Table 1. Summary of primary findings in the domains of inhibitory control and reward sensitivity from family history, imaging genetic and prospective studies of risk for substance use disorder in children, adolescents and emerging adults.

Study	Design	Participants	fMRI task	Main findings
Inhibitory control
Family history
Silveri 2011 [16]	Cross-sectional; Parental AUD	n=32; Ages 8–19; 59 % female	Stroop	During stroop interference: FH+ > FH−activation in frontal inhibition network, including middle frontal and cingulate gyri.
Hardee 2014 [22]	Longitudinal; 2–4 scans per subject; Parental AUD	n=73; Baseline age 7–12; Age range 7–19; 30 % female	Go/No-Go	Successful no-go trials: Age-by-groupinteraction found: At baseline (ages 7–12): FH+ <FH− activation inR caudate middle cingulate, middle frontalgyrus; With age: FH− youth showed decreasedactivation in caudate and middle frontal gyrus, not seen in FH+ youth; FH+ youth showedincreased middle cingulate activation withage, not seen in FH− youth.
Prospective
Norman 2011 [23]	Prospective; 4-yr follow-up; Heavy drinking	n=38; Ages 12–14; 50 % female	Go/No-Go	No-go trials and heavy drinking: Those who transitioned to heavy alcohol use showed widespread blunted activation—in frontal (including middle frontal gyrus), parietal, temporal cortices and striatum—at baseline.
Mahmood 2013 [24]	Prospective; 18-mo follow-up; Dependence symptoms	n=80; Ages 16–19; 29 % female	Go/No-Go	No-go trials and dependence symptoms/substance use: In youth who were high-frequency substance users at baseline—less vmPFC activation predicted more dependence symptoms at 18-month follow-up and increased activation in L angular and supramarginal gyri predicted more drug use occasions at follow-up.
Wetherill 2013 [27]	Prospective & longitudinal; 2nd scan at 3-yr follow-up; Heavy drinking	n=40; Ages 11–16; 45 % female	Go/No-Go	No-go trials before and after heavy drinking: At baseline, those who would become heavy drinkers had blunted activation in bilateral middle frontal gyrus, R inferior parietal lobule, L putamen, L cerebellum; at follow-up, heavy drinkers had greater activation in these regions (except putamen).
Heitzeg 2014 [29]	Prospective; 4-yr follow-up; Problem substance use	n=45; Ages 9–12; 22 % female	Go/No-Go	Successful no-go and problem substance use: No differences between problem users and controls. Inhibitory errors and problem substance use: (failed no-go trials): Problem users < controls in L middle frontal gyrus. Blunted activation in this area at baseline predicted problem substance use at follow-up.
Whelan 2014 [31]	Prospective; 2-yr follow-up; Binge drinking	n=692; Age 14; 52 % female	Stop signal	Inhibitory errors and binge drinking: Greater activation in right middle, medial and precentral gyri and left postcentral and middle frontal gyri at 14 predicted binge drinking by age 16.
Reward sensitivity
Family history
Stice 2014 [47]	Cross-sectional; Parental SUD	n=52; Ages 14–17; 52 % female	Coin flip	Reward anticipation: FH+ > FH- activation in L dlPFC cortex and bilateral putamen; FH+ < FH- activation in fusiform gyrus and inferior temporal gyrus.
Yau 2012 [52]	Cross-sectional; Parental AUD	n=40; Ages 18–22; 40 % female	Monetary incentive delay	Reward anticipation: Drinking-by-FH interaction with light drinking FH+ < heavy drinking FH+ and FH- in NAcc; no differences in NAcc activation between heavy drinking FH+ and FH-. NAcc activation positively correlated with drinking in FH+ only.
Muller 2014 [55]	Cross-sectional; Parental AUD	n=412; Ages 13–15; 49 % female	Monetary incentive delay	Reward anticipation and outcome: Nodifferences in activation between FH+ and FH-.
Ivanov 2012 [64]	Cross-sectional; Parental SUD	n=20; Ages 8–13; 10% female; All ADHD	Anticipation- conflict-reward	Reward anticipation and outcome: FH+ > FH- activation in motivational-reward circuitry, including L anterior insula/caudate, L inferior frontal gyrus, L OFC. Cognitive conflict: FH+ < FH- activation in behavioral inhibition circuitry, including right anterior cingulate cortex, L dmPFC.
