This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Behavioral/Cognitive Post-encoding Amygdala-Visuosensory Coupling Is Associated with Negative Memory Bias in Healthy Young Adults Sarah M. Kark1 and Elizabeth A. Kensinger1 1Department of Psychology, Boston College, Chestnut Hill, MA, USA https://doi.org/10.1523/JNEUROSCI.2834-18.2019 Received: 4 November 2018 Revised: 27 January 2019 Accepted: 5 February 2019 Published: 13 February 2019 Author contributions: S.M.K. and E.K. designed research; S.M.K. performed research; S.M.K. and E.K. analyzed data; S.M.K. and E.K. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. Author note: This research was supported by NSF Grant BCS 1539361 to E. Kensinger and Jessica Payne, NSF-GRFP DGE1258923 to S. Kark, pre-doctoral NRSA fellowship 5F31MH113304-02 awarded to S. Kark, Sigmi Xi Grant-in-Aid of Research to S. Kark, as well as NIH shared instrumentation grant S10OD020039 (Harvard Center for Brain Science). SMS-BOLD sequences were received by the University of Minnesota Center for Magnetic Resonance Research (CMRR). We would like to thank Tala Berro, Ryan Daley, Kevin Frederiks, Sandry Garcia, Olivia Hampton, Lauren Lu, and Stephanie Sherman for assistance with participant recruitment and data collection and processing. We thank Ehri Rhyu for helpful discussions of the mediation analysis. We want to thank Jaclyn Ford for her thoughtful comments and helpful discussions of this work. Further details of the recapitulation replication results and exploratory moderated mediation analysis can be obtained by contacting the corresponding author directly. Correspondence: Sarah M. Kark, Department of Psychology, Boston College, McGuinn Hall Room 300, 140 Commonwealth Avenue, Chestnut Hill, MA, USA 02467 Email: [email protected] Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.2834-18.2019 Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2019 the authors 1 Title: Post-encoding Amygdala-Visuosensory Coupling Is Associated with Negative 2 Memory Bias in Healthy Young Adults 3 4 Abbreviated title: Amygdala Connectivity and Emotional Memory Bias 5 6 Sarah M. Kark1 & Elizabeth A. Kensinger1 7 8 Department of Psychology, Boston College, Chestnut Hill, MA, USA 9 10 Correspondence: Sarah M. Kark, Department of Psychology, Boston College, 11 McGuinn Hall Room 300, 140 Commonwealth Avenue, Chestnut Hill, MA, USA 02467 12 Email: [email protected] 13 14 Number of pages: 51 15 Numbers of figures: 5 16 Number of tables: 2 17 Number of words in Abstract: 239 18 Number of words in Introduction: 640 19 Number of words in Discussion: 1499 20 21 Conflict of Interest: The authors declare no competing financial interests 22 23 Author note: This research was supported by NSF Grant BCS 1539361 to E. 24 Kensinger and Jessica Payne, NSF-GRFP DGE1258923 to S. Kark, pre-doctoral NRSA 25 fellowship 5F31MH113304-02 awarded to S. Kark, Sigmi Xi Grant-in-Aid of Research to 26 S. Kark, as well as NIH shared instrumentation grant S10OD020039 (Harvard Center 27 for Brain Science). SMS-BOLD sequences were received by the University of 28 Minnesota Center for Magnetic Resonance Research (CMRR). We would like to thank 29 Tala Berro, Ryan Daley, Kevin Frederiks, Sandry Garcia, Olivia Hampton, Lauren Lu, 30 and Stephanie Sherman for assistance with participant recruitment and data collection 31 and processing. We thank Ehri Rhyu for helpful discussions of the mediation analysis. 32 We want to thank Jaclyn Ford for her thoughtful comments and helpful discussions of 33 this work. Further details of the recapitulation replication results and exploratory 34 moderated mediation analysis can be obtained by contacting the corresponding author 35 directly. 36 Abstract 37 The amygdala is well-documented as the critical nexus of emotionally enhanced 38 memory, yet its role in the creation of negative memory biases—better memory for 39 negative as compared to positive stimuli—has not been clarified. While prior work 40 suggests valence-specific effects at the moment of ‘online’ encoding and retrieval—with 41 enhanced visuosensory processes supporting negative memories in particular—here 42 we tested the novel hypothesis that the amygdala engages with distant cortical regions 43 after encoding in a manner that predicts inter-individual differences in negative memory 44 biases in humans. Twenty-nine young adults (males and females) were scanned while 45 they incidentally encoded negative, neutral, and positive scenes, each preceded by a 46 line-drawing sketch of the scene. Twenty-four hours later, participants were scanned 47 during an Old/New recognition memory task