Attentional Bias, Pupillometry, and Spontaneous Blink Rate: Eye Characteristic Assessment Within a Translatable Nicotine Cue Virtual Reality Paradigm.

Background: Incentive salience processes are important for the development and maintenance of addiction. Eye characteristics such as gaze fixation time, pupil diameter, and spontaneous eyeblink rate (EBR) are theorized to reflect incentive salience and may serve as useful biomarkers. However, conventional cue exposure paradigms have limitations that may impede accurate assessment of these markers. Objective: This study sought to evaluate the validity of these eye-tracking metrics as indicators of incentive salience within a virtual reality (VR) environment replicating real-world situations of nicotine and tobacco product (NTP) use. Methods: NTP users from the community were recruited and grouped by NTP use patterns: nondaily (n=33) and daily (n=75) use. Participants underwent the NTP cue VR paradigm and completed measures of nicotine craving, NTP use history, and VR-related assessments. Eye-gaze fixation time (attentional bias) and pupillometry in response to NTP versus control cues and EBR during the active and neutral VR scenes were recorded and analyzed using ANOVA and analysis of covariance models. Results: Greater subjective craving, as measured by the Tobacco Craving Questionnaire-Short Form, following active versus neutral scenes was observed (F1,106=47.95; P<.001). Greater mean eye-gaze fixation time (F1,106=48.34; P<.001) and pupil diameter (F1,102=5.99; P=.02) in response to NTP versus control cues were also detected. Evidence of NTP use group effects was observed in fixation time and pupillometry analyses, as well as correlations between these metrics, NTP use history, and nicotine craving. No significant associations were observed with EBR. Conclusions: This study provides additional evidence for attentional bias, as measured via eye-gaze fixation time, and pupillometry as useful biomarkers of incentive salience, and partially supports theories suggesting that incentive salience diminishes as nicotine dependence severity increases.

A preliminary investigation of physical and mental health features of cannabis & nicotine co-use among adolescents and young adults by sex.

INTRODUCTION: Cannabis and nicotine/tobacco products (NTP) are commonly co-used in adolescence and young adulthood; however, limited research has been done on predictive health behaviors to co-use. The current study is a preliminary investigation into the relationships of modifiable health behaviors on cannabis and NTP co-use in adolescents and young adults. METHOD: 221 participants (ages 16-22) were characterized into cannabis use only (N = 55), NTP use only (N = 20), cannabis and NTP co-use (used cannabis and NTP; N = 96) and control (no use; N = 50) groups based on past 30-day use. Self-report measures for physical activity, sleep quality, mental health, and reward responsivity were utilized. Participants were given a comprehensive neurocognitive battery. Logistic regressions of self-report measures and fluid intelligence composite scores on substance use group status were run stratified by sex. RESULTS: Higher approach reward sensitivity traits were associated with increased likelihood of cannabis use only (Odds Ratio (OR) = 1.15, p = .036) in female participants. Increased aerobic activity was associated with decreased likelihood of cannabis use only (OR = 0.91, p = .047) and cannabis and NTP co-use (OR = 0.88, p = .007) in female participants. Higher anxiety was associated with increased likelihood of cannabis NTP co-use (OR = 1.51, p = 0.025) in male participants. DISCUSSION: Several health behaviors were linked with cannabis use and cannabis and NTP co-use in both females and male adolescents and young adults. Health markers differed by sex suggesting differing mechanisms of substance co-use. This study informs targetable health behaviors for prevention and intervention efforts.

First Used Nicotine/Cannabis Product and Associated Outcomes in Late Adolescents.

BACKGROUND: Nicotine and tobacco product (NTP) and cannabis use are common in adolescence/young adulthood and increase risk for negative psychosocial outcomes. This study investigated associations among adolescent/young adults' initial experiences with NTPs, lifetime frequency of substance use, substance-related problems, and mental health symptoms. METHOD: Adolescents and young adults enrolled in a study on NTP and cannabis use were asked at what age they initiated the use of NTPs and were assigned to groups based on which product or substance(s) they reported using at the earliest age. Participants who reported use of NTPs (in isolation, without cannabis) first (N = 78, "NTP-only"), simultaneous use of NTPs and cannabis first (e.g., blunt or bowl; N = 25, "Simult-only"), use of both NTPs in isolation and simultaneous use at the same age (N = 48, "NTP + Simult"), and no NTP use (N = 53, "NTP-naïve") were compared on substance use, substance-related problems, and mental health symptoms. RESULTS: Groups differed on lifetime frequency of NTP, simultaneous, and cannabis use, with NTP users reporting more substance use episodes and substance-related problems than the NTP-naïve group. The lifetime frequency of cannabis use did not differ across NTP use groups. NTP use was associated with increased anxiety and depression, with no significant differences between groups. CONCLUSIONS: Adolescents and young adults who use nicotine may be at increased risk for greater nicotine use and mental health consequences, but initiating NTP use simultaneously with cannabis may not increase the risk of negative outcomes above and beyond nicotine initiation. Prospective longitudinal research is needed to establish temporal associations between first-used NTP/cannabis products and relevant outcomes.

The effects of nicotine use during adolescence and young adulthood on gray matter cerebral blood flow estimates.

