Worry is considered as one processing about a future event. Superabundant worry might have adverse effects on daily behavior (MacLeod et al., 1991). Based on DSM-IV-TR (Battle, 2013), the main features of a generalized anxiety disorder (GAD) are highly related to the process of worrying, such as chronic and excessive worry. Notably, high worry-proneness is more likely to develop into an anxiety disorder, such as GAD (Cox et al., 2022). Anxiety has a heavy burden on individuals and society (Kujanpää et al., 2017). Thus, it is essential to identify the neural characteristic of high worry-proneness subjects. Specifically, anxiety is not only characterized by worry but also accompanied by somatic symptoms (Cui et al., 2020). More important, several psychophysiological studies suggest that interoception plays a vital role in the interaction between internal function and cognitive processing (Chan et al., 2014, 2015). Thus, these findings consistently agree that anxiety disorder is fundamental to impaired interoception (Mallorquí-Bagué et al., 2016; Khalsa et al., 2018). In contrast, the underlying relationship between interception and worry is poorly investigated in worry-prone individuals.

Interoception refers to the nervous system’s processing of internal stimuli from its internal organs (e.g., heart, lungs, stomach, and bladder). This internal information would further affect subjects’ cognition and behavior (Van Oudenhove, 2010). Locating the substrates of interoception processes might provide more evidence to investigate the effects of high worry and anxiety on the human brain. Importantly, Badoud Deborah and Tsakiris Manos pointed out that the insula plays a key role during the interoception processes (Badoud and Tsakiris, 2017). The insula is a functional heterogeneous region with extensive connections to the cerebral cortex and limbic system. Thus, it implicates functions ranging from consciousness, interoceptive awareness, emotion processing, motor control, and interpersonal experience (Craig, 2009; Zaki et al., 2012). A neuroimaging study has begun to parcel the insular regions based on their patterns of functional mapping (Deen et al., 2011). Specifically, a study by Craig has indicated that an anatomical posterior–anterior progressive connectivity contributes to the integration between interoception and emotion, as well as cognition in the human brain (Craig, 2002), while the insular region and its potential relationship to interoception have not been measured in worry-proneness subjects.

Recently, resting-state functional magnetic resonance imaging (rs-fMRI) has been commonly used to measure the inter-regional static functional connectivity (FC) in the human brain. Specifically, the developments of dynamic functional connectivity (dFC) analyses have documented that the FC is changing over time. Moreover, the dFC could sensitively capture the deficient dynamic feature associated with psychiatric symptoms (Ma et al., 2014; Du et al., 2016). A recent study also indicated that the feature of dFC significantly outperforms the static FC through the classification analysis (Rashid et al., 2016). The static FC might obscure the dynamic features of network behavior. Thus, these findings posit that static and dynamic FC could provide complementary information about the neural substrates of worry-proneness and anxiety disorder, while, in recent years, there has been no study exploring the interoception functional network in worry-proneness subjects through static and dynamic FC analyses.

The current study was conducted to investigate the deficient insular functional network in a sample of worry-prone individuals. To this end, participants were subjected to rs-fMRI. Based on the results from previous behavioral and neuroimaging research, we hypothesized that the differences in insular functional connectivity might be found in high worry-prone individuals. We posit that these changed insular functions may be associated with worry in healthy subjects.

Anxiety disorder would lead to significant personal and economic burdens. Exploring the change in the brain before the occurrence of the disease has great significance for the prevention and cure of anxiety disorder. In this study, we investigated the abnormal neural substrates of the insula in a sample of individuals with worry-proneness. The decreased FC of insula–ACC and increased insula–TPJ were observed in HWP compared to LWP, respectively. These changed FCs might reflect a remodeling of the insular function network with high worry.

Patients with GAD have high body perception scores than healthy controls (Ehlers and Breuer, 1992; Cui et al., 2020). Higher body perception scores reflected hypersensitive interoception in anxiety disorder. In the human brain, the posterior insula plays a crucial role in integrating the physical signal of interoception (Kuehn et al., 2016). Information is initially transferred to the posterior insula from the individual’s inner organs (e.g., heart rate) and self-generated movements (Limanowski et al., 2014). During the somatosensory integration, the posterior insula gate this signal (Palmer et al., 2016). Moreover, Jakub Limanowski’s research reported that the gating processing would extend to SMA from the posterior insula (Limanowski et al., 2020). These gating might underlie the brain’s capacity to attenuate self-generated somatosensory reafference. In this study, the decreased dynamic PI-TPJ and PI-SMA FCs were found in HWP. TPJ is located at the ventral–anterior section of the inferior parietal lobule and surrounds the posterior end of the Sylvian fissure. Specifically, the ventral intraparietal region is associated with multi-modal representations, such as visual, auditory, and somatosensory information (Avillac et al., 2005; Schlack et al., 2005). Decreased dynamic PI-TPJ/SMA FCs might induce deficient gating processing of PI. Thus, our results indicated that the high worry might be associated with the abnormal dynamic PI-TPJ/SMA FCs in the human brain.

