocampus structural deficit. Recently, a study using clustering method to identify brain networks demonstrated an important role of vermis in the ventral attention network. Indeed, both the hippocampus and vermis were found abnormal in the attention deficit hyperactivity disorder (ADHD), a disease that always has a high level of impulsivity and inattentiveness. In our study, we found that the functional connectivity between the vermis and hippocampus was significantly correlated with the MoCA scores, especially with the attention score. These results suggested that the altered functional connectivity between the vermis and hippocampus might imply the attention deficit in RT+ NPC patients.
The altered functional connectivity pattern and the significant correlations between 5 altered connections and MoCA scores demonstrated that RT may induce the brain cognitive dysfunctions, especially attention alterations. This indicates that radiation-induced brain impairments are not restricted to the exposed area, other encephalic region, such as cerebellum, sensorimotor, and cingulo-opercular areas, should be concerned as well.
Our study showed that RT would cause brain functional connectivity abnormalities in NPC patients. The 45 altered functional connections may serve as the potential biomarkers and may underlie the RT-induced functional impairments. Hence, the potential clinical value and application of our study may exist in 3 aspects. First, we suggest that to prevent the RT-induced cognitive impairments as much as possible, some necessary measures may be taken for the conventional MRI negative NPC patients, such as using hyperbaric oxygen therapy and radioprotector, like glucocorticoid, melatonin, magnesium sulfate, valproate, and cyclooxygenase inhibitors. Second, it is important for radiation oncologists to evaluate the cognitive deficits in NPC patients after the RT process. In our study, we found that RT may induce various functional impairment including domains of attention, visual processing, inhibition control, and executive processing. Based on these, some of the clinical interventions relative to these cognitive deficits shall be considered as a further follow-up recovery treatment. For example, the attention dysfunction and inhibition control deficit, which are coincident with ADHD, are clinically treated in 2 ways, including the pharmacological treatment such as applying stimulants and atomoxetine, and also the recommended nonpharmacological interventions such as neurofeedback, cognitive training, and restricted elimination diets. These widely used treatments may also help to decrease the RT-induced attention alterations in NPC patients. Last but not the least, recent studies have investigated some promising method such as brain stimulation, which aims to regulate the altered functional connectivity and reduce the brain functional impairments.[12,13] Thus, the 45 altered functional connections found in our study not only underlie the pathology of the RT-induced functional impairments but may also serve as the stimulating targets, which might to some extent help the RT+ NPC patients recover from the functional impairments.
In our study, apart from RT, the chemotherapy might also cause the functional connectivity alterations in RT+ NPC patients, since the RT− NPC patients did not receive RT or chemotherapy, while RT+ NPC patients received both treatments. Though there is no report on NPC patients, studies on breast cancer patients have demonstrated that chemotherapy would cause some functional connectivity changes, especially in the default mode network,[45–47] the connectivity relevant to anterior cingulate cortex and intraparietal sulcus. These functional connectivity alterations may be underlying the executive, attention impairments,[45,46] and memory difficulties. It was worth noting that the fMRI data in our study were scanned at least 6 months after the completion of chemotherapy, which would to a large extent reduce the chemotherapy-induced influence. Studies have demonstrated that the chemotherapy-induced functional impairments would recover largely over time, particularly after 6 months, in breast cancer patients or colon cancer patients. Despite these, the potential functional connectivity alterations induced by chemotherapy in NPC patients remained unclear. Further study is needed in investigating the chemotherapy-induced functional connectivity alterations.
There are still some limitations in this study due to the small sample size and the lack of a new and larger sample to confirm the results of the classification performance and correlation analysis. In the future, we expect to collect a larger sample of follow-up NPC patients to evaluate the functional connectivity abnormalities, which can contribute to find more accurate and reliable functional connectivity pattern in revealing the RT-induced functional impairments.
The present study demonstrated that the whole brain functional connectivity pattern of RT+ NPC patients was significantly impaired comparing to RT− NPC group and the altered functional connectivity pattern was highly correlated with the MoCA score. These findings suggested that RT process might notably induce functional deficits in brain cognition, especially attention function. The 45 altered functional connections, especially the 5 connections that were significantly correlated to the MoCA scores, may shed new light on the underlying radiation-induced functional impairments in NPC patients and may serve as the potential indicators for further clinical recovery treatment of the impaired functions.
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