University of Arizona

Today’s talk

Project 1. A pull to be close: Differential effects of stimulus type and oxytocin on approach behavior in complicated vs. non-complicated grief
(Arizmendi, Seeley, Allen, Killgore, Andrews-Hanna, Weihs, & O’Connor, under review)

Project 2. Static and dynamic resting state functional connectivity in bereaved older adults
(Seeley, Andrews-Hanna, Allen, & O’Connor, under review)

General Background

When a loved one dies…

  • For most, grief gradually resolves over time1
  • But some (~7-10%) continue to struggle2

How does grief get “complicated?”

A major task of bereavement adaptation is to integrate the loss:

  • Flexibly switch between focusing on loss- and restoration-related stressors & appraisals.3–6,8
  • Identity and self-narrative can accommodate the loss.9–14
  • Find new ways to get attachment needs met.15–18

How does grief get “complicated?”

Prolonged salience + perseverative thought get in the way of adaptation:

  • Unhelpful avoidance reinforces the salience of deceased-related cues (continued monitoring & more frequent intrusions)19–21
  • Mental simulation of anticipated reward (yearning) highlights discrepancy in current vs. desired state22,23

 

  • Behaviorally and cognitively, this may look like excessive proximity-seeking [approach]…
  • …and/or, excessive avoidance (places, reminders, cues).

Oxytocin

Does oxytocin facilitate new attachments,15 or perpetuate deceased’s place in attachment hierarchy?24

  • Death of primary attachment figure dysregulates oxytocin signaling25,26
  • Non-grief oxytocin studies: Oxytocin modulates brain networks to facilitate social/emotional stimulus processing; regulate internal vs. external attention27–29
  • Affects self-oriented processing, encoding, retrieval, interoception25,30,31

Summary

  • Theories of adaptation in bereavement highlight a need for flexible shifting between mental states.
  • Prolonged motivational salience of the deceased partner may be a complicating factor, particularly when coupled with perseverative thinking.
  • Oxytocin could mediate both salience/approach behavior and self-focused thought.
  • Investigate how implicit motivational bias, large-scale brain network activity, and oxytocin are involved in complicated grief symptom severity.

Parent study

Older adults with and without complicated grief participated in two resting state fMRI sessions, as part of a larger within-subjects crossover study using intranasal oxytocin as an experimental probe.

 

Grief-related AAT

Participants

N = 38 (71% female)

  • Time since death M = 15.4 months (SD = 8.2, range: 6 - 36)

  • Relationship length M = 38.5 years (SD = 12.4, range: 17 - 59)

  • Age M = 69.2 years (SD = 6.5, range: 57 - 79)

  • 94% non-Hispanic White

  • 80% retired

  • 63% four-year college degree or higher

  • CG (n = 15) vs. non-CG (n = 23):

    • Higher depression symptoms in CG group (p < .001)

    • Men overrepresented in CG group (χ2 p = .073 rest)

 

Static and dynamic resting state functional connectivity in bereaved older adults


Seeley, Andrews-Hanna, Allen, & O’Connor, under review

Where it started

 

Christoff, K., Irving, Z., Fox, K. et al. Nat Rev Neurosci. 17, 718–731 (2016).
https://doi.org/10.1038/nrn.2016.113


  • Functional connectivity altered in other disorders w/emotional distress & perseverative thought32–34
  • Large-scale brain network connectivity modulation by oxytocin27–29

Aim 1

To identify whether static and/or dynamic resting state functional connectivity (FNC/dFNC) is associated with complicated grief symptoms.

Aim 2

To investigate if/how intranasal oxytocin alters FNC/dFNC in older adults, & if oxytocin effects are moderated by complicated grief symptoms.

fMRI Data Processing

  • Nipype-based, open-source pipelines for quality control (MRIQC)35 and preprocessing (fMRIPrep).36

  • Analysis:

    • Group ICA with back-reconstruction to identify brain networks (GIFT37)

    • Look at network correlations averaged across entire scan (static FNC)

    • Sliding window time-varying connectivity analysis (dynamic FNC)


Results

 

Selected components

Spatial maps of independent components thresholded at Z = 2 and displayed on a standard T1 template image

Spatial maps of independent components thresholded at Z = 2 and displayed on a standard T1 template image

Static functional connectivity

dFNC state 1

  • Overall stability, with CoN-dACC & R FPN more variable (p <.05)

dFNC state 2

  • Large positive fluctuations between most component pairs (p <.05)

dFNC state 3

  • Negative fluctuations in R FPN - DNCore (p <.05)
  • Positive fluctuations in R FPN - CoN-dACC (p <.05)

dFNC state 4

  • CoNdACC shows variable anti-correlation with DNCore and R FPN (p <.05)

Aim 1

To identify whether static and/or dynamic resting state functional connectivity (FNC/dFNC) is associated with complicated grief symptoms.

Default-cingulo-opercular FNC predicts grief severity

 

Functional connectivity between the DNCore and CoNdACC components remained a significant predictor of grief severity when age, sex, and depressive symptoms score were included as covariates in the model (b = 8.48, 95%CI = [0.74, 16.21], SE = 3.80, t = 2.23, p = 0.03). The overall model explained 63% of the variance in grief severity (F(4,33) = 16.76, adjusted R2 = 0.63, p <.001.

Higher grief predicts longer dwell time in positively interconnected state

 

Participants with higher ICG scores spent more time in the highly interconnected state (dFNC state 2) than participants with lower ICG scores, b = 8.36, SE = 3.89, t(35) = 2.15, p = .039.

