Major depressive disorder (MDD) is a mental disorder characterized by persistent depressed emotions and diminished social functioning, contributing significantly to the global disease burden (Malhi and Mann, 2018). Emerging evidence highlights the role of disrupted interactions within the triple network model—comprising the default mode network (DMN), executive control network (ECN), and salience network (SN)—as a key framework for understanding psychopathology (Menon, 2011). The DMN, including the medial prefrontal cortex, the posterior cingulate cortex and adjacent precuneus plus the lateral parietal cortex, is linked to self-referential processing. The ECN, comprising the lateral prefrontal cortex and posterior parietal cortex, is implicated in executive functions such as goal-directed cognition, working memory, inhibition, and task switching. The SN, involving the anterior cingulate cortex and insula, is involved in detecting behaviorally relevant environmental stimuli and plays a crucial role in identifying salient information (Elton and Gao, 2014; Uddin, 2015).The interaction among these networks is essential for cognitive and emotional regulation.

While earlier research predominantly focused on static functional connectivity patterns, recent investigations have shifted toward characterizing dynamic functional connectivity (dFC)—a paradigm that captures the spontaneous fluctuations of neural network communication on a smaller time scale (Liégeois et al., 2017; Allen et al., 2014). This approach reveals how brain networks reorganize in response to different cognitive demands or environmental stimuli, offering insights beyond static measures of connectivity. In MDD patients, dFC shows increased or decreased variability within and between the DMN, ECN, and SN networks (Zhou et al., 2022; Pang et al., 2018; Kaiser et al., 2016; Wise et al., 2017; Zhang et al., 2020; Wang et al., 2020). Some studies have also reported that the network switching rates of the DMN and SN are reduced (Han et al., 2020; Wei et al., 2017). Data from REST-meta-MDD show that MDD patients have higher temporal variability, temporal efficiency, and lower temporal clustering, with changes mainly occurring in the DMN, sensory motor networks, and subcortical regions (Hayasaka et al., 2015). Another large-sample study from China suggests that MDD and healthy controls (HC) have similar dynamic functional connectivity states, but MDD patients tend to stay in a weak connectivity state for longer, and different states are associated with variations in depression severity and cognitive performance (Zhi et al., 2018). These findings highlight the critical need to investigate dynamic interactions among the triple-network to better understand the neural mechanisms underlying MDD. However, the biological drivers of these connectivity alterations remain poorly understood.

The kynurenine (KYN) pathway, recognized as a key mediator of inflammation and neurotransmitter imbalance in MDD, has emerged as a potential contributor. This pathway metabolizes tryptophan (TRP) into compounds that can be either neurotoxic or neuroprotective, thereby influencing glutamatergic transmission, neuroplasticity, and synaptic function (Brown et al., 2021; Savitz, 2020). In early studies, acute TRP depletion was found to alter brain functional connectivity (Salomon et al., 2011; Weinstein et al., 2015). A study on untreated MDD patients found that cerebrospinal fluid KYN metabolites mediate the effect of plasma KYN metabolites on connectivity between the dorsal prefrontal cortex and the basal ganglia (Chen et al., 2021). Additionally, it has been observed that the functional coupling of the triple network is associated with low-level inflammation; however, no studies have directly investigated the impact of KYN pathway dysregulation on dynamic interactions within this model and its effects on depressive symptoms (Kim et al., 2020).

We conducted a cross-sectional study comparing adults with MDD and HC, using dFC analysis and KYN pathway metabolite profiling to explore the relationship among neurochemical imbalances, disrupted triple-network interactions, and depressive symptoms. We hypothesize that MDD involves impaired dynamic coordination within this network, with these alterations co-occurring alongside aberrant KYN pathway activation, and contributing to depressive symptoms.