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. Author manuscript; available in PMC: 2018 Feb 1.
Published in final edited form as: Curr Opin Behav Sci. 2017 Feb;13:164–170. doi: 10.1016/j.cobeha.2016.12.005

Adolescence and Drug Use Vulnerability: Findings from Neuroimaging

Lindsay M Squeglia 1, Anita Cservenka 2
PMCID: PMC5241101  NIHMSID: NIHMS841447  PMID: 28111629

Abstract

Adolescence is a period of vulnerability for developing substance use disorder. Recent neuropsychological and neuroimaging studies have elucidated underlying neural vulnerabilities that contribute to initiation of substance use during adolescence. Findings suggest poorer performance on tasks of inhibition and working memory, smaller brain volumes in reward and cognitive control regions, less brain activation during executive functioning tasks, and heightened reward responsivity are predictive of youth initiating substance use during adolescence. In youth who are family history positive (FHP) for substance use disorder, poorer executive functioning, smaller volume of limbic brain regions (e.g., amygdala), sex-specific patterns of hippocampal volume, and a positive association between nucleus accumbens volume and family history density have been reported. Further, reduced white matter integrity, altered brain response during inhibitory control, including both greater and less frontal lobe response, blunted emotional processing, and weaker neural connectivity have also been found in FHP youth. Thus, there is significant overlap among the neural precursors shown to be predictive of alcohol and substance use initiation during adolescence and those that distinguish FHP from youth without a family history of substance use disorder, suggesting common targets for prevention and intervention. Understanding these predictive factors helps identify at-risk youth for prevention efforts, as well as create interventions targeting cognitive weaknesses or brain regions involved in substance use initiation.

INTRODUCTION

Underage alcohol and drug use is recognized as a leading public health and social problem for adolescents. Alcohol is by far the most commonly used substance among adolescents, with 64% of 18 year olds endorsing lifetime alcohol use, followed by marijuana (45%) and cigarette use (31%) (1). Acute alcohol and drug intoxication is related to a number of adverse outcomes, ranging from poor decision making to substance-related deaths (2). Long-term consequences include poorer academic performance (3), neurocognitive deficits (4), and psychosocial problems (5, 6). Earlier initiation of substance use is related to worse outcomes (7, 8), with youth who begin drinking before age 15 having four to six times the rate of lifetime alcohol dependence than those who do not drink by age 21 (9, 10). However, many of these associations reported in cross-sectional studies do not explain the directionality of alcohol use and these outcomes, thus necessitating longitudinal studies of risk factors for adolescent alcohol use, of which neuroimaging studies are reviewed herein.

One contributing factor to the peak in substance use during adolescence could be the “imbalance” in adolescent brain development, where emotion and reward systems develop before cognitive control systems, leaving youth more vulnerable to engage in risk-taking behaviors like substance use (11–13). Understanding the factors that contribute to initiation of substance use, particularly in regards to adolescent neurodevelopment, are important for developing targeted, effective prevention and intervention efforts to help avoid unwanted negative consequences associated with adolescent substance use.

Over the past decade, researchers have used sophisticated prospective, longitudinal designs to better understand factors that contribute to the initiation of substance use during adolescence. These studies assess youth before they have ever used any alcohol or drugs and continue assessing them over time as a portion naturally transition into substance use. This brief review will cover the existing longitudinal neuroimaging and neurocognitive studies that have identified key features that predate adolescent substance use and make youth more vulnerable to engage in substance use. Further, we review studies examining neurocognitive and neural differences that distinguish youth with a family history of substance use disorder from their peers. The majority of studies reviewed are alcohol-related, as alcohol is the most commonly used substance during adolescence and youth who use other drugs typically are also using alcohol (1).

Neural features related to alcohol and drug use vulnerability

Neuropsychological Precursors

Neurocognitive features, particularly executive functioning performance, may make youth more vulnerable to engage in substance use during adolescence. Executive functioning refers to higher-order cognitive processing skills, including inhibition, attention, working memory, planning, problem solving, and cognitive flexibility. Inhibition, or impulse control, appears to be a key cognitive feature involved in substance use initiation (14, 15). Compromised inhibitory function in substance-naïve 12–14 year olds has been related to greater subsequent alcohol and marijuana use by age 18, even after controlling for common predictors of youth substance use including sex, externalizing behaviors, familial substance use disorder, pubertal development, academic achievement, and age (16); 23% of the total variance in substance use was accounted for by predictors. Poorer performance on spatial planning and problem solving tasks (17), as well as deficits in working memory (18) have also been linked to escalation of drinking during adolescence. These findings suggest that neuropsychological data, particularly in regards to executive functioning, could be helpful in identifying teens at risk for initiating problematic substance use.