Cservenka 2012 [65]	Cross-sectional; Parental AUD	n=31; Ages 13–5; 35 % female	Wheel of fortune	Risky choices: FH+ < FH- activation in dlPFC and cerebellum.
Cservenka 2014 [67]	Cross-sectional; Parental AUD	n=97; Ages 10–16; 44 % female	Resting state	Intrinsic NAcc connectivity: FH+ < FH- segregation between L NAcc and bilateral inferior frontal gyri (reduced segregation showed trend association with sensation-seeking); FH+ had negative functional connectivity between R NAcc and L OFC, whereas FH− had positive functional connectivity.
Weiland 2013 [68]	Cross-sectional; Parental AUD	n=70; Ages 18–22; 33 % female	Monetary incentive delay	NAcc connectivity during incentive anticipation: NAcc connectivity with attention, motor, and default mode network regions was decreased in FH− but increased in FH+; connectivity strength mediated the relation between sensation-seeking and alcohol use in FH+.
Imaging genetics
Nikolova 2013 [75••]	Cross-sectional; GAL5.1	n = 138; Mean age 19; 52 % female; College students	Number guessing	GAL5.1 and VS reactivity: Genotype-by-gender interaction for activation in VS (male CA > female CA; female GG > female CA). Gender differences in VS activation as a mediator of genotype and problem drinking.
Villafuerte 2012 [76]	Cross-sectional; GABRA2	n=44; Ages 18–22; 45 % female	Monetary incentive delay	GABRA2 and insula activation: During reward anticipation, risk allele (G) homozygotes had greater activation in L insula, significant only in females. GG genotype and insula activation associated with impulsivity across all subjects.
Heitzeg 2014 [57•]	Longitudinal;1–4 scans per subject; GABRA2	n = 175; Baseline age 8–13 &18–23; Age range 8–27; 30 % female	Monetary incentive delay	GABRA2 and NAcc reactivity: Age-by-genotype interaction where G carriers (GG and AG) had higher NAcc activation to reward anticipation in adolescence (not childhood or young adulthood); AA showed no age-related changes.
Prospective
Heitzeg 2014 [57•]	Prospective; 4-yr follow-up; Alcohol problems	n= 104; Ages 8–13, 18–23; 30 % female	Monetary incentive delay	NAcc activation and alcohol problems: Increased NAcc activation during reward anticipation was associated with more alcohol problems over 3–5 years of follow-up.
Dager 2014 [82]	Prospective; 1-yr follow-up; Transition to heavy drinking	n=43; Ages 18–21; 53 % female	Pictorial cue reactivity (alcohol/non-alcohol pictures)	Cue-reactivity and heavy drinking: Transitioners to heavy drinking had greater response to alcohol vs. non-alcohol pictures in cue-reactive circuitry (caudate, vmPFC, anterior cingulate, OFC, insula); greater reactivity of this circuitry predicted more alcohol involvement over 1-yr follow-up.
Whelan 2014 [31••]	Prospective; 2-yr follow-up; Binge drinking	n=692; Age 14; 52 % female	Monetary incentive delay	Reward and binge drinking: Activations at age 14 predicted binge drinking at age 16: reduced activation in occipito-temporal and posterior cingulate regions during reward anticipation; increased activation in superior frontal gyrus and reduced activation in left temporal pole during reward outcome.

Studies are termed “prospective” if neuroimaging data from one time point are used to differentiate youth based on a later substance use outcome. Studies are termed “longitudinal” if neuroimaging data are collected at more than one time point. For prospective studies, age range in participant column refers to scan time. For longitudinal studies, age range in participant column refers to 1 st scan time

FH+ family history positive, FH− family history negative, AUD alcohol use disorder, SUD substance use disorder, ADHD attention deficit hyperactivity disorder, L left, R right, mo month, yr year, NAcc nucleus accumbens, OFC orbitofrontal cortex, VS ventral striatum, vmPFC ventromedial prefrontal cortex, dlPFC dorsolateral prefrontal cortex, dmPFC dorsomedial prefrontal cortex