The neurobiological mechanisms of complicated grief

Mary-Frances O'Connor, Ph.D.

The University of Arizona College of Medicine, Tuscon, AZ

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

January 2015, for 3 years

Funding Amount:


Lay Summary

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.

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.

Investigator Biographies

Mary-Frances O'Connor, Ph.D.

Dr. Mary-Frances O’Connor’s research focuses on the physiological correlates of emotion, particularly the wide range of emotional responses during bereavement. She has investigated the failure to adapt following the death of a loved one, termed Complicated Grief, which is a condition for further research in the DSM-5. In addition, she has studied the neurobiological, immune and autonomic parameters that vary between individual grief responses. Specifically, she has publications utilizing functional neuroimaging, immune, endocrine and genetic analysis of saliva and blood, and psychophysiological assessment of heart rate variability. She believes that a clinical science approach to the experience and physiology of grief can improve psychological treatment. Dr. O’Connor was an undergraduate at Northwestern University and then earned a PhD in clinical psychology from the University of Arizona. She completed her clinical internship at the University of California, Los Angeles (UCLA). Dr. O’Connor continued her studies at UCLA, where she was a post-doctoral fellow at the UCLA Cousins Center for Psychoneuroimmunology, and then joined the faculty there. Currently, Dr. O’Connor is an Assistant Professor at the University of Arizona Department of Psychology, where she teaches courses in psychoneuroimmunology and advanced psychopathology.