Distinct Trajectories of Cortisol Response to Prolonged Acute Stress Are Linked to Affective Responses and Hippocampal Gray Matter Volume in Healthy Females

Abstract

The development of robust laboratory procedures for acute stress induction over the last decades has greatly advanced our understanding of stress responses in humans and their underlying neurobiological mechanisms. Nevertheless, attempts to uncover linear relationships among endocrine, neural, and affective responses to stress have generally yielded inconsistent results. Here, 79 healthy females completed a well established laboratory procedure of acute stress induction that was modified to prolong its effect. Endocrinological and subjective affect assessments revealed stress-induced increases in cortisol release and negative affect that persisted 65 and 100 min after stress onset, respectively, confirming a relatively prolonged acute stress induction. Applying latent class linear mixed modeling on individuals' patterns of cortisol responses identified three distinct trajectories of cortisol response: the hyper-response (n = 10), moderate-response (n = 21), and mild-response (n = 48) groups. Notably, whereas all three groups exhibited a significant stress-induced increase in cortisol release and negative affect, the hyper-response and mild-response groups both reported more negative affect relative to the moderate-response group. Structural MRI revealed no group differences in hippocampal and amygdala volumes, yet a continuous measure of cortisol response (area under the curve) showed that high and low levels of stress-induced cortisol release were associated with less hippocampal gray matter volume compared with moderate cortisol release. Together, these results suggest that distinct trajectories of cortisol response to prolonged acute stress among healthy females may not be captured by conventional linear analyses; instead, quadratic relations may better describe links between cortisol response to stress and affective responses, as well as hippocampal structural variability.SIGNIFICANCE STATEMENT Despite substantial research, it is unclear whether and how individual neuroendocrine stress response patterns are linked to affective responses to stress and structural variability in neuroendocrine regulatory brain regions. By applying latent class linear mixed modeling on individuals' patterns of cortisol responses to a prolonged acute stressor, we identified three distinct trajectories of cortisol response. Relative to the group showing a moderate cortisol response, groups characterized by hyper and mild cortisol response were both associated with more negative affect. Moreover, a continuous measure of cortisol response showed that high and low levels of stress-induced cortisol release correlated with reduced hippocampal gray matter volume. Given that neuroendocrine stress responses are conceptualized as biomarkers of stress susceptibility, these insights may have clinical implications.

Keywords: HPA; cortisol; hippocampus; mood; stress.

Figure 1.

Schematic diagram illustrating the timeline and design of the study session. Participants provided written consent before completing two tasks, one probabilistic reward task (PRT) and one reaction time (RT) task, a clinical interview to determine eligibility (SCID), the MAST, and then the PRT and RT tasks again. To prolong the effect of the acute stressor, immediately upon MAST completion, participants were told by a nonemphatic male study staff member they had not yet met that their performance in the math portion was not good enough and that they would need to repeat the task after the administration of the remaining tasks and questionnaires. Later in the session, participants were informed that repeating the task was not necessary because their performance was “good enough” (i.e., relief). Throughout the session, participants provided six saliva samples, eight VAMS ratings, and three self-reported measures of anxiety and affect.

Figure 2.

Overall effect of stress. Change in cortisol (A), α-amylase (B), VAMS rating (C), state anxiety (D), positive affect (E), and negative affect (F) throughout the session. Across all measures, there was a significant effect of time driven by stress induced increase in cortisol release and negative affect. Notably, cortisol levels and negative affect were still elevated 65 and 100 min after stress onset, respectively, reflecting a relatively prolonged acute stress induction. Participants were fully debriefed and their mood had returned to baseline before they left the laboratory. *p < 0.05.

Figure 3.

LCMM. A, Individual patterns of cortisol response throughout the session (n = 79). B, Applying LCMM on these data revealed that the model that best fit our data included three latent classes, labeled based on their distinct trajectories of cortisol response to stress as the hyper-response (n = 10), moderate-response (n = 21), and mild-response (n = 48) groups. Note that all three groups exhibited a significant stress-induced increase in cortisol release 25 and 50 min after stress onset. *p < 0.05.

Figure 4.

Effects of stress by cortisol class. Change in happy–sad scale (A), relaxed–tense scale (B), friendly–hostile scale (C), state anxiety (D), positive affect (E), and negative affect (F) throughout the session as a function of cortisol class. Note that individuals in the moderate response class exhibited less stress-induced sadness and tension relative to individuals in the hyper-response class, as well as less hostility (trend) and negative affect relative to individuals in the mild-response class. *p < 0.05.

Figure 5.

Structural variability and cortisol AUCg. A hierarchical regression model revealed a quadratic link between the continuous cortisol measure AUCg and hippocampal gray matter volume (r = 0.421, p = 0.001, n = 79) such that individuals with both high and low levels of stress-induced cortisol release had less right hippocampal gray matter volume compared with individuals with moderate cortisol release.