Substance craving is a clinically important phenotype for the development and maintenance of addiction. Pictorial cue-exposure paradigms are conventionally used to induce craving in the lab; however, these paradigms are limited in their ability to simulate naturalistic substance use contexts. Thus, traditional cue-exposure paradigms may not effectively induce a true craving state. This report outlines the development of one of the first, naturalistic virtual reality (VR) paradigms designed to invoke craving and simultaneously assess eye-gaze, a potential psychophysiological marker of craving, in substance users. The process of developing a substance cue-exposure paradigm with eye-tracking in VR, including limitations and solutions, will be discussed. Pilot eye-tracking data acquired from a small sample (n=13) of young adult (M=21.67) heavy alcohol users tested on the alcohol version of the VR paradigm will also be presented. Analyses of this data revealed an effect for cue eye-gaze times (t(12) = 2.73, p < .05, d = .76) and subjective craving (t(12) = 2.13, p = .055; d = .59), indicating that heavy alcohol drinkers attend to VR alcohol cues more so than neutral cues and that active VR scenes invoke greater subjective alcohol craving than neutral scenes. These preliminary results suggest that this novel VR paradigm effectively invokes alcohol craving in the lab and advances eye-tracking as an additional, valid psychophysiological marker of craving in substance users. Once fully tested and validated, this VR paradigm could prove useful for enhancing measurement of in-lab craving and serve as a platform for novel treatment development.

Background

With the advent of electronic nicotine delivery systems, the use of nicotine and tobacco products (NTPs) among adolescents and young adults remains high in the US. Use of e-cigarettes additionally elevates the risk of problematic use of other substances like cannabis, which is often co-used with NTPs. However, their effects on brain health, particularly the hippocampus, and cognition during this neurodevelopmental period are poorly understood.

Methods

Healthy late adolescents/young adults (N = 223) ages 16-22 completed a structural MRI to examine right and left hippocampal volumes. Memory was assessed with the NIH Toolbox Picture Sequence Memory Test (PSMT) and Rey Auditory Verbal Learning Test (RAVLT). Cumulative 6-month NTP and cannabis episodes were assessed and modeled continuously on hippocampal volumes. Participants were then grouped based on 6-month NTP use to examine relationships with the hippocampus and memory: current users (CU) endorsed weekly or greater use; light/abstinent users (LU) endorsed less than weekly; and never users (NU).

Results

NTP use predicted larger hippocampal volumes bilaterally while cannabis use had no impact nor interacted with NTP use. For memory, larger left hippocampal volumes were positively associated with PSMT performance, RAVLT total learning, short delay and long delay recall for the NU group. In contrast, there was a negative relationship between hippocampal volumes and performances for LU and CU groups. No differences were detected between NTP-using groups.

Conclusion

These results suggest that the hippocampus is sensitive to NTP exposure during late adolescence/young adulthood and may alter typical hippocampal morphometry in addition to brain-behavior relationships underlying learning and memory processes.

Early life substance use, including cannabis and nicotine, may result in deleterious effects on the maturation of brain tissue and gray matter cortical development. The current study employed linear regression models to investigate the main and interactive effects of past-year nicotine and cannabis use on gray matter cortical thickness estimates in 11 bilateral independent frontal cortical regions in 223 16-22-year-olds. As the frontal cortex develops throughout late adolescence and young adulthood, this period becomes crucial for studying the impact of substance use on brain structure. The distinct effects of nicotine and cannabis use status on cortical thickness were found bilaterally, as cannabis and nicotine users both had thinner cortices than non-users. Interactions between nicotine and cannabis were also observed, in which cannabis use was associated with thicker cortices for those with a history of nicotine and tobacco product (NTP) use in three left frontal regions. This study sheds light on the intricate relationship between substance use and brain structure, suggesting a potential modulation of cannabis' impact on cortical thickness by nicotine exposure, and emphasizing the need for further longitudinal research to characterize these interactions and their implications for brain health and development.