Human vulnerability to stress depends on amygdala's predisposition and hippocampal plasticity

Abstract

Variations in people's vulnerability to stressful life events may rise from a predated neural sensitivity as well as from differential neural modifications in response to the event. Because the occurrence of a stressful life event cannot be foreseen, characterizing the temporal trajectory of its neural manifestations in humans has been a real challenge. The current prospective study examined the emotional experience and brain responses of 50 a priori healthy new recruits to the Israeli Defense Forces at 2 time points: before they entered their mandatory military service and after their subsequent exposure to stressful events while deployed in combat units. Over time, soldiers reported on increase in stress symptoms that was correlated with greater amygdala and hippocampus responsiveness to stress-related content. However, these closely situated core limbic regions exhibited different temporal trajectories with regard to the stress effect; whereas amygdala's reactivity before stress predicted the increase in stress symptoms, the hippocampal change in activation over time correlated with the increase in such symptoms. Hippocampal plasticity was also reflected by a modification over time of its functional coupling with the ventromedial prefrontal cortex, and this coupling magnitude was again predicted by predated amygdala reactivity. Together, these findings suggest that variations in human's likelihood to develop symptomatic phenomena following stressful life events may depend on a balanced interplay between their amygdala's predisposing reactivity and hippocampal posteriori intra- and interregional plasticity. Accordingly, an individually tailored therapeutic approach for trauma survivors should target these 2 neural probes while considering their unique temporal prints.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

(A) Timeline (months) of the prospective imaging study. Each participant was examined at 2 time points separated by ≈18 months. (B) Rating of stress symptoms at each time point according to the Posttraumatic Stress Diagnostic Scale (PDS), one-tailed paired t-test analysis. (C) The distribution of individual PDS scores Before Stress and After Stress in the paramedics group. (D) Slice views obtained from whole-brain parametric maps for the contrast (After Stress > Before Stress). Increased activation After Stress is shown in the left amygdala (coronal view, Upper) left hippocampus (coronal view, Middle), and vmPFC (sagittal view, Lower) (P < 0.0005, uncorrected, random effect). (E) Averaged percent signal changes extracted from each ROI for After Stress (open circles) and Before Stress (filled circles) separately for each content (civilian, military, and medical, left to right, respectively) regardless of presentation durations. Activation values were resampled at a rate of 1:3 for visualization purposes only. (F) Bar graphs presenting averaged percent signal changes per duration in the medical content (33 and 83 ms, left and right, respectively) in each scan time point. Post hoc analysis was calculated using Fisher's LSD (n = 37; error bars ± SEM; *P < 0.05; **P < 0.0001).

Fig. 2.

Scatter plots show the individual change in stress symptoms over time (Δ PDS) as correlated with the individual activation level in the amygdala and hippocampus in response to medical content presented for 33 ms. (A) After Stress. (B) Before Stress. (C) Activation change over time (n = 37).

Fig. 3.

Interregional functional coupling and stress symptoms change over time. (A) Sagittal view of the seed regions located in the amygdala (purple) and hippocampus (green) extracted from (After Stress > Before Stress) contrast. (B) Sagittal views of interregional functional coupling maps, focused on the medial prefrontal cortex (mPFC) coupling with the amygdala (clusters in purple), hippocampus (green), and both in overlay (yellow), separately obtained from Before Stress (Left) and After Stress (Right) (P < 5e-009 uncorrected, random effect). As indicated by the white circles, the ventromedial prefrontal cortex (vmPFC) was functionally coupled to the hippocampus only After Stress. (C) Individual change in coupling with vmPFC and stress symptoms change over time (Δ PDS). (D) Individual change in hippocampus-vmPFC coupling and amygdala's activation Before Stress. Note that weaker hippocampus-vmPFC change in functional coupling was related to more severe stress symptoms After Stress and was predicted by an increased amygdala activation level Before Stress (n = 37).