Table 1.

Summary of recent studies in the externalizing domain.

Study	Design	Participants	Behavioral/Imaging Measures of Interest	Alcohol-Related Measures of Interest	Main Findings	Gender-Related Differences
Neuroimaging Studies of Inhibitory Control
Heitzeg et al., 2014a	Prospective; Baseline fMRI and substance use follow-up 4 yrs later	N=45; Reference group=19 (M=10.9 yrs, SD=1.1); Non-users=13 (M=10.9 yrs, SD=0.9); Problematic users=13 (M=11.0 yrs, SD=1.0)	Go/No-Go task	Heavy drinking; alcohol problems	Lower baseline activation in left middle frontal gyrus during failed inhibition vs. correct inhibition trials, controlling for behavioral task performance and externalizing behavior problems, was prospectively associated with heavy drinking and alcohol-use problems at follow-up	22.2% female; Exploratory analyses showed that findings remained in the same direction for males and females
Mahmood et al., 2013	Prospective; Baseline fMRI and substance use follow-up 18 mos later	N=80; Low frequency substance users=71 (M=17.6 yrs, SD=1.0); High frequency substance users=39 (M=17.4 yrs, SD=0.9)	Go/No-Go task	Heavy drinking; alcohol problems	Lower activation in ventromedial prefrontal cortex and greater activation in left angular gyrus during response inhibition was prospectively associated with a greater extent of substance use and dependence symptoms at follow-up in youth who were high-frequency substance users at baseline	High frequency substance users: 31% female; low frequency substance users: 27% female; No gender-related differences examined
Wetherill et al., 2013	Prospective; Baseline fMRI and substance use follow-up 3–4 yrs later	N=40; Control subjects=20 (M=14.1 yrs, SD=1.2); Heavy drinkers=20 (M=14.7 yrs, SD=1.1)	Go/No-Go task	Heavy drinking	Future heavy drinkers showed preexisting differences in brain function associated with response inhibition, with less activation in inhibitory circuitry prior to initiating heavy drinking and greater activation in these regions at follow-up as drinking escalated	45% female; Gender included as a covariate
Whelan et al., 2014	Prospective; Baseline fMRI and substance use follow-up 2 yrs later	N=692; Control subjects=150 (M=14.53 yrs, SD=0.43); Current binge drinkers=115 (M=14.62 yrs, SD=0.39); Future binge drinkers=121 (M=14.45 yrs, SD=0.40); External validation sample=306	Stop Signal Task	Binge drinking	Future binge drinkers: greater activation in right middle, medial, and precentral gyri and in left postcentral and middle frontal gyri during inhibitory errors	Controls: 60% female; future binge drinkers: 46% female; No gender-related differences tested
Neuroimaging Studies of Reward Responsivity
Heitzeg et al., 2014b	Prospective; Baseline fMRI with up to 3 follow-up scans and substance use follow-up 3–6 yrs after baseline scan	N=175; Adolescent=76 (M=10.8 yrs, SD=1.2) or Young adult=99 (M=20.3 yrs, SD=1.4)	Monetary Incentive Delay Task	Alcohol problems	NAcc activation during reward anticipation mediated association between GABRA2 genotype and number of alcohol-use problems reported over at least 3 yrs following baseline	30.5% female; Exploratory analyses indicated no gender-related differences
Stice & Yokum, 2014	Substance naïve FH+ and FH− comparison	N=52: FH+ =26 (M=14.7 yrs, SD=0.9); FH− =26 (M=14.9 yrs, SD=1.0)	Monetary Incentive Delay Task; Food Reward Paradigm	Family history of substance use	FH+ adolescents had greater activation in reward circuitry, which may be a risk factor for later substance use	FH+: 46.2% female; FH−: 50.0% female; No gender-related differences examined
Waller et al., 2018	Mediation	N=139; Substance use: 11, 12, 15, 17 yrs, fMRI scan: 20 yrs, AUD symptoms: 22 yrs (no M or SD)	Card-Guessing Game	AUD symptoms	Accelerated alcohol use from ages 11 to 17 yrs old was associated with greater VS reactivity during reward anticipation at age 20. Greater VS reactivity was associated with a greater extent of AUD symptoms at age 22 yrs, even after accounting for comorbid psychopathology and marijuana and tobacco use	0% female
Whelan et al., 2014	Prospective; Baseline fMRI and substance use follow-up 2 yrs later	N=692; Controls=150 (M=14.53 yrs, SD=0.43); Current binge drinkers=115 (M=14.62 yrs, SD=0.39); Future binge drinkers=121 (M=14.45 yrs, SD=0.40); External validation sample=306	Monetary Incentive Delay Task	Binge drinking	Future binge drinkers: lower activation in occipito-temporal and posterior cingulate during reward anticipation. During reward outcome, future binge drinkers had lower activation in left temporal pole and greater activation in bilateral superior frontal gyrus	Controls: 60% female; Future binge drinkers: 46% female; No gender-related differences tested
The Externalizing Pathway and Stages of AUD Risk
