Psychological and Neurobiological Precursors of Alcohol Use Disorders in High-Risk Youth

Abstract

It has long been known that Alcohol Use Disorders (AUDs) run in families with substantial heritability. Determining the specific genetic underpinnings of these disorders has been challenging because of the clinical heterogeneity and variable expression across the lifespan. The search for endophenotypic biological variation associated with the AUD and related substance use disorder (SUD) phenotypes is based on the belief that an endophenotype is more proximal to the causative gene. Identification of genes conferring increased susceptibility has important implications for treatment through the potential development of medications that target specific genetic pathways. High risk family designs that contrast offspring with and without a familial/genetic background have provided valuable insights into the psychological characteristics (executive control, affective regulation, decision making and social cognition) that differentiate such individuals. The current chapter will review these with a focus on brain morphology of specific regions, the coordinated activity of neural networks, and developmental trajectories of electrophysiological activity.

Density and Dichotomous Family History Measures of Alcohol Use Disorder as Predictors of Behavioral and Neural Phenotypes: A Comparative Study Across Gender and Race/Ethnicity

“…F AMILY HISTORY (FH) of alcohol use disorder (AUD) has been consistently shown to be a major risk factor for developing AUD (Bohman et al, 1987;Cadoret et al, 1980;Dawson et al, 1992;Goodwin et al, 1974;Polich et al, 1994;Porjesz et al, 2005;Prescott et al, 2005;Rangaswamy et al, 2007). Ample evidence shows that FH is a robust predictor of alcohol problems and is associated with psychological and neurobiological precursors for AUD (Hill and O'Brien, 2015;Nurnberger et al, 2004;Porjesz et al, 2005). For example, FH is linked to greater risk for earlier initiation of drinking (Dawson, 2000;, increased frequency of alcohol intoxication (Pilatti et al, 2013), early onset of AUD (Lieb et al, 2002), and a higher prevalence of lifetime alcohol dependence across age, gender, and race (National Longitudinal Alcohol Epidemiological Survey, 2002), Additionally, FH has also been associated with aberrant electrophysiologic characteristics such as low P3/P300 (an event-related brain potential; ERP) amplitude in response to target stimuli, often considered as a biomarker of vulnerability for AUD (Begleiter et al, 1984, Begleiter et al 1987Cservenka, 2016;Hill et al, 1991;Hill et al, 2009;Porjesz et al, 2005).…”

Neural predictors of substance use disorders in Young adulthood

“…Structure and function of the OFC and amygdala may contribute to relative risk and resilience within both high- and low-risk populations given the putative role of these regions in a broad range of cognitive and psychological functions. Evidence from prospective family studies of high-risk offspring, as well as cross-sectional research with healthy children and adults, indicates that variation in volume of the OFC and amygdala relate to several established risk factors for SUD, including impulsivity (Hill et al, 2009b; Verdejo-Garcia et al, 2008), decision making (Hill and O’Brien, 2015; O’Brien et al, 2014), externalizing behaviors (Ameis et al, 2014), and early temperament (Caspi et al, 1996; Hill et al, 2010; Williams et al, 2010). The morphology of the OFC and amygdala also relate to genetic variation in 5-HTTLPR and BDNF (Hill et al, 2013; Hill et al, 2009b), with these candidate genes also associated with SUD (Feinn et al, 2005; Janak et al, 2006).…”

“…Accordingly, increased attention has been focused on finding biological variation associated with familial risk that predisposes individuals to increased risk for SUD. Longitudinal studies that follow individuals with a family history of AUD from childhood and adolescence into young adulthood may allow for identification of potential biomarkers that contribute to risk and resilience within at-risk populations (Hill and O’Brien, 2015). …”

“…High-risk offspring with a family history of AUD have been shown to demonstrate atypical structure and function of brain regions involved in executive control, affective regulation, decision making, and social cognition (Cservenka, 2016; Hill and O’Brien, 2015). Previous research indicates that compared to healthy controls from low-risk families, adolescent and young adult offspring with a family history of AUD show volumetric reductions in the right hemisphere of the orbitofrontal cortex (OFC) (Hill et al, 2010; Hill et al, 2009b) and the amygdala (Benegal et al, 2007; Dager et al, 2015; Hill et al, 2001; Hill et al, 2013).…”

“…Longitudinal family studies, as well as cross-sectional research on healthy adults and children, have demonstrated that reductions in orbitofrontal cortex volume and cortical thickness are associated with higher rates of externalizing behaviors (Ameis et al, 2014), greater impulsivity (Hill et al, 2009b; Schilling et al, 2013) and impaired decision-making (Hill and O’Brien, 2015), deficits that are independently associated with increased risk for substance use, abuse, and dependence (Bechara et al, 2001; O’Brien et al, 2014; Verdejo-Garcia et al, 2008). Amygdala volume has been shown to be significantly correlated with P300 amplitude (Hill et al, 2001), a well-established endophenotype of risk for substance use and externalizing behavioral disorders (Hill et al, 2009a; Iacono et al, 2002).…”