In addition to the connectivity between somatosensory cortices and posterior insula, cerebral substrates of interoception were consistently defined as the critical pathway, including the anterior insular region and anterior cingulate cortex (Craig, 2009; Craig, 2010). Importantly, these two pathways have been highly linked through anatomical connectivity with the insula. More important, one hypothesis of pathological mechanisms of mental disorder is that interoceptive input (i.e., posterior insula) becomes increasingly decoupled from the self-generated somatosensory region, leading to abnormal interoceptive prediction error (Bonaz et al., 2021; Weng et al., 2021). In this study, the increased static FC was observed between the anterior insula and TPJ. Moreover, a positive relationship was observed between increased static FC (anterior insula and TPJ) and decreased dynamic FC (posterior insula and TPJ) in LWP, whereas this correlation was not found in HWP. TPJ is one key region within the salience network and has highly functional connectivity with the anterior insula (Onofrj et al., 2022). Consistent with previous studies, our findings indicated that interoception processing might be associated with the function coupling between the anterior insula and posterior insula. Furthermore, our results revealed that the high worry might be associated with the deficient decoupling functional connectivity between the posterior insula and anterior insula through TPJ.

The anterior insula plays a central role in integrating multi-interoceptive physical features with emotional salience (Menon and Uddin, 2010; Kuehn et al., 2016; Sturm et al., 2018). Ventral insula functional connectivity with limbic and autonomic processing regions (e.g., PgACC, thalamus, and amygdala) makes up the salience network (Pasquini et al., 2020), which represents the homeostatic significance of prevailing stimuli and inner conditions. Specifically, the functional connectivity between the anterior insula and anterior cingulate cortex mainly contributes to the dorsal lateral prefrontal cortex (dlPFC)-involved cognitive control triggered by salience evaluation (Sridharan et al., 2008). Moreover, previous research indicated that high trait anxiety and GAD share common changed FC of the salience network (Etkin and Wager, 2007; Sylvester et al., 2012). Adolescents’ trait anxiety score was negatively related to FC between the anterior insula and anterior cingulate cortex (Geng et al., 2015). Thus, worry or anxiety might be negatively related to the FC between the two regions. In this study, the decreased static FC was observed between the left ventral insula and PgACC in high worry-proneness subjects compared to low worry-proneness subjects. Our findings indicated that the deficient static anterior insula–PgACC FC might be related to the effect of worry on healthy subjects. The findings of the changed function of the anterior insula in HWP might be of great significance to understanding the pathological mechanisms of anxiety disorder.

Several limitation issues need to be considered in this study. First, the seed-based FC analysis was performed. The regions of interest were defined as hypothesis-driven, which might have disregarded results. However, it is easy to replicate our findings. Second, the somatosensory and interoceptive functions were not acquired from the participants. Our results should be validated and expanded in further study. Finally, our results were observed in HWP, and this result should be validated and extended to anxiety disorder.

In conclusion, our results reveal the altered static and dynamic insular function network in HWP subjects through resting-state static and dynamic FC approaches. We show the functional decoupling between the anterior and posterior insular subregions in the HWP group. Combined with deficient static vAI-PgACC FC, our findings highlight that the remodeling of the insular function network might contribute to the effect of high worry on healthy subjects.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Ethics Committee of The Clinical Hospital of Chengdu Brain Science Institute following the Helsinki Declaration (IRB number: 2020036). The patients/participants provided their written informed consent to participate in this study.

YZ, MD, and HH had made a substantial contribution to the conception and drafting and revising the article. XC acquired the data. YZ and HH had made a substantial contribution to the analysis and interpretation of the data. All authors contributed to the article and approved the submitted version.

This study was partly supported by a grant from the National Nature Science Foundation of China (Grant numbers: 62003076, 81801775), the Chengdu Science and Technology Bureau (Grant number: 2021-YF09-00107-SN), the Project of Natural Science Foundation of Sichuan Province (2023NSFSC1489 and 2023NSFSC1186), and the Special Project of Sichuan Postdoctoral Foundation (TB2022089).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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