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Amygdala Functional Connectivity, HPA Axis Genetic Variation, and Life Stress in Children and Relations to Anxiety and Emotion Regulation

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Amygdala Functional Connectivity, HPA Axis Genetic Variation, and Life Stress in Children and Relations to Anxiety and Emotion Regulation Journal of Abnormal Psychology © 2015 American Psychological Association 2015, Vol. 124, No. 4, 817–833 0021-843X/15/$12.00 http://dx.doi.org/10.1037/abn0000094 Amygdala Functional Connectivity, HPA Axis Genetic Variation, and Life Stress in Children and Relations to Anxiety and Emotion Regulation David Pagliaccio, Joan L. Luby, Ryan Bogdan, Arpana Agrawal, Michael S. Gaffrey, Andrew C. Belden, Kelly N. Botteron, Michael P. Harms, and Deanna M. Barch Washington University in St. Louis Internalizing pathology is related to alterations in amygdala resting state functional connectivity, potentially implicating altered emotional reactivity and/or emotion regulation in the etiological pathway. Importantly, there is accumulating evidence that stress exposure and genetic vulnerability impact amygdala structure/function and risk for internalizing pathology. The present study examined whether early life stress and genetic profile scores (10 single nucleotide polymorphisms within 4 hypothalamic- pituitary-adrenal axis genes: CRHR1, NR3C2, NR3C1, and FKBP5) predicted individual differences in amygdala functional connectivity in school-age children (9- to 14-year-olds; N ϭ 120). Whole-brain regression analyses indicated that increasing genetic “risk” predicted alterations in amygdala connectivity to the caudate and postcentral gyrus. Experience of more stressful and traumatic life events predicted weakened amygdala-anterior cingulate cortex connectivity. Genetic “risk” and stress exposure interacted to predict weakened connectivity between the amygdala and the inferior and middle frontal gyri, caudate, and parahippocampal gyrus in those children with the greatest genetic and environmental risk load. Furthermore, amygdala connectivity longitudinally predicted anxiety symptoms and emotion regulation skills at a later follow-up. Amygdala connectivity mediated effects of life stress on anxiety and of genetic variants on emotion regulation. The current results suggest that considering the unique and interacting effects of biological vulnerability and environmental risk factors may be key to understanding the development of altered amygdala functional connectivity, a potential factor in the risk trajectory for internalizing pathology. General Scientific Summary Connections between the amygdala, a key region for emotion processing, and other regions of the brain are important to healthy functioning and development. Stress-related risk factors for depression and anxiety predict weakened connections between the amygdala and other regions of the brain in children. These weakened connections predict a worsening of children’s emotional skills and anxiety over time. Keywords: amygdala, functional connectivity, stress, genetics, anxiety Supplemental materials: http://dx.doi.org/10.1037/abn0000094.supp Editor’s Note. Theodore Beauchaine served as the guest editor for this was supported by a grant from the National Institute of General Medical article. —SG Sciences (No. 5T32GM081739). The NIMH had no further role in the design and conduct of the study (collection, management, analysis, or interpretation of the data) or in the preparation, review, or approval of David Pagliaccio, The Program in Neuroscience, Washington University the manuscript. Dr. Luby has also received research support from This document is copyrighted by the American Psychological Association or one of its alliedin publishers. St. Louis; Joan L. Luby, Department of Psychiatry, Washington Uni- Communities Healing Adolescent Depression and Suicide (CHADS) versity in St. Louis; Ryan Bogdan, The Program in Neuroscience and This article is intended solely for the personal use of the individual user and is not to be disseminated broadly. Coalition, and the Sydney R. Baer Foundation. Dr. Luby reports re- Department of Psychology, Washington University in St. Louis; Arpana ceiving royalties from Guilford Press for a book on Preschool Mental Agrawal, Michael S. Gaffrey, and Andrew C. Belden, Department of Health (2006). Dr. Barsch reports consulting for Pfizer, Roche, Takeda, Psychiatry, Washington University in St. Louis; Kelly N. Botteron, De- and Amgen. D.P. had full access to all study data and takes responsi- partment of Psychiatry and Department of Radiology, Washington Univer- bility for the integrity of the data and accuracy of the data analysis. This sity in St. Louis; Michael P. Harms, Department of Psychiatry, Washington work comprised a portion of D.P.’s dissertation: Pagliaccio, D. (2015). University in St. Louis; Deanna M. Barch, The Program in Neuroscience, The Effects of HPA Axis Genetic Variation