Amygdala Reward Reactivity Mediates the Association Between Preschool Stress Response and Depression Severity

Abstract

Background: Research in adolescents and adults has suggested that altered neural processing of reward following early life adversity is a highly promising depressive intermediate phenotype. However, very little is known about how stress response, neural processing of reward, and depression are related in very young children. The present study examined the concurrent associations between cortisol response following a stressor, functional brain activity to reward, and depression severity in children 4 to 6 years old.

Methods: Medication-naïve children 4 to 6 years old (N = 52) participated in a study using functional magnetic resonance imaging to assess neural reactivity to reward, including gain, loss, and neutral outcomes. Parent-reported child depression severity and child cortisol response following stress were also measured.

Results: Greater caudate and medial prefrontal cortex reactivity to gain outcomes and increased amygdala reactivity to salient (i.e., both gain and loss) outcomes were observed. Higher total cortisol output following a stressor was associated with increased depression severity and reduced amygdala reactivity to salient outcomes. Amygdala reactivity was also inversely associated with depression severity and was found to mediate the relationship between cortisol output and depression severity.

Conclusions: Results suggest that altered neural processing of reward is already related to increased cortisol output and depression severity in preschoolers. These results also demonstrate an important role for amygdala function as a mediator of this relationship at a very early age. Our results further underscore early childhood as an important developmental period for understanding the neurobiological correlates of early stress and increased risk for depression.

Keywords: Amygdala; Depression; Development; Reward processing; Stress; fMRI.

Figure 1

Child Gambling Task (CGT). Each trial of the CGT begins with a white fixation cue presented in the center of a black screen for 2000ms. Next, a screen displays a question mark for 2000ms. Children are asked to guess whether the person hiding behind the question mark is bigger or smaller than them and to indicate their choice by pressing a button on an MRI compatible single button response box designed specifically for use with young children. Following their choice, feedback is generated as a function of whether the trial was scheduled to be a reward, loss or neutral outcome and presented for 2000ms. Feedback images included either a baby, adult, or similarly sized child paired with: 1) a green up thumbs up next to 4 candies for gain, 2) a red thumbs down next to an image of 2 candies with a line through them for loss; or 3) two dashes (“- -”) for neutral trials. A jittered inter-trial interval using a black screen with central fixation cross occurred between each trial (M=4000ms, Min.=2000ms, Max=6000ms).

Figure 2

A) Attenuated differential responding in the left amygdala to gain/loss versus neutral outcomes mediates the relationship between elevated stress reactivity and depression severity in preschool age children. Values represent beta coefficients generated by the SPSS PROCESS macro procedure for mediation model 4. a = p < .05; b = includes maternal depression as a covariate; c = includes maternal depression and stress reactivity as covariates B) Scatter plots illustrating the positive correlation between AUC_g and child depression severity (r = .32, p = .021), the negative correlation between gain/loss minus neutral difference scores in the left amygdala and AUC_g (r = −.37, p = .006), and the negative correlation between gain/loss minus neutral difference scores in the left amygdala and child depression severity (r = −.40, p = .003). Plots including depression severity scores represent the residualized values for each variable after controlling for maternal depression.

Figure 3

Differential responses to reward outcomes were found in bilateral caudate and left amygdala. Specifically, greater reactivity to gain versus loss outcomes was found in the left and right caudate while great reactivity to both gain and loss outcomes versus neutral ones was found in the left amygdala. Dashed boxes highlight frames used to generate difference scores. ? = task guess period; OC = task outcome period