In this study, we found increased within-network connectivity in most RSNs in breast cancer patients one week after chemotherapy, and all the within-network connectivity of RSNs tended to recover towards the baseline level six months after chemotherapy. Chemotherapeutics showed selective damage to the between-network connectivity. The connectivity between pDMN and SMN showed a recovery trend six months after chemotherapy, while the connectivity between aDMN and CN, SMN and VN continued to decline. Furthermore, both within- and between-network connectivity changes significantly correlated with blood indicators and cognitive function alterations. This prospective longitudinal study provided the evidence that chemotherapy may induce widespread connectivity abnormalities in RSNs, which might serve as potential biomarkers of chemotherapy related cognitive deficits in breast cancer patients.
Our results suggested that chemotherapeutics can damage the large-scale resting state brain networks, including aDMN, pDMN, LFPN, RFPN, SRN, CN and VN. These findings provided the evidence that chemotherapy induced widespread cognitive deficits across various domains. DMN is one of the most common RSNs, which is considered to support process such as active episodic memory and introspection, and would be deactivated during specific goal-directed task. In our study, abnormal within-network functional connectivity in DMN were mainly located in the superior frontal gyrus and posterior cingulate cortex (PCC), which were consistent with the most previous studies[25, 20, 12], indicating that DMN is more vulnerable to chemotherapeutic agent attack. The CN, FPN, SRN and VN also showed abnormal within-network functional connectivity changes after chemotherapy. The LFPN is associated with language-related cognition, while the RFPN is associated with working memory, abstract reasoning, planning and somatosensory processing. SRN is involved in self-understanding and self-reference processing, which is considered to be the hub network regulating primary perception, self-reference processing and advanced cognitive processing[27, 28]. CN is related to activity inhibition, emotion and participates in multiple advanced cognitive tasks, playing an important role in adaptive cognitive control. Abnormalities in multiple within-network functional connectivity provided the evidence that chemotherapy induced widespread cognitive deficits in attention, executive function, memory, learning ability and processing speed.
In addition, chemotherapy induced abnormal RSNs functional connectives were mainly located in the superior frontal gyrus, PCC, supplementary motor area, orbital inferior frontal gyrus and calcarine sulcus. Neuroimaging studies have shown that some intrinsic network regions exhibit task-induced activation or deactivation during goal-directed tasks, which also namely the “task-positive network” or “task-negative network”. It was considered to support the process of target activity by regulating the allocation of neural resources[29, 30]. PCC and superior frontal gyrus mainly located in the task-negative network and deactivated for self-referential processing tasks, while the supplementary motor area and orbital inferior frontal gyrus located primarily within or near the task-positive network and activated for demanding cognitive tasks. These different task-evoked neuronal responses reflected the integrative role of the brain functional organization across several spatial and temporal ranges. The increased within-network functional connectivity after chemotherapy may represent a compensation for dysfunction which needed to recruit more neural regions and increase the strength of functional connectivity in order to maintain normal neural activity. The functional connectives strength of RSNs also predicted chemotherapy induced higher or lower neural activity during task. Previous multitask-based fMRI of CRCI showed increased[32, 33, 34] and decreased activity[35, 36, 37] located mainly in several frontal and parietal regions, anterior cingulate cortex and supplementary motor area. The altered RSNs functional connectivity regions in our study were matched well with previous task-related studies.
Chemotherapeutics also showed selective damage to the between-network connectivity in this study. The DMN can integrate primary perception and advanced cognitive functions. It accepts more information from other RSNs than it outputs. Liao et al. showed that SRN, CEN, CN and AN had significant effect on connections to the DMN. Sridharan et al. found that CN may regulate DMN, CEN and dorsal attention network. The collaborative work among these RSNs completes the integration and transformation of information. In this study, the decreased functional connectivity between networks after chemotherapy suggested that chemotherapeutic drugs did not alter central brain regions and hemodynamics through a single resting brain network, but the multiple between-networks dysfunction. The chemotherapy related cognitive impairments were the result of reduced coordination between multiple networks. The RSNs compete more processing resources from the “central cognitive operator” to compensate for their impaired cognition. This may explain that functional impairment in multiple cognitive domains after chemotherapy but without significant difference from the baseline period.
