Persistent and reversible consequences of combat stress on the mesofrontal circuit and cognition

Abstract

Prolonged stress can have long-lasting effects on cognition. Animal models suggest that deficits in executive functioning could result from alterations within the mesofrontal circuit. We investigated this hypothesis in soldiers before and after deployment to Afghanistan and a control group using functional and diffusion tensor imaging. Combat stress reduced midbrain activity and integrity, which was associated to compromised sustained attention. Long-term follow-up showed that the functional and structural changes had normalized within 1.5 y. In contrast, combat stress induced a persistent reduction in functional connectivity between the midbrain and prefrontal cortex. These results demonstrate that combat stress has adverse effects on the human mesofrontal circuit and suggests that these alterations are partially reversible.

Fig. 1.

Combat stress reduces midbrain activity and integrity, which is associated to reduced executive functioning. (A) The reduction in midbrain activity from baseline to short-term follow-up in the combat group (blue), projected on the main effect of working memory load (white). The corresponding reduction in midbrain integrity as measured with DTI is presented (B) for reduced fractional anisotropy, and (C) for increased mean diffusivity. (D) The reduction in midbrain activity is associated to attenuated improvement in sustained attention from baseline to short-term follow-up (blue), projected on the main effect of working memory load (white). This correlation shows that a larger reduction in midbrain activity led to less improvement on the sustained attention test. (E) The corresponding negative association for fractional anisotropy. (F) The positive association for mean diffusivity. All statistical tests were corrected for multiple comparisons (P < 0.05, SVC). The panels are presented at P < 0.005 uncorrected to illustrate the spatial extent of the results (y = −16). The clusters that are significant after correction for multiple comparisons (P < 0.05, SVC) are presented in green or yellow. The scatter plots illustrate the voxel-wise correlations at the peak voxel.

Fig. 2.

Combat stress reduces functional connectivity of the midbrain with the lateral prefrontal cortex. The reduction from baseline to short-term follow-up is presented in blue. The persistent reduction from baseline to long-term follow-up at 1.5 y after military deployment is presented in green. The overlap between the short-term and long-term effects is presented in cyan. All statistical tests were corrected for multiple comparisons (P < 0.05, SVC). The figures are presented at P < 0.005 uncorrected to illustrate the spatial extent of the results (−36, 36, 6).

Fig. 3.

Reversible effects of combat stress on midbrain function and structure. (A, Left) The normalization of midbrain activity at 1.5 y after military deployment (red; quadratic polynomial contrast), projected on the main effect of working memory load (white). (Right) Bar graph illustrating the normalization of midbrain activity. Data for the combat group (Combat) and control group (Control) are presented as mean (± SEM) at baseline (BL), short-term follow-up (ST), and long-term follow-up (LT). The corresponding normalization of midbrain integrity as measured with DTI is presented for fractional anisotropy (B) and mean diffusivity (C). All statistical tests were corrected for multiple comparisons (P < 0.05, SVC). The figures are presented at P < 0.005 uncorrected to illustrate the spatial extent of the results (y = −16). The clusters that are significant after correction for multiple comparisons (P < 0.05, SVC) are presented in yellow or green. The bar graphs illustrate the voxel-wise comparisons at the peak voxel.