Amygdala reactivity during socioemotional processing and cortisol reactivity to a psychosocial stressor

https://doi.org/10.1016/j.psyneuen.2022.105855Get rights and content

Highlights

  • Greater amygdala activation to fear associated with greater cortisol activation slope.

  • We found coupling of amygdala and HPA axis activation to threat in separate tasks.

  • Our findings are based on a highly diverse sample of adolescents.

Abstract

Threat-related amygdala reactivity and the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis have been linked to negative psychiatric outcomes. The amygdala and HPA axis have bidirectional connections, suggesting that functional variation in one system may influence the other. However, research on the functional associations between these systems has demonstrated mixed findings, potentially due to small sample sizes and cortisol sampling and data analytic procedures that investigate only pre-post differences in cortisol rather than the specific phases of the cortisol stress response. Further, previous research has primarily utilized samples of adults of mostly European descent, limiting generalizability to those of other ethnoracial identities and ages. Therefore, studies addressing these limitations are needed in order to investigate the functional relations between amygdala reactivity to threat and HPA axis stress responsivity. Using a sample of 159 adolescents from a diverse cohort (75% African American, ages 15–17 years), the present study evaluated associations between amygdala reactivity during socioemotional processing using fMRI and HPA axis reactivity to a socially-evaluative cold pressor task. Greater amygdala activation to fearful and neutral faces was associated with greater cortisol peak values and steeper activation slope. As cortisol peak values and cortisol activation slope capture the intensity of the cortisol stress response, these data suggest that greater activation of the amygdala in response to social distress and ambiguity among adolescents may be related to hyper-reactivity of the HPA axis.

Introduction

The amygdala and Hypothalamic-Pituitary-Adrenal Axis (HPA axis) represent key nodes of the stress system. The bidirectional connections between these systems influence physiological stress responses and individual variability in risk for psychopathology. For instance, dysregulation of the stress response system has been linked with risk for Major Depressive Disorder (Zorn et al., 2017) and Post-Traumatic Stress Disorder (Duval et al., 2015). Therefore, examining the association between the amygdala and HPA axis is critical for understanding the functioning of each system independently and the link between dysregulation of the stress response and long-term psychiatric outcomes. However, research on the functional associations between these systems has been mixed (Harrewijn et al., 2020). Furthermore, we know little about how variation in amygdala reactivity to threatening and ambiguous social stimuli relate to HPA axis reactivity to psychosocial stressors during adolescence, a key developmental period for stress reactivity.

The amygdala provides rapid processing of ambiguous or threatening stimuli (Davis and Whalen, 2001). In response to threat, the amygdala sends efferent signals to the paraventricular nucleus of the hypothalamus, contributing to the initiation of the HPA axis stress response (Dedovic et al., 2009, Segal, 2016). HPA axis activation promotes a cascade of excitatory inputs resulting in the release of cortisol and adaptive biological changes that help the body respond to the threat (Jankord and Herman, 2008). Cortisol also contributes to the downregulation of the response by binding to glucocorticoid receptors (GR) within key limbic regions, such as the hippocampus and medial prefrontal cortex, that have a direct inhibitory role on the HPA axis response (Herman et al., 2012). In contrast, when cortisol binds to GR within the amygdala it promotes a feed-forward input to the HPA axis, prolonging the duration of the response (Shepard et al., 2003). Thus, the amygdala plays a role in the activation and duration of the HPA axis stress response highlighting the intricate, intertwined relationship between these systems.

Previous research examining variability in amygdala and HPA axis function has been mixed (Harrewijn et al., 2020). Several studies examining cortisol reactivity and amygdala activation during in-scanner psychosocial stress tasks (e.g., Montreal Imaging Stress Task, ScanSTRESS) have observed an association between greater cortisol reactivity and decreased amygdala activation to a challenging mental arithmetic task (Lederbogen et al., 2011, Pruessner et al., 2008). Other studies utilizing similar in-scanner psychosocial stress tasks have found no association between cortisol levels and amygdala activation to the arithmetic task (Dahm et al., 2017, Kogler et al., 2015, Orem et al., 2019). Conflicting results also emerge when examining the association between amygdala activation to threatening and ambiguous stimuli and HPA axis reactivity to a separate psychosocial stressor (i.e., outside the scanning session). For instance, amygdala activation to cues signaling an unpleasant noise has been positively associated with cortisol levels during anticipation of a skydive (Mujica-Parodi et al., 2014). However, another study found no association between amygdala activation to emotional faces and HPA axis reactivity to a psychosocial stressor (Liu et al., 2012).

These conflicting findings may result from different methodologies used to measure the cortisol response. Lopez-Duran et al. (2014) demonstrated that measuring each phase of the cortisol response (baseline, activation slope, peak, recovery slope) while accounting for peak latency may be more sensitive than traditional methods (e.g., pre-post change, area under the curve) at detecting subtle group differences. Given that excitatory inputs from the amygdala in response to threat initiate the cortisol stress response (Dedovic et al., 2009) and cortisol binding to GR within the amygdala feeds the response forward (Shepard et al., 2003), metrics of the intensity of the cortisol stress response (cortisol activation slope and peak) may correspond to amygdala activation in response to threat. In contrast, inhibition of the HPA axis response is driven by cortisol binding to GR throughout the brain (Herman et al., 2012). Since numerous neural inputs regulate the duration of the excitatory phase and the intensity of cortisol recovery slope, these metrics may not be as strongly associated with amygdala activation to threat. Further research is warranted to determine whether amygdala activation to threat relates more specifically to the intensity of the cortisol stress response (i.e., cortisol activation slope and peak levels).