Interestingly, most of the within-network connectives tended to recover to the baseline levels six months after chemotherapy, while the between-network connectives showed partial recovery. Recovery of some brain regions to baseline levels has also been reported in other CRCI-related functional and structural MRI studies[40, 41, 42, 8], and the acute damage mostly appeared 1 month after chemotherapy and (partially) recovered one year later. These studies suggested that chemotherapy-induced brain structural and functional damage may be temporary, the frontal regions (such as frontal and temporal gyrus) may recover over time, and the brain abnormalities in the posterior region may persist for a long time. Brain function and structural recovery may be attributed to neuroplasticity mechanisms. In this study, most of the subjects were young women, cognitive challenges in daily work and social activities promoted early rehabilitation through neuroplasticity mechanisms. Additionally, the frontal regions began to show signs of recovery six months after chemotherapy. We hypothesized that the frontal lobe might be one of the first sensitive brain regions to experience functional recovery. However, our finding was inconsistent with some previous studies as for recovery time, which may be related to the age, chemotherapy dose, chemotherapeutic drug, treatment stage, cognitive function type and the different control groups. The recovery to the baseline level may reflect compensation ability improvements over time to some extent, it does not mean a return to normal level, and some brain dysfunction may persist for a long time. Sustained networks alterations may further affect patient's cognitive function, such as sustained memory deterioration and executive ability impairment, which showed poor WDT and NST scores in this study. We are not sure whether the brain abnormality in the posterior brain region (such as visual function areas) alteration was a sustained change in acute effects after chemotherapy or a delayed brain injury occurring at a certain time after chemotherapy. Further long-term follow-up studies are thus needed.
Breast cancer patients also showed decreased visual ability and memory at baseline compared to HC group. This pre-treatment mild cognitive decline may be associated with tumor-related physical and psychological stress[44, 37]. Additionally, the improved test scores in LTT, SDT and Stroop test after chemotherapy may be related to the compensatory effect of the functional network. Furthermore, partial networks alterations were associated with estrogen, fasting blood glucose and blood lipids changes, though the improved blood indicator was still in the abnormal range compared to HC group. We speculated that the increased blood estrogen levels, decreased blood sugar and lipid levels six months later may play a positive role in the cognition improvement. Estrogen can alter the metabolic level of the frontotemporal lobe, affecting the structure and function of specific brain regions. Animal experiments and clinical practice have shown that estrogen can be used to treat attention and memory loss. Abnormalities in blood lipids, fasting blood glucose, and hemoglobin have also been found in neuropsychiatric diseases such as Alzheimer disease and diabetic encephalopathy[46, 47]. The improved cholesterol metabolism would reduce the risk of vascular related cognitive impairment. However, the use of chemotherapeutic agents and endocrine therapy confuses the assessment of underlying metabolic changes. Although there was no direct evidence that baseline metabolism changes were significantly associated with cognitive improvement six months after chemotherapy, we speculate that the improvement of baseline metabolism in patients can play an irreplaceable role in the recovery mechanism of CRCI.
Anxiety and depression scores were significantly higher in the breast cancer group than HC group at baseline, and continued to increase one week after chemotherapy, but decreased over time after the end of chemotherapy. The dynamic changes of depression and anxiety scores were similar as that of some cognitive functions. Studies have suggested that there were competitive interactions between emotion and cognition[7, 30], we speculate that the decreased negative emotion may benefit cognitive function recovery in this study.
The study had some limitations. Although HC was included in this study, the control group had no serial follow-up, making it impossible to evaluate the interaction between the groups and time. However, all breast cancer patients performed a series of neuropsychological tests, blood examination and MRI scans at three times points, which enabled the longitudinal analysis of RSNs in these patients. Secondly, the breast cancer patients were heterogeneous, some confounding factors such as the different severities of the disease, the different treatment strategies may induce some impacts on the results of our study. Thirdly, the basic metabolism and hormone level may fluctuate greatly in a relatively short time, and untangling these effects was difficult. Fourthly, the sample size is relatively small due to some patients refusing follow-up. Finally, the definition and selection of the RSN may affect the results, and the source of abnormal nodes is not fully understood.