Nicotine and tobacco product (NTP) use remains prevalent in adolescence/young adulthood. The effects of NTPs on markers of brain health during this vulnerable neurodevelopmental period remain largely unknown. This report investigates associations between NTP use and gray matter cerebral blood flow (CBF) in adolescents/young adults. Adolescent/young adult (16-22 years-old) nicotine users (NTP; N = 99; 40 women) and non-users (non-NTP; N = 95; 56 women) underwent neuroimaging sessions including anatomical and optimized pseudo-continuous arterial spin labeling scans. Groups were compared on whole-brain gray matter CBF estimates and their relation to age and sex at birth. Follow-up analyses assessed correlations between identified CBF clusters and NTP recency and dependence measures. Controlling for age and sex, the NTP vs. non-NTP contrast revealed a single cluster that survived thresholding which included portions of bilateral precuneus (voxel-wise alpha < 0.001, cluster-wise alpha < 0.05; ≥7 contiguous voxels). An interaction between NTP group contrast and age was observed in two clusters including regions of the left posterior cingulate (PCC)/lingual gyrus and right anterior cingulate cortex (ACC): non-NTP exhibited positive correlations between CBF and age in these clusters, whereas NTP exhibited negative correlations between CBF and age. Lower CBF from these three clusters correlated with urine cotinine (rs=-0.21 - - 0.16; ps < 0.04) and nicotine dependence severity (rs=-0.16 - - 0.13; ps < 0.07). This is the first investigation of gray matter CBF in adolescent/young adult users of NTPs. The results are consistent with literature on adults showing age- and nicotine-related declines in CBF and identify the precuneus/PCC and ACC as potential key regions subserving the development of nicotine dependence.

Evaluation of Gaze-to-Object Mapping Algorithms for Use in "Real-World" Translatable Neuropsychological Paradigms.

Objective: Eye-tracking technology is commonly used for identifying objects of visual attention. However, applying this technology to virtual reality (VR) applications is challenging. This report analyzes the performance of two gaze-to-object mapping (GTOM) algorithms applied to eye-gaze data acquired during a "real-world" VR cue-reactivity paradigm. Methods: Two groups of participants completed a VR paradigm using an HTC Vive Pro Eye. The gazed objects were determined by the reported gaze rays and one of two GTOM algorithms - naïve ray-casting (n=18) or a combination of ray-casting and Tobii's G2OM algorithm (n=18). Percent gaze duration was calculated from 1-second intervals before each object interaction to estimate gaze accuracy. The object volume of maximal divergence between algorithms was determined by maximizing the difference in Hedge's G effect sizes between small and large percent gaze duration distributions. Differences in percent gaze duration based on algorithm and target object size were tested with a mixed ANOVA. Results: The maximum Hedge's G effect sizes differentiating large and small target objects was observed at an 800cm3 threshold. The combination algorithm performed better than the naïve ray-casting algorithm (p=.003, ηp2=.23), and large objects (>800cm3) were associated with a higher gaze duration percentage than small objects (≤800cm3; p<.001, ηp2=.76). No significant interaction between algorithm and size was observed. Conclusions: Results demonstrated that Tobii's G2OM method outperformed naïve ray-casting in this "real-world" paradigm. As both algorithms show a clear decrease in performance for detecting objects with volumes <800cm3, we recommend using gaze-interactable objects >800cm3 for future HTC Vive Pro Eye applications.

Using Virtual Reality to Induce and Assess Objective Correlates of Nicotine Craving: Paradigm Development Study.

BACKGROUND: Craving is a clinically important phenotype for the development and maintenance of nicotine addiction. Virtual reality (VR) paradigms are successful in eliciting cue-induced subjective craving and may even elicit stronger craving than traditional picture-cue methods. However, few studies have leveraged the advances of this technology to improve the assessment of craving. OBJECTIVE: This report details the development of a novel, translatable VR paradigm designed to both elicit nicotine craving and assess multiple eye-related characteristics as potential objective correlates of craving. METHODS: A VR paradigm was developed, which includes three Active scenes with nicotine and tobacco product (NTP) cues present, and three Neutral scenes devoid of NTP cues. A pilot sample (N=31) of NTP users underwent the paradigm and completed subjective measures of nicotine craving, sense of presence in the VR paradigm, and VR-related sickness. Eye-gaze fixation time ("attentional bias") and pupil diameter toward Active versus Neutral cues, as well as spontaneous blink rate during the Active and Neutral scenes, were recorded. RESULTS: The NTP Cue VR paradigm was found to elicit a moderate sense of presence (mean Igroup Presence Questionnaire score 60.05, SD 9.66) and low VR-related sickness (mean Virtual Reality Sickness Questionnaire score 16.25, SD 13.94). Scene-specific effects on attentional bias and pupil diameter were observed, with two of the three Active scenes eliciting greater NTP versus control cue attentional bias and pupil diameter (Cohen d=0.30-0.92). The spontaneous blink rate metrics did not differ across Active and Neutral scenes. CONCLUSIONS: This report outlines the development of the NTP Cue VR paradigm. Our results support the potential of this paradigm as an effective laboratory-based cue-exposure task and provide early evidence of the utility of attentional bias and pupillometry, as measured during VR, as useful markers for nicotine addiction.