Structural Brain Precursors

Pre-existing structural brain differences may also predispose youth to engage in heavy substance use. Smaller orbitofrontal cortex (a region of the brain involved in reward processing and decision making) volumes at age 12 predicted marijuana use by age 16 (19). Similarly, other studies have found that smaller frontal gray matter volume (20–22) and less cerebellar white matter volume (21) predict initiation of drinking by late adolescence (20). Reward-related subcortical brain structures also appear to be involved in initiation of substance use. In substance-naïve 15–18 year olds, smaller volume of the left nucleus accumbens (NAcc), predicted greater substance use at 2 year follow-up (23). Smaller volumes of the anterior cingulate, a region implicated in affective processes, self-control, and substance use, have also been found to predict later alcohol-related problems (24). White matter integrity, as measured by diffusion tensor imaging, has been examined in relation to development of substance use. In 16 to 19 year old youth, lower white matter integrity in fronto-limbic regions predicted alcohol and marijuana use at an 18 month follow-up (25). Overall, less volume in brain regions involved in impulsivity, reward sensitivity, and decision making and lower white matter integrity appear to influence initiation of alcohol and marijuana use during adolescence.

Functional Brain Precursors

Beyond structural neuroimaging studies, functional magnetic resonance imaging (fMRI) has been used to elucidate brain function precursors of adolescent substance use. Longitudinal fMRI studies of substance-naïve youth have shown that even in the presence of comparable behavioral performance, abnormal brain activation during inhibition tasks, including both less (26, 27) and greater (22) frontal lobe response, predict alcohol use by mid-to-late adolescence. Less frontal activation also predicts future substance use and dependence symptoms (26, 28), while greater frontal response has been shown to predict significant alcohol-related consequences like blackouts (29). On tasks of visual working memory, less brain activation during early adolescence is predictive of greater substance involvement by late adolescence (17, 30). Brain activation during reward processing has also been found to predict future adolescent substance use engagement; reduced resting-state cerebral blood flow within reward and default mode networks has been associated with greater alcohol consumption during mid-to-late adolescence (31). In a large multisite European neuroimaging study, hyperactivity in superior frontal regions during reward processing at age 14 was predictive of initiation of alcohol use by age 16 (22). Greater brain activation while observing alcohol-related pictures predicted larger increases in drinking and more alcohol-related problems, beyond other measured risk factors, at a one year follow-up in a study of first-year college students (32). Increased saliency of alcohol-related cues and overactive reward response appear to make youth more vulnerable to substance use initiation. Overall, findings suggest that less brain activation during tasks of inhibition and working memory, as well as greater brain activation during reward processing and alcohol cue reactivity, could identify youth who are more likely to initiate substance use during adolescence. Findings suggest that prevention and intervention techniques that either boost executive functioning or dampen reward response could be helpful in delaying or avoiding early adolescent substance use.

Family history of alcohol use disorder

Experimentation with alcohol and drugs is characteristic of adolescence, but vulnerability for developing substance-related problems is especially heightened among individuals with a family history of substance use disorder (SUD) (33). While family history of various SUDs heightens risk for the development of the disorder in offspring (34), family history of alcohol use disorder (AUD) has been more extensively investigated (for detailed review, see (35)). In particular, adolescents with familial AUD (family history positive; FHP) are more likely to transition into hazardous drinking (36) and are 3–5 times more likely to go on to develop an AUD (37) than youth without a family history of alcoholism (FHN). A large portion of this research has aimed to uncover the neurobiological and behavioral markers that may increase risk for AUD in FHP adolescents who are largely alcohol and substance-naïve. Ultimately, the goal is to inform prevention efforts aimed at reducing the incidence of AUD, so that they may target specific behaviors or design interventions that strengthen and/or modify neural networks identified to contribute to the vulnerability for developing AUD in at-risk youth.

Neurocognitive functioning

FHP youth have shown differences in neurocognitive functioning from their FHN peers in various neuropsychological domains, including verbal and language abilities (38), visuospatial functioning (39), planning (40), and executive functioning (41–43). Importantly, studies of executive functioning have found weaknesses in FHP adolescents in different frontal lobe-mediated functions, including working memory (41), set-shifting (42), and response inhibition (43). Since AUD has been characterized by deficits in executive functioning (44), these findings may indicate the presence of early risk markers that may lead FHP adolescents to make poor decisions with regards to alcohol use.

