Understanding Neural Mechanisms of Prolonged Grief in Suicide Loss Survivors

The death of a loved one due to suicide is one of the greatest life stressors to which individuals must adapt. Significant adaptation to the death of a close attachment is commonly seen by the end of one year. Loss due to suicide, however, has been identified as one of the strongest risk factors for Prolonged Grief Disorder (PGD), with reported rates ranging from 18% to as high as 80%. PGD was recently defined in DSM-5-TR and includes persistent, pervasive focus including yearning and preoccupation with the deceased loved one, intense emotional pain, avoidance of reminders that the death is permanent, and other symptoms that cause substantial distress and impair functioning. Compared with other types of losses, suicide loss survivors have been reported to have higher levels of PGD symptoms and emotional distress, comorbidity, the highest rates of active suicidal ideation, and poorer PGD treatment outcomes. While some PGD psychotherapeutic treatments exist, the behavioral and neural mechanisms underlying PGD remain unclear in general, and even more so for suicide loss survivors, resulting in a lack of biological targets for treatment development and precision psychiatry approaches for this population.

In this proposal, we seek to develop evidence demonstrating roles in PGD for dysfunctions in the regulation of reward, negative affect and memory retrieval hypothesized to interfere with updating and adapting after loss of a loved one due to suicide. Specifically, we hypothesize that in PGD the loss of a close attachment due to suicide leads to hyperactivation of neurophysiological stress responses interrupting the process of neural adaptation to the loss. We hypothesize that this impaired adaptation drives reduced top-down regulation of prefrontal circuits on affective and reward value circuits, which (1) enhances the reliance on habitual reward learning, mediated by dopaminergic fronto-striatal circuits; (2) reduces the efficacy of cognitive reappraisal strategies to regulate negative affect; and (3) biases memory retrieval toward more vivid and intense memories for the deceased loved one, driven by enhanced hippocampal-striatal interactions. Thus, we hypothesize that PGD after a suicide results from persistent dysregulation of these well-defined reward learning, emotion regulation, and memory circuits, and that this neurobiological dysregulation in which striatal activations become fixed and dominant, perturbs restoration of adaptive affective function. To establish support for these hypotheses that could be more definitely examined in subsequent R01-level study, suicide-bereaved adults (n=15 suicide loss survivors with PGD and n=15 suicide bereaved controls) will be deeply characterized with well-validated clinical assessments, and experimental behavioral and fMRI paradigms. This novel neural-behavioral characterization of this newly-defined disorder, proposed by a neuroscientific and psychiatric team collaborating on experiments which have already been preliminarily piloted successfully with feasibility and encouraging early results in a PGD cohort, will begin to address critical gaps in knowledge by laying the foundation for a mechanistic understanding of PGD in suicide loss survivors that may ultimately offer new behavioral and neural therapeutic targets for suicide loss survivors affected by PGD, a condition that causes substantial distress and impairment for millions of bereaved Americans each year.