Stress causes a chain of reactions in multiple neurobiological circuits, enabling us to cope with challenging demands. Most individuals are mentally resilient and quickly bounce back and recover after the subsidence of the stressor (1, 2). However, among a smaller fraction of individuals, sustained activation of stress-related neurobiological circuits results in prolonged stress reactions and psychopathology, such as post-traumatic stress disorder (PTSD), anxiety, and depression (3, 4, 5). While there is extensive research on stress, it remains unclear how acute stress response reflects on our ability to cope with chronic stress (like military deployment). It is therefore important to better characterize the neurological processes involved in acute stress reactivity and recovery and identify how these processes may relate to chronic stress. Here we examined the unfolding brain process following lab-induced acute stress and its prediction of vulnerability to later real-life chronic stress. We identified the dynamics between brain networks using an advanced time-varying whole brain-network approach.
Neuroimaging work initially focused on key brain regions involved in stress-related neurocircuitry processes, such as limbic regions (i.e., amygdala, insula, hypothalamus, hippocampus) and cortical structures (i.e., the medial prefrontal cortex and the anterior cingulate cortex; e.g., 6, 7). However, it becomes evident that these regions systematically co-activate or co-deactivate across different demands as well as in rest (8, 9). Accordingly, a model for the dynamics of acute stress and recovery was suggested (10), by which during stress, there is a hyperactivation of the salience network (SN), which is a cingulate-frontal operculum system responsible for vigilance to interoceptive and emotional information. This increase in activity is at the cost of activity in the executive control network, a frontoparietal system that relates to functional executive control. As the stressor subsides, this effect reverses, enabling emotional regulation, and high-level cognitive processing. Aberrations in this recovery process may be indicated by neuroimaging findings on chronic stress reactions. In these studies, the salience network is elevated at the cost of the default mode network and executive control network (8, 11). Unfortunately, extant knowledge relies primarily on cross-sectional studies, providing at best an account for stable factors for successful or unsuccessful recovery (e.g., 12). In contrast, longitudinal studies can reveal how the brain transitioned from acute stress to recovery and how these brain patterns may predict later psychological vulnerabilities (e.g., 13, 14, 15, 16, 17, 18, 19). Several fMRI studies examined the changes in resting-state functional connectivity (rsFC) following acute stress induction. For example, Vaisvaser et al., (19) reported that immediately after stress induction several rsFC changes were noted including altered coupling within the default mode network (DMN) and between the hippocampus and amygdala. After 2 hours, the observed changes returned to pre-stress levels, except for the amygdala-hippocampal connectivity which was sustained. Another study by Maron-Katz et al. (15) that used a whole-brain data-driven approach, revealed increased thalamo-cortical connectivity and decreased cross-hemispheral parieto-temporal connectivity in response to induced stress. Neural changes were further associated with subjective stress experience. Other fMRI studies examined the neural predictors of chronic stress using laboratory anger induction (14, 17). Findings revealed that limbic neural activity in response to an angering experience predicts stress-related symptoms a year later, following combat deployment. Notably, these studies used time-averaged approaches, in which activation or connectivity between regions within a network, is based on fMRI signal averaged over several minutes (14). Averaging the fMRI signal assumes that patterns remain constant over the observed time window. However, this may miss important information, which is the rapid changes that happen in the whole-brain networks. In the context of stress, it is even more crucial to identify neuronal alterations over time. Thus, using a time-varying perspective can gain a better understanding of the dynamic processes following acute stress and recovery.
The development of time-varying approaches for the analysis of brain activity has opened a new promising possibility to compare conditions based on the relative expression of different functional networks over time (20, 21). Indeed, a growing body of evidence shows that brain connectivity is not stable even at rest and slowly wanders through a repertoire of reoccurring states of coupling among various brain regions (22, 23). In the present study, we use Leading Eigenvector Dynamics Analysis (LEiDA), a method that operates in the temporal domain and characterizes recurrent FC states in terms of probabilities of occurrence and duration on a subject-by-subject level. This method identifies patterns of blood oxygen level-dependent (BOLD) phase coherence, or functional connectivity (FC) states, that reoccur over time both within and across scanning sessions (24). Previous studies using LEiDA have shown that properties of the FC states relate to neuropsychological traits of human participants, such as cognitive performance (24), a propensity to fall into major depressive disorder (25, 26), and a capacity of trait self-reflectiveness (27), among others. In the context of a stress response, one study indicated that PTSD was related to abnormal activity duration of default mode sub-networks and salience network during exposure to trauma-related reminders and that these alterations were rebalanced to normal levels following therapy (28). Another study revealed that increased perceived stress was associated with increased moments of synchrony between the amygdala and frontal cortical regions, whereas participants with lower stress scores exhibited anti-phase relationships between the amygdala and the anterior frontal cortex (29). While there is preliminary evidence for the association between stress and whole-brain dynamics, the causal mechanism and its prediction of chronic stress remain unclear.
In the present study, we examined how the alterations of FC states in response to lab-induced stress predict vulnerability to real-life chronic stress a year later. To this end, 60 pre-deployed soldiers underwent a standardized acute stress induction task (i.e., the Trier Social Stress Test; 30), in which their brain functional activity was recorded via resting-state functional magnetic resonance imaging (rsfMRI) at three different time-points: before the acute stress induction, immediately afterward, and 90 minutes later (i.e., reflecting a recovery period). Moreover, to study individual differences in stress and recovery responses, participants repeatedly reported their subjective stress over the experiment. In addition, we followed up with depression and post-traumatic stress symptoms a year later, at combat deployment, a period characterized by high prolonged stress. This exploration tested whether the dynamic brain patterns that are prompted through experimental acute stress are also predictive of later vulnerability to prolonged stress.
We expected that the process of transition from acute stress to recovery would be associated with distinct alterations of FC networks, involving the frontoparietal, the default mode (DMN), and the salience networks, including limbic areas (14, 17, 28). Furthermore, we predict that these brain alterations would be sensitive to inter-individual differences in psychological responses to real-life stress a year later.