Review of Neurobiological Influences on Externalizing and Internalizing Pathways to Alcohol Use Disorder
Purpose of Review
Two developmental courses through which alcohol use disorder (AUD) may emerge include externalizing and internalizing pathways. We review recent neuroimaging studies of potential neural risk factors for AUD and link findings to potential behavioral risk factors for AUD.
There is evidence that early emerging weakness in prefrontal functioning and later-emerging differences in reward system functioning contribute to an externalizing risk pathway. Stress may be an important contributor in the internalizing pathway through a blunting of reward-related activation, which may act alone or in combination with heightened emotion-related reactivity.
This review highlights areas for future work, including investigation of the relative balance between prefrontal and subcortical circuitry, attention to stages of AUD, and consideration of environmental factors such as stress and sleep. Particularly important is longitudinal work to understand the temporal ordering of associations among brain maturation, behavioral risk, and alcohol use.
KeywordsAdolescence Stress Sleep Emotion Reward Inhibitory control
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.Miech RA, Johnston LD, O'Malley PM, Bachman JG, Schulenberg JE, Patrick ME. Monitoring the future national survey results on drug use, 1975–2017: volume I, secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan 2018.Google Scholar
- 2.Schulenberg JE, Johnston LD, O'Malley PM, Bachman JG, Miech RA, Patrick ME. Monitoring the future national survey results on drug use, 1975–2017: volume II, college students and adults ages 19–55. Ann Arbor: Institute for Social Research, The University of Michigan, 2018.Google Scholar
- 3.2016 National Survey on drug use and health: detailed tables. Rockville MD: Substance Abuse and Mental Health Services Administration: Center for Behavioral Health Statistics and Quality 2017.Google Scholar
- 4.Casey BJ. Beyond simple models of self-control to circuit-based accounts of adolescent behavior. Annu Rev Psychol. 2015;66:295–319. https://doi.org/10.1146/annurev-psych-010814-015156.CrossRefPubMedGoogle Scholar
- 7.Hussong AM, Rothenberg WA, Smith RK, Haroon M. Implications of heterogeneity in alcohol use disorders for understanding developmental pathways and prevention programming. In: Fitzgerald HE, Puttler LI, editors. Alcohol use disorders: a developmental science approach to etiology. New York: Oxford University Press; 2018. p. 30–8.Google Scholar
- 10.Heitzeg MM, Nigg JT, Hardee JE, Soules M, Steinberg D, Zubieta JK, et al. Left middle frontal gyrus response to inhibitory errors in children prospectively predicts early problem substance use. Drug Alcohol Depend. 2014;141:51–7. https://doi.org/10.1016/j.drugalcdep.2014.05.002.CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Whelan R, Watts R, Orr CA, Althoff RR, Artiges E, Banaschewski T, et al. Neuropsychosocial profiles of current and future adolescent alcohol misusers. Nature. 2015;512:185–9. https://doi.org/10.1038/nature13402.Neuropsychosocial.CrossRefGoogle Scholar
- 14.• Heitzeg MM, Villafuerte S, Weiland BJ, Enoch MA, Burmeister M, Zubieta JK, et al. Effect of GABRA2 genotype on development of incentive-motivation circuitry in a sample enriched for alcoholism risk. Neuropsychopharmacology. 2014;39(13):3077–86. https://doi.org/10.1038/npp.2014.161 This is the first study to demonstrate that risk-related reward activation may be developmentally modulated. CrossRefPubMedPubMedCentralGoogle Scholar
- 16.• Waller R, Murray L, Shaw DS, Forbes EE, Hyde LW. Accelerated alcohol use across adolescence predicts early adult symptoms of alcohol use disorder via reward-related neural function. Psychol Med. 2018:1–10. doi: https://doi.org/10.1017/S003329171800137X.. Using a novel analytic approach, this study identified linkages between alcohol use trajectories during adolescence, reward reactivity in the ventral striatum during young adulthood, and later alcohol use disorder symptoms in a large community sample.
