Neural Mechanisms of Enhancing Emotion Regulation in Bereaved Spouses

This study investigates the underlying mechanisms of a novel emotion regulation intervention among recently bereaved spouses. More specifically, this study examines how thinking about an emotional stimulus in a more adaptive way can affect the relationship between psychological stress, psychophysiological biomarkers of adaptive cardiac response, and brain activity. The emotion regulation strategy targeted is reappraisal, specifically reappraisal-by-distancing (i.e., thinking about a negative situation in a more objective, impartial way) versus reappraisal-by-reinterpretation (i.e., thinking about a better outcome for a negative situation than what initially seemed apparent). The study seeks to determine if relatively brief, focused reappraisal training in bereaved spouses will result in reduction of self-reported negative affect, increases in respiratory sinus arrhythmia (RSA; a measure of heart rate variability reflecting adaptive cardiac vagal tone), reduction in blood-based inflammatory biomarkers, and changes in neural activity over time. Reappraisal-by-distancing is expected to lead to greater changes in these variables relative to reappraisal-by-reinterpretation. Additionally, it is expected that across time decreases in self-reported negative affect, increases in RSA, reductions in blood-based inflammatory biomarker levels, and changes in neural activity will in turn lead to reductions in depressive symptoms and grief rumination. Finally, it is expected that distancing training will lead to reductions in depressive symptoms and grief rumination that are mediated by changes in the targeted neurobiological and behavioral mechanisms.

The objective of this study is to use an experimental medicine approach to evaluate the basic psychological, psychophysiological, and neural mechanisms underlying a novel cognitive emotion regulation intervention aimed at improving psychological outcomes (e.g., reducing depressive symptoms and grief rumination) in recently bereaved spouses. Cognitive reappraisal (i.e. the ability to modify the trajectory of an emotional response by thinking about and appraising emotional information in an alternative, more adaptive way) represents a highly promising target for psychological intervention in bereavement. Reappraisal can be operationalized via two primary tactics: psychological distancing (i.e. appraising an emotional stimulus as an objective, impartial observer) and reinterpretation (i.e. imagining a better outcome than what initially seemed apparent). The current study builds upon promising preliminary work to investigate the effectiveness and underlying neurobiological mechanisms of a novel, five-session cognitive reappraisal intervention in bereaved spouses. Recently bereaved participants (i.e. approximately 6 months post-spousal loss) will be randomly assigned to receive training in either distancing or reinterpretation, with five sessions occurring every 1-3 days, with longitudinal collection of affective, psychophysiological, physiological (i.e., blood draws to assess inflammatory biomarkers) and functional magnetic resonance imaging (fMRI) data. Follow-up questionnaire assessments will occur at one- and two-months post-intervention. The study aims to mechanistically relate changes in psychological, psychophysiological, physiological, and neural function during a novel emotion regulation intervention never before implemented in this stressed, high risk group. This research represents a Phase I, Stage I clinical trial. The primary endpoints are the assessments of the psychological, psychophysiological, physiological, and neural mechanisms mediating behavior change as a function of the cognitive emotion regulation intervention. The secondary endpoint is testing the efficacy of the intervention via assessment of psychological outcomes (i.e., the behavior change, as represented in changes in depressive symptoms, stress, and grief rumination).

Participants will receive structured cognitive emotion regulation training from an experimenter during an approximately 10-minute interaction in which detailed instructions for implementation of the distancing strategy is explained (i.e. appraising an emotional stimulus as an objective, impartial observer).

Participants will receive structured cognitive emotion regulation training from an experimenter during an approximately 10-minute interaction in which detailed instructions for implementation of the reinterpretation strategy is explained (i.e. imagining a better outcome than what initially seemed apparent).

Cognitive emotion regulation training via cognitive reappraisal involves the ability to modify the trajectory of an emotional response by thinking about and appraising emotional information in an alternative, more adaptive way. Reappraisal to down-regulate negative emotion can be operationalized via two tactics: psychological distancing and reinterpretation. The current study will randomly assign participants to receive a brief course of reappraisal training using either psychological distancing or reinterpretation.

Self-reported negative affect data collected at the completion of emotion regulation task, with 1 meaning "not negative at all" and 5 meaning "very negative".

At each training session immediately after emotion regulation task, approximately every 2-3 days for 2 weeks.

During emotion regulation task at baseline and at final training session, approximately 2 weeks post-baseline

Grief rumination assessed via Utrecht Grief Rumination Scale (UGRS) and the Inventory for Complicated Grief (ICG). The URGS assesses grief by asking participants to rate how often they have experienced certain thoughts over the past month on a five-point scale ranging from 1 (never) to 5 (very often). Total scores range from 15 to 75, with higher numbers representing higher overall grief rumination. The ICG assesses grief via 19 first-person statements that participants rate on a scale of 1 (Never) to 5 (Always). Higher numbers reflect greater grief.

At baseline, final training session (approximately 2 weeks post-baseline), and at 1 and 2 months post-intervention

Symptoms of depression assessed via the Center for Epidemiological Studies Depression (CES-D) scale, which asks participants to rate how often in the past week they have experience symptoms of depression, ranging from 0 (Rarely or none of the time) to 3 (Most of the time). Scores range from 0 to 60, with higher scores indicating higher levels of depressive symptoms.

At baseline, final training session (approximately 2 weeks post-baseline), and at 1 and 2 months post-intervention

Perceived stress assessed via the Perceived Stress Scale, which consists of 10 self-reported items asking participants how often they felt or thought a certain way, ranging from 0 (Never) to 4 (Very Often). Higher scores indicate higher levels of perceived stress.

At baseline, final training session (approximately 2 weeks post-baseline), and at 1 and 2 months post-intervention

At baseline, final training session (approximately 2 weeks post-baseline), and at 1 and 2 months post-intervention

At baseline, final training session (approximately 2 weeks post-baseline), and at 1 and 2 months post-intervention

Inclusion Criteria: Recent loss of romantic partner within the past 5-7 months At least 18 years of age Minimum score of 25 on the Inventory for Complicated Grief Must be able to speak, read, and write in English Must be eligible to safely complete MRI scanning Exclusion Criteria: Death of a second close family member/friend in the past year Currently receiving psychotherapy Diagnosed with obstructive pulmonary and/or heart disease, diabetes, liver failure, or kidney failure Significant visual, auditory, or cognitive impairment Divorced within the last year Prior participation in a similar emotion regulation training protocol in Dr. Denny's lab Any contraindication of MRI scanning (e.g., pregnancy, presence of any non-removable metal on or in the body, implanted medical devices, tattoos, medication patches, orthodontic braces or permanent retainers, hearing aids, history of claustrophobia or breathing disorders)

Pursuant to the NIH Data Sharing Policy, we have created a Data Sharing Plan for the proposed research. Under this plan, and pursuant to IRB regulations, fully de-identified raw data (defined below) will be made publicly available. Available data will include a compendium of de-identified training condition assignments; raw (i.e. individual subject-by-condition level) negative affect self-reports; questionnaire data; raw heart rate variability data; and raw subject-level brain data (i.e. unpreprocessed functional and structural MRI data, converted to the widely-sharable Brain Imaging Data Structure [BIDS] standard).

De-identified data will be made available after the analysis process is complete and research manuscripts are finalized. There is no fixed end date for data access.

Data will be publicly available on OpenNeuro (https://openneuro.org), a free, open- science neuroinformatics data repository.

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