Brain structure

Neuroimaging studies of FHP and FHN youth have contributed greatly to our understanding of the neurobiological underpinnings that may be related to heightened risk for developing AUD. Three important limbic structures involved in addiction have been examined in FHP youth, including the amygdala (45, 46), hippocampus (47), and NAcc (46). A study of FHP youth found smaller amygdalar volumes in FHP vs. FHN youth (45), although family history density (FHD) of AUD was unrelated to amygdalar volume in adolescents with no heavy alcohol or drug use (46). In another study, FHP males had larger left hippocampal volume than FHN males, suggesting that sex-specific patterns of family history risk may be present (47). This was also seen in a study that found FHD was significantly positively associated with left NAcc volume in adolescent girls (46). Future longitudinal studies should investigate how volumes of these subcortical structures may contribute to heavy alcohol use among FHP youth. Furthermore, it will be important to examine whether there are volumetric differences between FHP and FHN youth in other brain areas, such as the prefrontal cortex, since neuropsychological testing has shown executive functioning deficits among FHP adolescents (41–43).

Increases in white matter integrity are related to improvements in cognitive functioning during adolescence (48), but several studies have reported decreased white matter integrity in FHP adolescents (49, 50), with one exception (51). FHP youth have decreased white matter integrity in frontal cortical tracts such as the anterior corona radiata (49, 50), and long-range association tracts, such as the superior longitudinal fasciculus (49, 50), which connects frontal and parietal areas involved in top-down executive functioning. These findings may explain some of the executive functioning deficits reported on neuropsychological tests in FHP youth. Longitudinal studies will be able to elucidate whether these decreases in white matter integrity represent developmental delays in FHP adolescents, and/or contribute to hazardous drinking.

Both macro (45–47) and microstructural (49–51) investigations of brain morphometry in FHP adolescents suggest that gray and white matter development may be altered in youth with familial AUD, warranting further research to understand how brain structural alterations may represent risk factors for heavy alcohol use.

Brain function

FMRI studies of FHP adolescents have focused on brain activity during both task and resting conditions. During inhibitory control, FHP youth have shown less brain response in frontal and parietal cortex (52), which was also seen during cognitive control within emotional contexts (53), despite comparable behavioral performance between the groups. These two studies exemplify that inhibitory control weaknesses may be present in FHP youth, with the latter study highlighting the importance of examining inhibition within emotional contexts as day-to-day decision making may take place in heated situations that could promote risky decisions. However, other analyses found increased frontal brain response during inhibitory control in FHP youth (54) and positive associations between FHD and cognitive control (55), even in the absence of group differences in commission or interference errors. Thus, identifying whether task-related or analytical differences are related to discrepancies among findings is an important step for future studies.

While frontal and cerebellar response is lower in FHP youth during risky decision making relative to their FHN peers (56), studies of reward processing have not found differences in brain activity between FHP and FHN adolescents (57, 58), suggesting that reward salience may not be significantly different between FHP and FHN youth. On the other hand, reduced brain activity in response to emotional faces has been reported in FHP youth in temporal (53) and parietal (59) areas. Blunted emotional reactivity may be a risk factor that drives FHP youth to seek out emotionally arousing experiences, such as risky alcohol use.

Finally it should be noted, that differences in both task-related connectivity (60, 61) and resting state connectivity (53, 62) are present between FHP and FHN youth. Specifically, fronto-cerebellar (60) and fronto-parietal (61) synchrony is reduced in FHP vs. FHN youth. Furthermore, reward and cognitive control brain regions are less segregated in FHP youth compared with their FHN peers (62), which could suggest that miscommunication may occur between regions that process rewards (i.e. NAcc) and areas involved in inhibitory control (i.e. inferior frontal gyrus).

These fMRI investigations highlight that FHP youth consistently show altered brain activity during both executive functioning and emotional processing tasks compared with their FHN peers, and that some of these differences could be explained by neural connectivity of functional brain networks in FHP adolescents. Future longitudinal studies will need to examine if any of these neural markers explain increases in heavy alcohol use in FHP adolescents relative to their low-risk peers.