Charles et al., 2016	Prospective; Assessment every 6 mos (max follow-up 54 mos, median 36 mos)	T1: N=386 (M=11.9 yrs; no SD); Use=117; No use=269	Impulsivity and sensation-seeking	Substance use and breath/urine testing (used to categorize Use and No Use groups)	At baseline: Use group more impulsive than No use group; Use group marginally higher on sensation-seeking than No use group. Greater decrease in impulsivity in No use vs. Use group, and greater increase in sensation-seeking in Use vs. No use group	51.6% female; Use and No use groups did not differ on gender; No gender-related differences examined
Khurana et al., 2015	Prospective; 4 annual assessments	T1: N=382 (M=12.4 yrs, SD=0.87)	Working memory, sensation-seeking, acting without thinking, delay discounting	Recent substance use	Acting without thinking and delay discounting fully mediated the association between weak working memory and progression of substance use; sensation-seeking was marginally associated with experimentation but was not related to class membership after controlling for acting without thinking and delay discounting	52% female; Gender was included in the model
Kim-Spoon et al., 2016	Cross-sectional	N=157 (M=14.13 yrs, SD=0.54)	Behavioral inhibition and approach systems, inhibitory control	Age of initiation and frequency of substance use	High reward sensitivity was associated with earlier onset of substance use among those with low, but not high, inhibitory control	48% female; Gender was not associated with any of the outcome variables
Lopez-Vergara et al., 2017	Prospective; Assessment over 3 yrs with 6 waves	Wave 1: N=944 (M=12.16 yrs, SD=0.96) (alcohol-naïve); Wave 6: 17% attrition (M=15.14 yrs, SD=0.95)	Sensation-seeking, other individual and social levels of influence	Alcohol initiation and level of drinking	Parental conflict, perceived prevalence of peer drinking, and sensation-seeking was prospectively associated with alcohol-use initiation. Grades and perceived descriptive norms of peer drinking were prospectively associated with level of drinking	52% female; Being female was associated with initiation
Quinn & Harden, 2013	Prospective; Biennial assessment between ages 15 and 26	N=5,632 (no M or SD)	Impulsivity and sensation-seeking	Frequency of past-year alcohol use	Slower decreases in impulsivity, but not sensation-seeking, were associated with greater increases in alcohol use
Environmental Influences on Externalizing Pathways for AUD
Fava et al., in press	Mediation	Model 1: N=465 (adverse childhood experiences: ages 3–11 yrs, externalizing: M=13 yrs, SD=1.21, substance use: M=16.55 yrs, SD=0.94); Model 2: N=92 (fMRI scan: M=12 yrs, SD=1.59)	Go/No-Go Task	Problematic alcohol use	ACEs prior to age 11 associated with externalizing at 12–14 yrs, which in turn was associated with problematic alcohol use at 15–17 yrs. Greater ACEs associated with reduced ACC activity, which in turn was associated with higher externalizing	Model 1: 26% female; Model 2: 34.8% female; Controlled for gender, no gender-related differences examined
Hasler et al., 2017	Prospective cross-lagged; fMRI and behavioral assessments at ages 20 and 22 yrs	N=93 males, ages 20 and 22 yrs (no M or SD)	Card-Guessing Game	Alcohol-use frequency and problems	Later sleep-wake timing at age 20 was prospectively associated with increased mPFC and VS activation during reward responsivity and greater alcohol dependence at age 22	0% female
Nikolova et al., 2016	Prospective; Baseline fMRI and substance use follow-up 3 mos later	N=759; M=19.65 yrs, SD=1.24	Stressful life events; Number Guessing Reward Task	Alcohol problems	Stress was associated with AUD diagnosed at scan time and problem drinking reported 3 mos later among young adults with low reward-related VS reactivity and high threat-related amygdala reactivity	56% female; Males showed greater activation in the amygdala and VS and higher AUDIT scores
Telzer et al., 2013	Psychophysiological interaction analysis; mediation	N=46; M=15.23 yrs, no SD	Go/No-Go Task/Balloon Analogue Risk Task	General risk-taking	Poor sleep disrupted balance between affective and cognitive control systems. Adolescents showed reduced activation in dlPFC during response inhibition, greater activation in insula during increasing reward salience, and lower functional coupling between dlPFC and affective brain regions	59% female; Controlled for gender, no gender-related differences examined

Note. yrs years, M mean age, SD standard deviation, mos months, NAcc nucleus accumbens, GABRA gamma-aminobutyric acid A receptor, FH+ family history positive, FH− family history negative, AUD alcohol use disorder, T time, VS ventral striatum, fMRI functional magnetic resonance imaging, ACEs adverse childhood experiences, ACC anterior cingulate cortex, mPFC medial prefrontal cortex, AUDIT Alcohol Use Disorders Identification Test, dlPFC dorsolateral prefrontal cortex