with only the line-drawings presented as 48 retrieval cues. We replicated and extended our prior work, showing that enhanced 49 ‘online’ visuosensory recapitulation supports negative memory. Critically, resting state 50 scans flanked the encoding task, allowing us to show for the first time that individual 51 differences in ‘offline’ increases in amygdala resting state functional connectivity 52 (RSFC) immediately following encoding relate to negative and positive memory bias at 53 test. Specifically, post-encoding increases in amygdala RSFC with visuosensory and 54 frontal regions were associated with the degree of negative and positive memory bias, 55 respectively. These findings provide new evidence that valence-specific negative 56 memory biases can be linked to the way that sensory processes are integrated into 57 amygdala-centered emotional memory networks. 58 Amygdala Connectivity and Emotional Memory Bias 59 Significance Statement 60 Decades of research has placed the amygdala at the center of the emotional memory 61 network. Despite the clinical importance of disproportionate memory for negative 62 compared to positive events, it is not known whether post-encoding increases in 63 amygdala-cortical coupling—possibly reflective of early consolidation processes—bear 64 any influence on the degree or direction of such emotional memory biases. We 65 demonstrate that, across participants, increases in post-encoding amygdala coupling 66 with visuosensory and frontal regions are associated with more pronounced negative 67 and positive memory biases, respectively. These findings provide the first evidence 68 linking post-encoding amygdala modulation to the degree of negative or positive 69 memory bias, emphasizing the need for valence-based accounts of the amygdala’s role 70 in emotional memory. 71 72 Introduction 73 We tend to remember the good and bad events in our lives long past the time 74 when trivial events have slipped from our memories, but recent work suggests negative 75 and positive memories are not always created equally in brain or behavior (Bowen et 76 al., 2018). Despite the clinical relevance of understanding how disproportionate memory 77 for negative events over positive events—a cognitive risk factor for depression 78 (Gerritsen et al., 2012)—arises from individual differences in neural memory processes, 79 these relationships have yet to be tested empirically. The bulk of task-based fMRI work 80 on emotional memory has focused on the encoding of negative stimuli, with a focus on 81 the amygdala, hippocampus, ventral visual stream, and prefrontal cortex (Murty et al., 3 Amygdala Connectivity and Emotional Memory Bias 82 2011). However, studies comparing memory for positive and negative events have 83 suggested that while the amygdala is engaged by both valences (Hamann et al., 1999), 84 the effect of arousal on the targets of amygdala-cortical coupling during encoding can 85 depend on valence (Mickley Steinmetz et al., 2010). Our prior research has shown 86 valence-specific memory effects during retrieval, with greater retrieval-related 87 reactivation of encoding processes in visuosensory regions for negative events relative 88 to positive and neutral ones (Kark and Kensinger, 2015; Bowen and Kensinger, 2016, 89 2017), evidence that contributed to our proposed valence-based model of emotional 90 memory (Bowen et al., 2018). 91 Decades of animal and human work in support of the modulation hypothesis of 92 amygdala function has shown that the amygdala is the critical “nexus” of emotional 93 memory formation and consolidation due to its ability modulate neural processes in 94 medial temporal lobe (MTL) regions and distant cortical regions (Cahill and McGaugh, 95 1998; McGaugh, 2000; Hermans et al., 2014), including visual cortices (Dringenberg et 96 al., 2004; Vuilleumier et al., 2004). Feedback projections from the amygdala to almost 97 all levels of visual cortex are thought to enhance their response during emotional 98 situations (Amaral et al., 2003; Silverstein and Ingvar, 2015) and likely continue to 99 influence memory processes after the initial encoding experience itself (Müller and 100 Pilzecker, 1900; McGaugh, 2005). Thus, the amygdala is well-positioned to exert long- 101 lasting negative memory enhancing effects in visuosensory regions. 102 The work described above has monitored ‘online’ memory processes to reveal 103 neural mechanisms that support emotional memory formation and retrieval during task. 104 However, ‘offline’ post-encoding resting-state functional connectivity (RSFC) analysis 4 Amygdala Connectivity and Emotional