Neuroimaging data in the context of other important factors

Clearly other factors play an important role in adolescent substance use initiation, including demographic, behavioral, environmental, and personality factors. Two recent neuroimaging studies have attempted to incorporate the multitude of factors that are associated with adolescent substance use initiation (17, 22). In the most recent study, 12 to 14 year old substance-naïve youth underwent extensive clinical interviewing, neuropsychological testing, and neuroimaging (17). Youth were followed annually until age 18 and classified as either continuous non-users or moderate-to-heavy alcohol initiators. Machine learning was used to understand which variables best predict alcohol use outcomes based on demographic, behavioral, neuropsychological, and neuroimaging data. Thirty-four predictors were found to contribute to alcohol use by age 18. Demographic and behavioral factors included being male, coming from more affluent families, dating by age 14, endorsing more externalizing behaviors, and believing alcohol would affect them positively in social settings; neuropsychological factors included poorer executive functioning; and neuroimaging factors included thinner cortices and less brain activation during a visual working memory task in diffusely distributed regions of the brain, consistent with previous findings (7, 21, 26, 29, 30, 63). This study showed that multimodal neuroimaging data, as well as neuropsychological testing, is important in prediction of future behaviors. In a large European multisite neuroimaging study, a mix of history, personality, and brain factors at age 14 were able to predict which youth transitioned into alcohol use by age 16. The results indicated that romantic history (beta = −0.18), 1–2 alcohol use occasions by age 14 (beta = −0.18), reduced temporal and increased frontal response during reward outcome activity (beta = 0.23), greater frontal and sensorimotor response during failed inhibitory control (beta = 0.18), and smaller bilateral superior frontal gyrus and parahippocampal as well as larger premotor and postcentral gyrus gray matter volume (beta = 0.164), were some of the markers most predictive of future binge drinking at age 16 (22). Taken together, these studies suggest that neurocognitive and neuroimaging data can be useful in predicting future substance use behaviors. Future studies incorporating multiple predictors, as opposed to focusing on singular predictors, will be helpful in understanding the complex, multifaceted transition into adolescent substance use.

Conclusion

Neurocognitive aberrations predate initiation of alcohol use and appear to leave youth more vulnerable to engage in risk-taking behaviors like alcohol and drug use. Neuropsychological and neuroimaging studies show poorer performance on tasks of inhibition and working memory, smaller brain volumes in reward and cognitive control regions, less brain activation during executive functioning tasks, and hyperactivation during reward processing is predictive of youth who initiate substance use during adolescence. In FHP youth, poorer executive functioning, smaller amygdalar volume, and sex-specific patterns of hippocampal and nucleus accumbens volume been reported. Thus, there is significant overlap among the neural precursors shown to be predictive of alcohol and substance use initiation during adolescence and those that distinguish FHP and FHN youth. This suggests that particular attention should be given to at-risk FHP adolescents who may exhibit neurocognitive and neural vulnerabilities for future engagement in heavy alcohol and/or substance use.

To date, most of the reported findings are from high-functioning samples and examine risk factors for initiation into any and up to moderate levels of substance use, as opposed to problematic or severe levels of use. Furthermore, some effect sizes reported in the literature are quite small, potentially reducing their clinical relevance (e.g., (16). Larger sample sizes over multiple years are needed to further clarify the most important predictors of alcohol and drug use initiation versus escalation of problematic use during adolescence. Large-scale multisite studies are already underway, including the National Consortium on Alcohol and Neurodevelopment in Adolescence [NCANDA; (64); following >800 youth for at least 10 years] and the Adolescent Brain Cognitive Development (ABCD; http://abcdstudy.org/); following 11,500 youth for 10 years). These studies will help identify the most important risk factors for substance use along the spectrum of substance use. Understanding these factors may help identify at-risk youth for prevention efforts, as well as create interventions targeting cognitive weaknesses or brain regions involved in substance use initiation. For example, training self-control during childhood in both laboratory-based and ecologically valid (i.e. school, community, family) settings has shown success in improving executive functioning skills, and targeting the structure and/or function of the right inferior frontal gyrus may be one brain region that could support improvements in cognitive control (65). However, adolescents may require more tailored and direct interventions to benefit from self-control training compared with children who may exhibit greater brain plasticity amenable to interventions during earlier development (65). Furthermore, other cognitive control interventions for substance abuse, including mindfulness-based interventions that target the anterior cingulate cortex (66), and physical activity, which may modify prefrontal cortical activity (67) hold promise for improving neurocognitive functioning, and are currently being actively explored.

Highlights.

  • Adolescence is a period of vulnerability for developing substance use disorder.

  • Executive functioning deficits are predictive of substance use initiation.

  • Reduced brain volume and response are present prior to initiating substance use.

  • Youth with familial substance use disorder have altered brain structure/activity.

  • These findings may aid prevention studies aimed at reducing youth substance use.

Acknowledgments

Role of Funding Sources

Funding for this study was provided by NIDA grant K12 DA031794 (Squeglia) and K23 AA025399 (Squeglia). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

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Contributors

Authors Squeglia and Cservenka conducted literature searches and wrote and edited the first draft and revised version of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of Interest

All authors declare that they have no conflicts of interest.

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