Cumulative Effect of ACEs on the Neurocircuitry of Drug Withdrawal

The proposed project examines how cumulative Adverse Childhood Experiences (ACEs) influence the
brain mechanisms underlying nicotine withdrawal symptoms, specifically cognitive control and craving
sensations, in users of Electronic Nicotine Delivery Systems (ENDS). ACEs significantly increase
vulnerability to addiction, contributing to earlier drug use initiation, heavier lifetime use, and more failed quit
attempts. Two critical brain regions may underlie these effects: the prefrontal cortex (PFC), essential for
cognitive control and resisting cravings, and the mid-insular cortex (dmIC), crucial for sensing internal
bodily states associated with withdrawal. Forty-six adult ENDS users (aged 18-50) with varied histories of
childhood adversity (1-10 ACEs) will participate in this two-week study. Participants will exclusively use
provided ENDS devices that objectively measure daily nicotine intake. They will undergo two weekly fMRI
sessions—one following regular nicotine use and another after 24-hour abstinence—to measure brain
responses during cognitive control, interoceptive attention, and cue-reactivity tasks. Behavioral, subjective
craving, and serum cotinine measures will complement imaging data. The current study aims to determine:
1) how ACEs influence patterns of nicotine use and withdrawal symptoms, such as craving intensity and
diminished behavioral inhibition; 2) how ACEs impact neural mechanisms underlying altered craving
(dmIC) and impaired behavioral inhibition (PFC) during nicotine abstinence. This research is innovative
though integrating assessments of interoceptive and executive control systems in ENDS users with
objective nicotine use measurements. Results will advance understanding of how childhood adversity
potentiates nicotine dependence, providing critical insight to inform public health interventions targeted at
improving treatments for substance use disorders.

Grant Number: 5P20GM109097-09
NIH Institute/Center: NIH
Principal Investigator: Jason Avery