Health Effects of E-cigarette Use on Brain Functions and Cognitive Development among Adolescents: A US Population-Based Study - Project Summary Electronic Nicotine Delivery System (ENDS) use has been a major public health concern. The U.S. Food and Drug Administration (FDA) continues to cite health effects as a chief rationale in FDA enforcement priorities and marketing denials. Childhood to adolescence represents a critical period with rapid development in brain maturation. Combustible cigarette smoking during adolescence can negatively impact brain development, and animal models also show that nicotine exposure in adolescent rodents slows brain maturation, including the prefrontal cortex. However, the impact of rising ENDS use on youth brain functions and cognitive outcomes is poorly understood. Vaping delivers much lower levels of tobacco smoke chemicals but similar levels of nicotine compared to cigarette smoking. Studying the effects of vaping on brain maturation can illuminate nicotine effects without tobacco smoking. Importantly, there is a dearth of evidence on the relative effects of exclusive ENDS use vs. combustible cigarette smoking on youth brain maturation, which is critical to the FDA’s regulatory actions on ENDS and prioritizing public health programs. This population study will analyze the longitudinal Adolescent Brain Cognitive Development (ABCD) study with 11,878 youth aged 9-10 years old at baseline from 21 U.S. study sites, to assess the effects of exclusive ENDS use on youth’s brain structure and cognitive performances and further examine potentially differential effects of vaping vs. smoking on neurocognition. The study will link the first 5 biannual waves of ABCD magnetic resonance imaging (MRI) data during 2016-2024 with semiannual tobacco use assessments and annual behavioral measures by Subject ID to create a harmonized longitudinal dataset. In Aim 1, the team will prospectively examine the effects of exclusive ENDS use (vs. never tobacco use) on whole-brain morphometric measures (e.g., white/gray matter, cortical thickness). In Aim 2, the team will assess the longitudinal associations of exclusive ENDS use (vs. never tobacco use) on attention, memory, executive function, emotion regulation, and reward processing at the cognitive level, using validated behavioral tasks sensitive to youth development (e.g., NIH Toolbox), and at the brain level using functional MRI tasks. In both Aims 1 and 2, we will further test whether differences in brain maturation are negatively associated with vaping frequency, intensity, and duration among ENDS users. In Aim 3, the relative effect of exclusive ENDS use vs. cigarette smoking on whole brain structure and NIH Cognition Toolbox will be tested. This study is innovative by 1) leveraging the largest brain development and child health study with state-of-the-art neurocognitive assessments, and 2) applying the mariginal structural modeling to handle time-dependent exposure and time-varying confounders, thus allowing for unbiased effect estimation and teasing out potentially reverse causality. This study is also significant in providing vital evidence on vital evidence of vaping effects on brain health, thus providing vital evidence to inform effective regulatory actions and public policies. 1