- 18.•• Khurana A, Romer D, Betancourt LM, Brodsky NL, Giannetta JM, Hurt H. Experimentation versus progression in adolescent drug use: A test of an emerging neurobehavioral imbalance model. Dev Psychopathol. 2015;27(3):901–13. https://doi.org/10.1017/s0954579414000765 This paper found that heightened reward-seeking balanced by strong executive control was associated with substance use experimentation, whereas heightened reward-seeking and weak executive control was associated with progression of substance use. This is important work highlighting the importance of considering the balance between executive and reward systems and stages of substance use. CrossRefPubMedGoogle Scholar
- 19.Kim-Spoon J, Deater-Deckard K, Holmes C, Lee J, Chiu P, King-Casas B. Behavioral and neural inhibitory control moderates the effects of reward sensitivity on adolescent substance use. Neuropsychologia. 2016;91:318–26. https://doi.org/10.1016/j.neuropsychologia.2016.08.028.CrossRefPubMedPubMedCentralGoogle Scholar
- 20.• Lopez-Vergara HI, Merrill JE, Janssen T, Jackson KM. Social and individual-level predictors of alcohol use initiation and escalation: replicating and extending tests of differential effects. J Studies Alcohol Drugs. 2017;78(3):452–7. https://doi.org/10.15288/jsad.2017.78.452 One of the largest prospective studies of alcohol-naïve youth, this 3-year study focused on risk factors (including sensation-seeking) for alcohol initiation and use. CrossRefGoogle Scholar
- 22.Fava NM, Trucco EM, Martz ME, Cope LM, Jester JM, Zucker RA et al. Childhood adversity, externalizing behavior, and substance use in adolescence: mediating effects of anterior cingulate cortex activation during inhibitory errors. Dev Psychopathol In press.Google Scholar
- 24.•• Nikolova YS, Knodt AR, Radtke SR, Hariri AR. Divergent responses of the amygdala and ventral striatum predict stress-related problem drinking in young adults: possible differential markers of affective and impulsive pathways of risk for alcohol use disorder. Mol Psychiatry. 2016;21:348–56. https://doi.org/10.1016/j.cogdev.2010.08.003.Personal This study is the first to identify distinct internalizing and externalizing pathways to problem drinking and how these risk phenotypes are associated with recent life stress. It is an important large cross-sectional study of older adolescents and young adults examining how stress and drinking affect two neural pathways associated with AUD risk: a positive emotion enhancement and behavioral impulsivity pathway, and a negative emotion relief and coping pathway. CrossRefPubMedGoogle Scholar
- 25.Telzer EH, Fuligni A, Lieberman MD, Galvan A. The effects of poor sleep quality on brain function and risk taking in adolescence. NeuroImage. 2013;71:275–83. https://doi.org/10.1111/j.1743-6109.2008.01122.x.Endothelial.CrossRefPubMedGoogle Scholar
- 30.• Heitzeg MM, Cope LM, Martz ME, Hardee JE. Neuroimaging risk markers for substance abuse: recent findings on inhibitory control and reward system functioning. Curr Addict Reports. 2015;2(2):91–103. https://doi.org/10.1007/s40429-015-0048-9 Review paper that summarizes and discusses the functional neuroimaging literature on inhibitory control and reward in the context of risk for substance use disorder. CrossRefGoogle Scholar
- 33.Dick DM, Latendresse SJ, Lansford JE, Budde JP, Goate A, Dodge KA, et al. Role of GABRA2 in trajectories of externalizing behavior across development and evidence of moderation by parental monitoring. Arch Gen Psychiatry. 2009;66(6):649–57. https://doi.org/10.1001/archgenpsychiatry.2009.48.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Heitzeg MM, Casey BJ. Brain development and the risk for substance abuse. In: Charney DS, Nestler EJ, Sklar P, Buxbaum J, editors. Charney & Nestler’s Neurobiology of Mental Illness. 5th ed. New York: Oxford University Press; 2018. p. 629–39.Google Scholar
- 36.Zuckerman M. Behavioral expressions and biosocial bases of sensation seeking. New York: Cambridge University Press; 1994.Google Scholar
- 46.• Hardee JE, Cope LM, Munier EC, Welsh RC, Zucker RA, Heitzeg MM. Sex differences in the development of emotion circuitry in adolescents at risk for substance abuse: a longitudinal fMRI study. Soc Cogn Affect Neurosci. 2017;12(6):965–75. https://doi.org/10.1093/scan/nsx021 A unique longitudinal study examining sex differences in emotion processing neurocircuitry and one of the few studies to directly examine internalizing symptomatology in at-risk adolescents. CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Hulvershorn LA, Finn P, Hummer TA, Leibenluft E, Ball B, Gichina V, et al. Cortical activation deficits during facial emotion processing in youth at high risk for the development of substance use disorders. Drug Alcohol Depend. 2013;131(3):230–7. https://doi.org/10.1016/j.drugalcdep.2013.05.015.CrossRefPubMedPubMedCentralGoogle Scholar
- 56.• Hussong AM, Ennett ST, Cox MJ, Haroon M. A systematic review of the unique prospective association of negative affect symptoms and adolescent substance use controlling for externalizing symptoms. Psychol Addict Behav. 2017;31(2):137–47. https://doi.org/10.1037/adb0000247 An important review paper that demonstrates the importance of controlling for externalizing symptoms and attending to subtypes of internalizing problems and specific substance use outcomes in studies investigating associations between negative affect and addiction risk. CrossRefPubMedPubMedCentralGoogle Scholar
- 58.Schulenberg JE, Maslowsky J, Patrick ME, Martz ME. Substance use in the context of adolescent development. In: Brown SA, Zucker RA, editors. The Oxford handbook of adolescent substance abuse. New York: Oxford University Press; 2016.Google Scholar
- 62.Keren H, O’Callaghan G, Vidal-Ribas P, Buzzell GA, Brotman MA, Leibenluft E et al. Reward processing in depression: a conceptual and meta-analytic review across fMRI and EEG studies. Am J Psychiatry. 2018:appiajp201817101124. doi: https://doi.org/10.1176/appi.ajp.2018.17101124.CrossRefGoogle Scholar
- 67.Conroy DA, Hairston IS, Zucker RA, Heitzeg MM. Sleep patterns in children of alcoholics and the relationship with parental reports. Austin J Sleep Disorders. 2015;2(1):1009.Google Scholar