Anxiety, a prevalent emotional state, was characterized by persistent experiences of worry, apprehension, fear, and heightened arousal (C. D. Spielberger, 1983; Tian et al., 2016; Tovote, Fadok, & Lüthi, 2015; Xu et al., 2019). Individuals with high trait anxiety demonstrated a greater inclination towards potential internal or external threat stimuli, encountered difficulties in relaxation, and exhibited increased vulnerability to anxiety-related disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and social anxiety disorder (SAD) (Cremers et al., 2010; Grupe & Nitschke, 2013; Huo, Zhang, Seger, Feng, & Chen, 2020; Modi, Kumar, Kumar, & Khushu, 2015; Xu et al., 2019).
It had been confirmed by numerous neuroimaging studies that the amygdala, a critical brain region for emotional processes, played a significant role in the functional and structural neural substrates of anxiety (Ironside et al., 2019; Kim, Loucks, et al., 2011; Phelps & LeDoux, 2005). Converging evidence highlighted a robust association between the amygdala and trait anxiety during the detection and processing of threatening stimuli (Etkin et al., 2004; Günther et al., 2020; Hyde, Gorka, Manuck, & Hariri, 2011). For example, the participants with higher trait anxiety scores exhibited more increased amygdala activation in response to masked fearful faces (Günther et al., 2020). Moreover, at the structural level, studies revealed a positive relationship between amygdala volume and trait anxiety in healthy adults and children (Baur, Hänggi, & Jäncke, 2012; Qin et al., 2014). Notably, patients with GAD also showed increased amygdala volumes compared to control groups, consistent with findings observed in healthy populations (Schienle, Ebner, Schäfer, & neuroscience, 2011).
The amygdala-associated neural network, encompassing the prefrontal cortex (PFC) and hippocampus, had also been consistently implicated in anxiety (Kim & Whalen, 2009; Mah, Szabuniewicz, & Fiocco, 2016). A previous study found that trait anxiety was associated with functional connectivity alterations within the superior frontal gyrus, underscoring the significance of the PFC's role in anxiety (Saviola et al., 2020). What was more important, the efficacy of top-down inhibition exerted by the PFC on the amygdala, regulating emotional processes through their functional and structural connectivity, appeared to be attenuated in individuals with high trait anxiety and in those diagnosed with anxiety-related disorders (Amaral & dysfunction, 1992; Burghy et al., 2012; Ghashghaei, Hilgetag, & Barbas, 2007; Kim, Gee, Loucks, Davis, & Whalen, 2011; Kim & Whalen, 2009; Porta-Casteràs et al., 2020). For instance, Kim and Whalen reported a negative correlation between trait anxiety scores and the strength of white matter pathways connecting the amygdala and PFC (Kim & Whalen, 2009). Furthermore, compared to healthy controls, SAD patients exhibited more negative connectivity between the amygdala and PFC compared to healthy controls, and this aberrant connectivity was found to be associated with the severity of symptoms, indicative of compromised automatic recruitment of the PFC for regulatory functions in SAD (Young et al., 2017). In addition, by using Granger causal analysis (GCA), Dong et al. found that the middle frontal cortex exhibited a significant direct inhibitory influence on the amygdala in healthy controls, while this inhibitory influence was markedly attenuated in individuals diagnosed with GAD (Dong et al., 2019). Consequently, this study provided empirical evidence regarding the anxiety-related alterations in effective connectivity between the amygdala and PFC specifically. Importantly, it is noteworthy that, to the best of our knowledge, no previous investigations had examined the alterations in amygdala-PFC effective connectivity in relation to trait anxiety among healthy adults.
The hippocampus was another significant brain structure within the amygdala-centered network associated with anxiety (Mah et al., 2016). Extensive research in both rodents and humans had indicated its involvement not only in memory processes but also in anxiety (Bannerman et al., 2004; Lau et al., 2012; MacMillan et al., 2003; Mah et al., 2016; Satpute, Mumford, Naliboff, & Poldrack, 2012). For instance, Satpute et al. demonstrated a significant correlation between trait anxiety and activation of the posterior hippocampus (Satpute et al., 2012). Furthermore, individuals with GAD had been found to exhibit reduced hippocampal volume compared to healthy controls (Alper et al., 2023; Bremner et al., 2000; Gray, Müller, Eickhoff, & Fox, 2020). In contrast to the amygdala's primary role in processing cues that predicted threatening or aversive stimuli, the hippocampus was crucial in processing contextual information related to threat (Alexandra Kredlow, Fenster, Laurent, Ressler, & Phelps, 2022). The interaction between these two brain regions allowed individuals to effectively discriminate between safe and threatening stimuli, facilitating appropriate responses (Mah et al., 2016; Phillips & LeDoux, 1992; VanElzakker et al., 2014). However, any disruption in the delicate balance of neural circuits could result in significant dysfunction in the processing and expression of anxiety. For instance, an excessive information flow from the amygdala to the hippocampus had been observed to induce anxiety-related behaviors in mice (Felix-Ortiz et al., 2013; Felix-Ortiz & Tye, 2014; J.-Y. Zhang et al., 2019). Nonetheless, limited knowledge existed regarding alterations in the effective connectivity between the amygdala and hippocampus associated with trait anxiety in humans.
In the present study, we employed the GCA using the amygdala as seed region, in conjunction with multiple regression analysis, to examine alterations in the causal connectivity network between the amygdala, PFC and hippocampus associated with trait anxiety in a large cohort of young adults. The GCA, a hypothesis-free approach widely utilized in neuroimaging research, had been employed to delineate effective connectivity patterns of the amygdala in anxiety-related disorders (Dong et al., 2019; K. Friston, Moran, & Seth, 2013; Liao et al., 2010; Seth, Barrett, & Barnett, 2015; Shan et al., 2023). Building upon previous investigations (Dong et al., 2019; Felix-Ortiz & Tye, 2014), we hypothesized a negative association between the effective connectivity from the PFC to the amygdala and trait anxiety, while postulating a positive correlation between amygdala-to-hippocampus connectivity and trait anxiety.