The neurobiological mechanisms of complicated grief

Mary-Frances O'Connor, Ph.D.

The University of Arizona College of Medicine

Funded in January, 2015: $200000 for 3 years


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Can oxytocin reverse biological and psychological factors associated with complicated grief?

Researchers will use fMRI imaging and other measures in 40 adults whose spouses have recently passed away to determine whether an oxytocin nose spray reverses signs of complicated (intense) grief and therefore might lead to an effective treatment.

While most bereaved adults gradually adjust to the death of their spouse, about 10-15 percent experience what is termed “complicated” grief. Physicians base this diagnosis on their patient’s persistent intense yearning and inability to enjoy meaningful events, making them more vulnerable to health problems and to suicide.  The investigators’ prior research suggests that there are three signs of complicated grief: 1) higher than normal levels of the stress hormone cortisol during waves of grief; 2) more intense and persistent yearning; and 3) greater activation, as  measured by fMRI, in the brain’s “nucleus accumbens” when looking at a picture of the deceased loved one. This region is involved in motivation, pleasure, and addiction in other studies. All three of these signs of complicated grief, the investigators hypothesize, are attributable to abnormally low release of the neuropeptide oxytocin during bereavement.

While oxytocin’s most commonly recognized function is its role in stimulating lactation for breastfeeding after childbirth, central oxytocin also has a demonstrated role in social attachments. The investigators suggest that the common adaptation to bereavement-related stress following the death of a spouse is a rise in oxytocin levels. This rise motivates bereaved people to seek out living loved ones for support. The ensuing support then decreases the stress hormone cortisol and lessens yearning for their deceased spouse. These responses are reflected lower levels of activation in the brain’s nucleus accumbens, as measured by fMRI, when the surviving spouse looks at cues such as reminiscent pictures and words.

The investigators hypothesize that adults with complicated grief do not experience this usual increase in central oxytocin release during bereavement stress. In effect, complicated grief can be considered an oxytocin-deficient state. They further hypothesize, therefore, that providing oxytocin through a nose spray to adults with complicated grief will temporarily reverse the three signs of this condition.        

They liken this potential approach to treating complicated grief with oxytocin to that of treating diabetes with insulin. Just as treating insulin deficiency reduces the signs of diabetes, treating oxytocin deficiency may reverse the signs of complicated grief. If that is the case, the findings then would lead to research on why oxytocin is deficient in those with complicated grief. That exploration would include examining the possible interaction of epigenetic factors with a precipitating event, such as the death of a spouse.

The investigators will test whether using a nasal spray that increases central oxytocin, compared to using a nasal spray placebo, is sufficient to reduce nucleus accumbens activation, self-reported yearning and cortisol levels in grieving spouses. The researchers will enroll 40 adults who have lost a spouse within six months to three years. They will be divided into two groups: 20 assessed with complicated grief and 20 assessed with non-complicated grief. All forty participants will participate in two sessions: one in which they are given intranasal oxytocin and one in which they are given an intranasal placebo. In each session, all participants will be exposed to cues of their deceased spouse (photos and words) and of other people. Thereafter, the investigators will measure nucleus accumbens activation using fMRI, salivary cortisol levels, and yearning intensity. They anticipate that: 1) following placebo treatment, the complicated grief group will continue to show increased levels for all three signs compared to the non-complicated group; but 2) following oxytocin treatment, the complicated grief groups’ measures will be the same as those seen in the adults with non-complicated grief.  

Significance : If intranasal oxytocin is found to reduce the signs of complicated grief, the findings will demonstrate a new approach to treatment and exploring the causes of this condition.  


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Project aims: Although most widows and widowers adjust gradually, 10-15% of bereaved persons experience Complicated Grief (CG). CG is diagnosed with a set of empirically derived criteria, including persistent intense yearning and inability to enjoy meaningful activities. This disorder is an independent predictor of poor health and suicidality, making it a major public health concern. CG has been discriminated from Non-Complicated Grief (Non-CG) using functional imaging, self-reported yearning, and cortisol sampling in research by the applicant, leading to a candidate neurobiological mechanism: central levels of the neuropeptide oxytocin (OT). OT is a potential mechanism in CG due to its demonstrated role in social attachments. Normally functioning neurobiology causes proximity to loved ones to be rewarding. Central OT plays a critical role in motivational processes that associate cues of our loved ones with reward. In Non-CG, bereavement stress is hypothesized to lead to an increase in OT release. OT promotes exploratory social behaviors, promoting seeking social support from living loved ones, and may reduce the reward associated with cues of the deceased. However, I hypothesize that in CG, bereavement stress does not lead to increased OT release. After bereavement, persons with CG continue to yearn for the deceased loved one and have decreased attachment to living loved ones (relative to Non-CG grievers), and show dysregulation of cortisol. Functional imaging shows that those with CG have greater activation in the nucleus accumbens than those with Non-CG in response to cues of the deceased, and the nucleus accumbens is rich in OT receptors. The present study investigates the following innovative Aim: To test whether increasing central OT through administering intranasal OT vs. placebo is a sufficient to reduce a neurobiological marker of CG (nucleus accumbens activation), reduce an affective marker of CG (self-reported yearning) and reduce an endocrine marker of CG (cortisol level). Methods: Forty adults (20 Complicated Grief, 20 Non-Complicated Grief) will participate in two experimental sessions. Participants will be between the ages of 35 and 70, and will have experienced the death of a spouse in the prior 6 to 36 months. They will be healthy, with no current psychiatric disorders. Participants will be excluded for beta-blockers, corticosteroids, oral contraception, hormone replacement therapy, or smoking for its effects on oxytocin uptake and cortisol. A single dose of 24 IU oxytocin (Syntocinon spray, Novartis) or saline placebo will be administered intranasally 45 min before the fMRI task in a double-blind, within-subject, counterbalanced design. To control for nonspecific effects, arousal and mood will be assessed before intranasal administration, before and after the fMRI, as well as demographics, length of spousal relationship, and expectedness of the death. Grief Elicitation Task: Participants will provide five photos of their deceased loved one, and five photos of a living loved one, which will be matched on age, sex, environment and type of photo with five photos of a stranger and five photos of familiar famous persons. Keywords specific to participants’ memory of the death event (e.g., cancer) will be matched with neutral words (e.g., ginger). These photos and words will be combined as composites. The Grief Elicitation task is an event-related design, with counterbalanced presentation of the factors. A yearning scale will be given pre- and post-fMRI, during OT or placebo effects, to capture state changes. Salivary cortisol will be collected pre- and post-fMRI, and 45 minutes post-fMRI. All assessments will occur in the afternoon, due to the circadian rhythm of cortisol. fMR Image Acquisition: A Siemens 3.0 Tesla Magnetom Skyra MRI scanner will acquire a high-resolution structural T1-weighted scan acquired coplanar with the functional scan, acquired with a gradient-echo echo planar imaging (EPI) sequence.