The impact of familial risk and early life adversity on emotion and reward processing networks in youth at-risk for bipolar disorder

RESEARCH ARTICLE The impact of familial risk and early life adversity on emotion and reward processing networks in youth at-risk for bipolar disorder a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 Lindsay C. Hanford ID1*, Kristen Eckstrand1, Anna Manelis1, Danella M. Hafeman1, John Merranko1, Cecile D. Ladouceur1, Simona Graur1, Alicia McCaffrey1, Kelly Monk1, Lisa K. Bonar1, Mary Beth Hickey1, Tina R. Goldstein1, Benjamin I. Goldstein2,3, David Axelson4, Genna Bebko1, Michele A. Bertocci1, Mary Kay Gill1, Boris Birmaher1, Mary L. Phillips1 1 Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America, 2 Psychiatry, Sunnybrook Health Sciences Centre, Toronto, Canada, 3 Pharmacology and Toxicology, University of Toronto, Toronto, Canada, 4 Nationwide Children’s Hospital and The Ohio State College of Medicine, Columbus, Ohio, United States of America * OPEN ACCESS Citation: Hanford LC, Eckstrand K, Manelis A, Hafeman DM, Merranko J, Ladouceur CD, et al. (2019) The impact of familial risk and early life adversity on emotion and reward processing networks in youth at-risk for bipolar disorder. PLoS ONE 14(12): e0226135. https://doi.org/10.1371/ journal.pone.0226135 Editor: Raoul Belzeaux, Assistance Publique Hopitaux de Marseille, FRANCE Received: February 3, 2019 Accepted: November 20, 2019 Published: December 12, 2019 Copyright: © 2019 Hanford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: The data used to support the findings of this study are restricted by The Human Research Protection Office at the University of Pittsburgh on regulations regarding confidentiality. In order to gain access to deidentified human subject data from this project, outside investigators can submit a request to Mary L Phillips (), who is the principal investigator on the NIMH-funded grant that support the current study or Richelle Stiffler (). Abstract A recently developed risk calculator for bipolar disorder (BD) accounts for clinical and parental psychopathology. Yet, it is understood that both familial predisposition and early life adversity contribute to the development of BD. How the interplay between these two factors influence emotion and reward processing networks in youth at risk for BD remains unclear. In this exploratory analysis, offspring of BD parents performed emotion and reward processing tasks while undergoing a fMRI scan. Risk calculator score was used to assess risk for developing BD in the next 5 years. Environmental risk was tabulated using the Stressful Life Events Schedule (SLES). Emotion and reward processing networks were investigated for genetic and/or environment interactions. Interaction effects were found between risk calculator scores, negative SLES score and activity in right amygdala and bilateral fusiform gyri during the emotion processing task, as well as activity in the fronto-, striatal, and parietal regions during the reward processing task. Our findings are preliminary; however, they support the unique and interactive contributions of both familial and environmental risk factors on emotion and reward processing within OBP. They also identify potential neural targets to guide development of interventions for youth at greatest risk for psychiatric disorders. Introduction Neurodevelopmental models for Bipolar Disorder (BD) posit the involvement of both genetic predisposition, such as having a parent diagnosed with BD, and life stressors, such as early life adversity [1]. The interplay between these two factors results in a variety of epigenetic changes that impact different neurodevelopmental processes. These include altered hypothalamic-pituitary-adrenal axis activity [2, 3], altered immunological response [4, 5], and altered PLOS ONE | https://doi.org/10.1371/journal.pone.0226135 December 12, 2019 1 / 20 Impact of adversities on functional networks in at-risk youth Funding: This research was supported by NIH R01 MH060952-12S1 (Birmaher, Axelson, Phillips), and R01 MH073953 (Birmaher, Phillips), and the Pittsburgh Foundation (Phillips). Funding had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations: ACC, anterior cingulate cortex; BD, bipolar disorder; dlPFC, dorsolateral prefrontal cortex; HCO, healthy control offspring; mPFC, medial prefrontal cortex; nSLES, negative stressful life events schedule; OBP, offspring of bipolar parents; OFC, orbitofrontal cortex; SLEs, stressful life events; VS, ventral striatum; vlPFC, ventrolateral prefrontal cortex. development of emotion and reward processing circuitry [6–8]. Repeated exposure to stress may worsen emotional and behavioral problems in youth, and predispose to development of psychiatric disorders such as BD [9–11]. Mood symptoms in BD are thought to be a function of dysregulation within emotion and reward processing networks [7, 8, 12, 13]. A better understanding of the unique contributions and interplay between genetic and environmental risk factors on the development of emotion and reward processing networks may thus help to identify specific neural mechanisms associated with each of these influences, and, in turn, yield neural targets to guide preventative strategies and targeted interventions for youth at the greatest risk of future psychiatric disorders. BD has one of the highest heritability rates among psychiatric disorders [14–17]. Offspring of parents diagnosed with BD (OBP) have a tenfold increased risk for developing BD across their lifetime relative to individuals without a family history of BD [17–19]. Moreover, those who develop psychopathology early on are more likely to develop BD in the future [20–23]. A recently developed predictive risk calculator supports this idea by showing good discrimination (AUC 0.76) for the 5-year outcome of those OBP who would go on to develop BD [20]. Here, the greatest predictor of future BD in OBP was parental age at onset of mood symptoms [20], highlighting that both genetic risk and early onset of BD in the parent are important risk factors contributing to the development of BD in offspring. Dysregulation within emotion and reward processing networks are thought to underlie mood symptoms in BD [7, 8, 12, 13]. As such, these networks would be among the best avenues for exploring the underlying architecture for the development of BD. In the emotion processing network, the amygdala plays a central role for the detection of emotional cues [24–26]. The medial prefrontal cortex (mPFC) and insula are important for subjective salience and value assignment, the dorsolate (...truncated)