Aim 2

To investigate if/how intranasal oxytocin alters FNC/dFNC in older adults, & if oxytocin effects are moderated by complicated grief symptoms.

Oxytocin increased default - cingulo-opercular connectivity

Figure 9.

Figure 9.

 

Intranasal oxytocin had a significant positive effect on DNretrosplenial - CoNdACC FNC, b = 0.07, SE = 0.03, 95% CI [0.02, 0.12], p = .008.

…but no oxytocin x complicated grief interaction.

Grief severity had no significant effect on functional connectivity, alone or in interaction with session.

No effect of oxytocin on dFNC

  • No main or interaction effect of oxytocin on dwell time in any state.

  • No effects of complicated grief severity or session on n transitions between states.

Conclusions

Summary

  • We identified a pair of network components (DNcore + cingulo-operculardACC) whose resting state functional connectivity strength was associated with complicated grief symptom severity in older adults.
  • Adults with higher complicated grief symptoms also spent more consecutive time in a dynamic state characterized by extensive interconnectivity between default, frontoparietal, and cingulo-opercular networks.
  • Complicated grief symptoms were not significantly associated with number of times participants transitioned between dFNC states.
    • Less anti-correlation between default and other networks (including cingulo-opercular) may support idea that prolonged attachment figure salience and internal thought are mutually reinforcing in CG.16
    • MBCT reduced DN intra- and inter-network resting state functional connectivity in Taiwanese adults with “unresolved grief” (but no change in rsFC during emotional task).38

Summary

  • Contrary to hypothesis, effect of intranasal oxytocin on functional connectivity was NOT moderated by complicated grief.
  • However, oxytocin did increase functional connectivity between DNretrosplenial + cingulo-operculardACC.
    • Intranasal oxytocin reconfigures large-scale brain networks to facilitate socio-emotional information processing even in the absence of immediate social stimuli.29,39

    • OXTR mRNA highly expressed in ACC and RSC;40 regions important for social cognition, learning, behavior.41

 

Differential effects of stimulus type and oxytocin on approach behavior in complicated vs. non-complicated grief

Arizmendi, Seeley, Allen, Killgore, Andrews-Hanna, Weihs, & O’Connor, under review

Grief-related AAT: Main findings

A. Main effect of group: The non-CG group demonstrated greater approach bias (emm = 26.31, SE = 7.88) than the CG group (emm = -3.66, SE = 8.96) and the groups were significantly different (b = 30.0, SE = 11.9, t[37] = 2.51, p = .017)

B. AAT performance by stimulus category and group, in the placebo condition. There was no group x stimulus interaction).

In the placebo condition, averaging across all stimuli, the CG group is significantly more avoidance-biased compared to the non-CG group. In the oxytocin condition, the groups do not differ significantly as the CG group becomes significantly more approach-biased under oxytocin while the non-CG group’s behavior does not change significantly from the placebo condition.

Exploratory analysis: oxytocin effects on spouse > stranger contrast

  • Linear mixed-effects analysis of trial-level data to increase power (500+ trials/participant):
  • Group x Stimulus x Condition (dummy-coded for spouse) x Direction
  • Oxytocin produced a significantly greater approach bias towards the spouse in the CG group than the non-CG group (b = 52.8, SE = 23, t[21955] = 2.29, p = .022).
  • In the oxytocin condition, both groups were significantly slower to PULL photos of their spouse, but only the CG group was slower to PUSH, possibly indicating decreased avoidance under oxytocin.

Summary

  • Compared to CG, the non-CG group showed an overall relative approach bias across stimuli.
  • Intranasal oxytocin increased relative approach bias in the CG group, but not the non-CG group.
  • Oxytocin may specifically increase relative approach bias for the spouse in CG.
  • Context-specific effects of oxytocin?

Future directions

  • Link brain network connectivity to specific thought form & content.
  • Replicate placebo-session results in larger sample (Rotterdam Scan Study; n = 350+ bereaved older adults).
  • Comparison of functional connectivity in acute vs. complicated/prolonged grief (do grief disorders represent quantitatively or qualitatively distinct phenomena?)
  • Modeling complicated grief & bereavement adaptation: relationships between constructs of loss, attachment, frustrative non-reward, effort, valuation/updating, etc.

 

Acknowledgements

Mary-Frances O’Connor
Brian Arizmendi

John JB Allen
Jessica Andrews-Hanna
Elena Plante
Scott Squire
Dianne Patterson & UA Brain Mapping Workgroup

This research was funded by:

National Institute on Aging (1F31AG062067, PI: Seeley)
DANA Foundation (Neuroscience Research Grant, PI: O’Connor)

Additional training funded by:
University of Washington eScience Institute
Academy of Psychological Clinical Science
Stanford Center for Reproducible Neuroscience
John and Laura Arnold Foundation
New York Academy of Sciences


Contact:
sarenseeley@email.arizona.edu

Website:
https://sarenseeley.github.io

Supplemental slides

Hypothesized models

gAAT effect of stimulus type

Motivational bias to “grief-related” stimuli differs by stimulus content: Main w/s effect of stimulus F(4,152) = 4.49, pGG-corr. = .002.

A statistically significant difference between the spouse vs. stranger contrast and the non-specific grief vs. neutral contrast (b = 51.0, SE = 21.3, t[38] = 2.40, p = .022) suggests that personal photos of the spouse produced larger differences from control than did non-specific grief-related images.

Models

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