Sex-Specific Effects of Early Life Unpredictability on Hippocampal and Amygdala Responses to Novelty in Adolescents

Abstract

Background: Unpredictable childhood experiences are an understudied form of early life adversity that impacts neurodevelopment in a sex-specific manner. The neurobiological processes by which exposure to early-life unpredictability impacts development and vulnerability to psychopathology remain poorly understood. The present study investigates the sex-specific consequences of early-life unpredictability on the limbic network, focusing on the hippocampus and the amygdala.

Methods: Participants included 150 youth (54% female). Early life unpredictability was assessed using the Questionnaire of Unpredictability in Childhood (QUIC). Participants engaged in a task-fMRI scan between the ages of 8 and 17 (223 total observations) measuring BOLD responses to novel and familiar scenes.

Results: Exposure to early-life unpredictability associated with BOLD contrast (novel vs. familiar) in a sex-specific manner. For males, but not females, higher QUIC scores were associated with lower BOLD activation in response to novel vs. familiar stimuli in the hippocampal head and amygdala. Secondary psychophysiological interaction (PPI) analyses revealed complementary sex-specific associations between QUIC and condition-specific functional connectivity between the right and left amygdala, as well as between the right amygdala and hippocampus bilaterally.

Conclusion: Exposure to unpredictability in early life has persistent implications for the functional operations of limbic circuits. Importantly, consistent with emerging experimental animal and human studies, the consequences of early life unpredictability differ for males and females. Further, impacts of early-life unpredictability were independent of other risk factors including lower household income and negative life events, indicating distinct consequences of early-life unpredictability over and above more commonly studied types of early life adversity.

Keywords: early life adversity; functional magnetic resonance imaging (fMRI); limbic system; novelty; sex differences; unpredictability.

Figure 1.. Age Distribution by Visit.

Age distribution across imaging sessions/visits is shown.

Figure 2.. Task Paradigm.

Participants underwent an initial training session prior to imaging to familiarize themselves with the task and outdoor scenes. Novel and familiar outdoor scenes were presented in a block design.

Figure 3.. Early Life Unpredictability (QUIC) Is Associated with Amygdala and Hippocampal Head Activation to Novel vs. Familiar Scenes in a Sex-Specific Manner.

A) The amygdala and hippocampus (split by head and body/tail) were considered for analysis. B) The amygdala and head of the hippocampus functional BOLD activation associate with QUIC scores in a sex-specific manner (* denotes p<0.05). C) Scatter plot depicting sex-specific associations. In stratified analyses, QUIC scores were associated with amygdala and head of hippocampus (not shown) activation in males, but not females.

Figure 4.. Early Life Unpredictability Is Associated with Task-Based Functional Connectivity of the Right Amygdala in a Sex-Specific Manner.

A) Synthesized examples of raw signals occurring in a Psychophysiological Interaction (PPI, upper left panel) and their task-dependent correlation structure (upper right panel). B) Empirical scatter plot showing sex-specific associations between early-life unpredictability (QUIC) and PPI-based task-dependent correlations. In a sex-stratified analysis, QUIC scores were significantly (p<0.05) associated with PPI measures in both sexes but in opposing directions. C) QUIC by sex interactions are depicted across the observed amygdala and hippocampus ROIs.