Additionally, there is a matter of representation and representativeness of the existing literature. The majority of studies have focused on (convenience samples of) European or White Americans (Falk et al., 2013). This fact is problematic from a representation and generalizability standpoint and means that what the literature notes as the “normative” association between these two systems, may only generalize to relatively advantaged people of European origin. Additionally, beyond the need for exploring these questions in those from different ethnoracial backgrounds, given the history of inequality and structural racism in the United States (Bailey et al., 2017), African Americans are, on average, exposed to greater structural and personal adversity and have access to fewer resources than their European American peers. Racial disparities in stress exposure and resource deprivation suggest that studies are needed to examine whether associations between the HPA axis and limbic system are present in African Americans who have been marginalized in society and under-represented in this area of research.

Developmentally, adolescence represents a critical period for brain development (Blakemore, 2012), including regions associated with HPA axis responsivity. During adolescence, social signals are incredibly important for driving behavior and stress responses (Foulkes and Blakemore, 2016). Relatedly, social evaluation itself appears most important for driving cortisol responses (Sumter et al., 2010), particularly among adolescents (Peckins et al., 2020). However, the existing literature in this area has focused on adults, leaving open the question of how the HPA axis and limbic system are related during adolescence. Thus, this study focuses on amygdala reactivity during socioemotional processing of threat and ambiguity and cortisol responses during a socially evaluative task within a sample of adolescents.

The present study examined the association between amygdala reactivity to threat-related and ambiguous racially-diverse facial expressions and HPA-axis reactivity to the Socially Evaluated Cold-Pressor Task (SECPT; Scwabe et al., 2008) in a longitudinal community sample of adolescents from families living in large American cities, most of whom were exposed to substantial socioeconomic disadvantage and identify as African American. This study expands on previous research by assessing amygdala activation and cortisol reactivity in separate tasks and by using best practices in cortisol collection and analysis to capture individual differences in HPA axis responsivity (i.e., baseline and peak cortisol levels, cortisol activation and recovery slope). We examined whether amygdala activation to threatening (fearful and angry) or ambiguous (neutral) faces compared to baseline activation was associated with HPA axis reactivity to the SECPT in adolescents. We hypothesized that greater amygdala activation to fearful, angry, and neutral facial expressions during the fMRI session would be associated with a steeper cortisol activation slope and greater peaks in response to the SECPT. We also sought to explore the relationship between amygdala activation to emotional faces and cortisol baseline and recovery slope.

Section snippets

Participants

Two-hundred and thirty-seven adolescents were recruited from the Detroit, MI, Toledo, OH, and Chicago, IL, subsamples of the Fragile Families and Child Wellbeing Study (FFCWS). The FFCWS is a longitudinal birth cohort of 4898 children (52.4% boys) born in large (> 200,000) US cities between 1998 and 2000 with a substantial oversample for non-marital births (~3:1). This sampling strategy resulted in substantial racial/ethnic and sociodemographic diversity in the sample, with a large portion of

Correlations among study variables

At the zero-order level, cortisol baseline was positively correlated with cortisol peak and activation slope (Table 2), suggesting that individuals who had higher initial cortisol levels at the start of the SECPT also evidenced higher peaks and a more intense cortisol increase in response to the stressor. Cortisol baseline was not significantly associated with cortisol recovery slope suggesting that intensity of the cortisol recovery was not influenced by starting levels. As expected, cortisol

Discussion

The present study investigated the associations between different phases of the cortisol stress response (e.g. cortisol baseline and peak levels, activation slope, and recovery slope) to the SECPT and amygdala activation to emotional faces in a birth-cohort study of primarily African American adolescents. We found that the intensity of HPA axis activation to the SECPT in the form of a steeper activation slope (i.e. greater intensity of cortisol increase) was associated with greater amygdala

CRediT authorship contribution statement

Andrea G. Roberts: Conceptualization, Methodology, Formal analysis, Investigation, Writing – original draft. Melissa K. Peckins: Conceptualization, Writing – review & editing, Visualization. Arianna M. Gard: Investigation, Writing – review & editing, Visualization, Formal analysis. Tyler C. Hein: Software, Validation, Formal analysis, Data curation, Writing – review & editing, Funding acquisition. Felicia A. Hardi: Writing – review & editing, Visualization, Formal analysis. Colter Mitchell:

Conflict of interest statement

The authors do not have any conflicts of interest to report.

Acknowledgments

The research reported in this paper was supported by grants from the National Institutes of Health, R01MH103761 (Monk) and T32HD007109 (McLoyd & Monk) as well as a Doris Duke Fellowship for the Promotion of Child Well-Being (Hein). We are grateful for the past work of the Fragile Families and Child Wellbeing Study, the families for sharing their experiences with us, and the project staff for making the study possible.

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