The objective of the present work was to explore the changes in FC patterns of different insular subregions between different groups (HC, PD-NC, PD-MCI). Corresponding with our hypothesis, we found that FC of the bilateral dAI of drug-naïve PD-MCI patients was significantly higher than that of control subjects. Then, correlation analysis indicated that altered FC has different effects on cognitive function. Thus, our study further confirms that the bilateral dAI is functionally independent and suggests that bilateral dAI might contribute to cognitive impairment in PD patients.
Previous studies have indicated that the insula is mainly affected by alpha-synuclein deposition in PD, showing altered FC and abnormalities in dopaminergic and serotonergic function related to cognition (Christopher, Koshimori, Lang, Criaud, & Strafella, 2014; Christopher, Marras, et al., 2014). Now, we found that abnormal FC of bilateral dAI was related to cognition, proving the dorsal anterior insula is more involved in human cognition than the ventral anterior and posterior networks (Chang, Yarkoni, Khaw, & Sanfey, 2013; Kurth et al., 2010; Touroutoglou et al., 2012). Compared with the PD-NC group, the PD-MCI group showed increased FC between the left dAI and right SPG, which were positively correlated with executive and memory domain z scores. In past studies, the SPG, a hub of the central executive network (CEN) (Wang et al., 2020), was considered a key region affected by different kinds of deficits in MCI. Meta-analysis revealed, both in rs-fMRI and task-related MRI studies, hyperactivation in the SPG was present in MCI patients (Gu & Zhang, 2019). In subcortical vascular mild cognitive impairment (svMCI) patients, increased intermodule connectivity was also observed in the SPG and was associated with worse memory performance (Yi et al., 2015). Besides fMRI results, the FDG-PET study showed that significant hypometabolism was observed in the SPG in newly diagnosed PD-MCI patients (Pappata` et al., 2011); structural MRI also demonstrated that SPG atrophy in PD-MCI patients was related to memory and executive function (Pereira et al., 2014; Uribe et al., 2016; Zhang et al., 2015). In sum, SPG dysfunction was related to executive function and memory impairment in PD-MCI. In addition, in newly diagnosed PD cases, impairment was the most frequent in executive function and memory (Muslimovic, Post, Speelman, & Schmand, 2005). Abnormal FC between the left dAI and right SPG was not shown in PD-NC and HC groups. Therefore, our study indicates that the abnormal FC between the left dAI and right SPG contributes to executive function and memory impairment in PD-MCI patients.
Interestingly, compared with the HC group, the current study found increased FC between the right dAI and right DCG in PD-MCI patients but not in PD-NC patients, which might represent a characteristic change in PD-MCI patients. The anterior insula (AI) is one of the core brain regions anchoring the SN (Chong, Ng, Lee, & Zhou, 2017), and the DCG is part of the DMN. In healthy adults, interactions between the SN and the DMN were thought to be important for cognitive control (Kelly, Uddin, Biswal, Castellanos, & Milham, 2008). To our knowledge, changes were detected in the DMN subnetworks in three preclinical stages of AD (Xue et al., 2019), and DMN hubs could be the first to show disruptions in early, cognitively unimpaired PD patients (Disbrow et al., 2014; Hou et al., 2018). Nevertheless, Jones et al proposed that the DMN in AD seems to follow the model of cascaded network failure (Jones et al., 2016), and the successive failure of intrinsic connectivity networks in each stage of PD (DMN dysfunction in PD-NC patients, SN dysfunction in PD-MCI patients) seems to follow such a model as well (Aracil-Bolanos et al., 2019). Therefore, as the disease progresses, disruption in SN hubs, such as the dAI, appears to signal the onset of PD-MCI (Aracil-Bolanos et al., 2019). On the other hand, a previous study indicated increased FC between the SN and DMN, a relative decrease in the DMN and an increase in the SN; these changes were viewed as a rapid allocation of resources toward potential external risks (Jilka et al., 2014). Thus, increased FC values between the right dAI and the right DCG were positively correlated with attention/working memory, visuospatial function, and language, which was considered as compensatory mechanisms in PD-MCI.
In sum, the increased FC between the left dAI and the right SPG and the increased FC between the right dAI and the right DCG were a feature in PD-MCI patients. In terms of networks, the SN, the dAI in particular, plays the critical role in switching between activating the DMN and the CEN in the triple model of cognition (Aracil-Bolanos et al., 2019; Menon & Uddin, 2010), and dAI dysfunction may lead to abnormalities in the DMN and CEN.
We acknowledge some limitations of our study. First, in our research, 65% of PD patients were diagnosed with PD-MCI, which is higher than the percentage in previous reports (Y. Li et al., 2019). There are several reasons for this discrepancy: a small sample size and the use of level 2 criteria for PD-MCI. However, we've been recruiting volunteers to participate in this study and will perform regular follow-up in the future. In addition, we used MDS PD-MCI Task Force Level 2 diagnostic criteria to obtain a reliable diagnosis of PD-MCI and facilitate subsequent analysis of cognitive domains. Second, compared with the PD-NC patients, the PD-MCI patients are older, have less education and higher UPDRS-III scores in numerical value. Indeed, meta-analysis revealed that PD-MCI patients were characterized by older age, more severe motor symptoms, and less education compared with PD-NC patients (Baiano, Barone, Trojano, & Santangelo, 2020). Moreover, to exclude the influence of the above factors, we used age, years of education, and UPDRS-III score as covariates in analysis. Third, the MCI group was missing in our research, so we may ignore alter FC in individual with MCI. We will recruit MCI group in the future to avoid all possibilities of potential bias in our data. Last, it was a pilot exploratory study, we performed the correlation analyses between the altered FC in insular subregion and cognitive function. Future studies, with more patients recruited, will help to confirm the current results.