and Early Life Stress on Department of Psychiatry, Department of Psychology, and Department of Cortisol Levels in Preschool Age Children and on Amygdala and Radiology, Washington University in St. Louis. Hippocampus Volumes, Reactivity, and Connectivity at School Age This work was supported by the National Institute of Mental Health (Doctoral dissertation). We thank all participants and their families who (Grant Nos. MH64769 to J.L.L. and MH090786 to J.L.L., D.M.B., and provided time and effort to making this study possible. K.N.B.) and a NARSAD award to J.L.L. A.C.B.’s work was supported Correspondence concerning this article should be addressed to David by a grant from the National Institute of Mental Health (No. Pagliaccio, The Program in Neuroscience, Washington University in St. 1K01MH090515-01). M.S.G.’s work was supported by a grant from the Louis, Campus Box 1125, One Brookings Drive, St. Louis, MO 63130. National Institute of Mental Health (No. K23MH098176). D.P.’s work E-mail: [email protected] or [email protected] 817 818 PAGLIACCIO ET AL. Major depressive disorder (MDD) and anxiety disorders are a network of regions, including the hippocampus, insula, thalamus, among the most prevalent and disabling psychiatric conditions striatum, and medial frontal gyrus (Roy et al., 2009). The (Kessler et al., 2005) and are characterized by deficits in emotional amygdala also shows normative negative connectivity (anticorre- and overall adaptive functioning (American Psychiatric Associa- lation) with a separate network of regions, including the superior tion, 2013). Neuroimaging studies implicate the amygdala as a key frontal gyrus (SFG), middle frontal gyrus (MFG), posterior cingu- region involved in emotional reactivity (e.g., Sergerie, Chochol, & late, parietal regions, and occipital regions (Roy et al., 2009). Armony, 2008) and find that successful emotion regulation mod- These patterns are similar to regions often coactivated with the ulates amygdala reactivity (Lapate et al., 2012; Wager, Davidson, amygdala in fMRI studies of emotion processing, congruous with Hughes, Lindquist, & Ochsner, 2008). Importantly, amygdala the idea that rsFC represents a history of coactivation (e.g., Dosen- structure and function are altered in patients with depression and bach et al., 2007; Fair et al., 2007; Kelly et al., 2009). Specifically, anxiety (for meta-analyses, see Etkin & Wager, 2007; Hamilton et many of the regions that typically show positive rsFC with the al., 2012; Hamilton, Siemer, & Gotlib, 2008) and are linked to amygdala are seen in meta-analyses to be activated in response to individual differences in emotional experience and regulation emotional faces (Fusar-Poli et al., 2009) or during emotional (Abler et al., 2010; Drabant, McRae, Manuck, Hariri, & Gross, memory tasks (Murty, Ritchey, Adcock, & Labar, 2010). Further- 2009). Recent work has examined the functional connectivity of more, many of the regions typically showing negative connectivity the amygdala with a variety of regions, particularly prefrontal with the amygdala are involved in cognitive reappraisal of emotion cortex, cingulate cortex, the striatum, and the hippocampus (e.g., and down-regulation amygdala activity (Buhle et al., 2013; Frank Gabard-Durnam et al., 2014; Roy et al., 2009), aiding our under- et al., 2014; Kohn et al., 2014), that is, activity in regions down- standings of communication between regions that subserve effec- regulating amygdala reactivity tend to be negatively correlated tive emotion reactivity and regulation. with amygdala activity. Increasingly in the literature, studies examine disrupted amygdala connectivity as a potential intermediate phenotype be- tween risk factors and psychological outcomes. This type of work Alterations in Amygdala Connectivity aims to identify mechanisms linking risk factors to pathology by Associated With Internalizing Pathology understanding the relations between risk factors and more proxi- mal outcomes, like brain function. Particularly, genetic predispo- Internalizing psychopathology, that is, affective and anxiety sitions and individual environmental factors, such as stressful life disorders (Krueger, 1999), is typically linked to weakened events, are among the most potent predictors of depression and amygdala connectivity as summarized in Table 1. Particularly, anxiety onset (e.g., Kendler, Gardner, & Lichtenstein, 2008; Ken- weakened connectivity between the amygdala and regions often dler, Hettema, Butera, Gardner, & Prescott, 2003; Kendler, showing positive connectivity, for example, ventromedial prefron- Karkowski, & Prescott, 1999; Kendler, Neale, Kessler, Heath, & tal cortex (vmPFC), anterior cingulate cortex (ACC), caudate, Eaves, 1992; Kessler, Davis, & Kendler, 1997). As such, the goal nucleus accumbens, and orbitofrontal cortex (OFC) is observed in of the current study was to investigate whether stressful life events adults
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