Focused Ultrasound for Prolonged Grief Disorder: A Novel Approach to Targeting Reward Circuitry Underlying Persistent Yearning and Related Clinical Features.

Abstract

Prolonged Grief Disorder (PGD) is a recently recognized psychiatric disorder in ICD-11 and DSM-5-TR, characterized by persistent yearning and/or preoccupation with the deceased, alongside other grief-related symptoms. PGD affects 5%-16% of bereaved individuals and is associated with mental and physical morbidity, functional impairment, elevated suicidality, and premature death, underscoring its importance as a public health priority, with particular relevance to older adults given their increasing and often cumulative exposure to bereavement. Current treatment for PGD relies primarily on grief-focused psychotherapy, which is associated with substantial dropout, and does not lead to full remission for many patients. Despite growing interest in pharmacological, psychedelic, and neuromodulatory approaches, no biologically-based intervention has yet demonstrated efficacy for the core symptoms of PGD. At the same time, emerging neurobiological evidence implicates alterations across multiple interacting neural systems in PGD, with reward-related circuitry showing particular relevance to persistent yearning. Low-intensity Focused Ultrasound (LIFUS) enables noninvasive, reversible, high-precision modulation of deep brain structures. This addresses several key limitations of conventional neuromodulation approaches (e.g., rTMS and DBS) while maintaining a promising safety and tolerability profile. Recent studies have investigated LIFUS across a range of neurological and psychiatric disorders, including opioid use disorder, with early findings suggesting therapeutic potential. Taken together, these observations suggest that LIFUS may offer a promising and theoretically grounded direction for future research in PGD. In this paper, we outline the scientific rationale for investigating LIFUS neuromodulation as a novel intervention for PGD, discuss its potential implications for research and clinical translation, and conclude that an initial clinical trial is warranted to evaluate the feasibility, safety, tolerability, and preliminary efficacy of LIFUS for PGD.