, Volume 235, Issue 4, pp 1041–1054 | Cite as

Earlier alcohol use onset prospectively predicts changes in functional connectivity

  • Tam T. Nguyen-Louie
  • Alan N. Simmons
  • Lindsay M. Squeglia
  • M. Alejandra Infante
  • Joseph P. Schacht
  • Susan F. Tapert
Original Investigation



Half of all new alcohol initiates are between 12 and 17 years old. This is a period of intense neurodevelopment, including changes in functional connectivity patterns among higher-order function areas. It is crucial to understand how alcohol-related neurotoxicity may be influenced by drinking onset age.


This study prospectively examined the effects of age of first drink on frontoparietal context-dependent functional connectivity (cdFC) during a visual working memory task. Youth 13.5 years of age (SD = 1.2) underwent a neuropsychological and neuroimaging session before drinking initiation and at follow-up 6 years later. Hierarchical linear regressions examined if youth with earlier ages of onset for first and weekly alcohol use showed higher follow-up cdFC between the dorsolateral prefrontal cortex and posterior parietal cortex regions of interest and whole-brain exploratory regions, controlling for pre-drinking cdFC. Higher follow-up cdFC was hypothesized to be correlated with poorer performances in neuropsychological performance.


Exploratory whole-brain analyses showed that, as hypothesized, earlier ages of weekly drinking onset were associated with higher cdFC between the bilateral posterior cingulate and cortical and subcortical areas implicated in attentional processes, which was in turn associated with poorer performance on neuropsychological tasks of attention, ps < .05. No relationship between age of onset and cdFC between the two ROIs were found.


Earlier ages of weekly alcohol use initiation may adversely affect neurodevelopment by reducing developmentally appropriate integration of attentional circuits during a cognitive challenge. Delaying the onset of weekly alcohol use patterns well after early adolescence may reduce the risk for harm of alcohol use on the brain.


Anticorrelations Alcohol use Alcohol onset Context-dependent functional connectivity 



The authors thank the participants, family, and other informants; the San Diego Unified School District; and the outstanding research staff: Norma Castro, Claudia Cota, and Irene Lee. This study was supported by National Institute on Alcohol Abuse and Alcoholism Grants R01 AA13419, U01 AA021695 (PI: Tapert), T32 AA013525 (PI: Riley), and F31 AA024389 (PI: Nguyen-Louie).


  1. Achenbach T, Rescorla L (2003) Manual for the ASEBA adult forms & profiles. University of Vermont, Burlington, VTGoogle Scholar
  2. Achenbach TM (1991) Manual for the child behavior checklist/4-18 and 1991 profile. University of Vermont Burlington, VT, Department of PsychiatryGoogle Scholar
  3. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders 4th ed., text revision edn., Washington, DCGoogle Scholar
  4. Bandettini PA, Jesmanowicz A, Wong EC, Hyde JS (1993) Processing strategies for time-course data sets in functional MRI of the human brain. Magn Reson Med 30:161–173. CrossRefPubMedGoogle Scholar
  5. Barber AD, Caffo BS, Pekar JJ, Mostofsky SH (2013) Developmental changes in within- and between-network connectivity between late childhood and adulthood. Neuropsychologia 51(1):156–167. CrossRefPubMedGoogle Scholar
  6. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300Google Scholar
  7. Boly M, Moran R, Murphy M, Boveroux P, Bruno MA, Noirhomme Q, Ledoux D, Bonhomme V, Brichant JF, Tononi G, Laureys S, Friston K (2012) Connectivity changes underlying spectral EEG changes during propofol-induced loss of consciousness. J Neurosci 32(20):7082–7090. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Brown SA, Myers MG, Lippke L, Tapert SF, Stewart DG, Vik PW (1998) Psychometric evaluation of the Customary Drinking and Drug Use Record (CDDR): a measure of adolescent alcohol and drug involvement. J Stud Alcohol 59:427–438. CrossRefPubMedGoogle Scholar
  9. Cabeza R, Ciaramelli E, Olson IR, Moscovitch M (2008) The parietal cortex and episodic memory: an attentional account. Nat Rev Neurosci 9(8):613–625. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cahalan D, Cisin IH, Crossley HM (1969) American drinking practices: a national study of drinking behavior and attitudes. Monographs of the Rutgers Center of Alcohol StudiesGoogle Scholar
  11. Campanella S, Peigneux P, Petit G, Lallemand F, Saeremans M, Noël X, Metens T, Nouali M, de Tiège X, de Witte P, Ward R, Verbanck P (2013) Increased cortical activity in binge drinkers during working memory task: a preliminary assessment through a functional magnetic resonance imaging study. PLoS One 8(4):e62260. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cavanna AE, Trimble MR (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129(3):564–583. CrossRefPubMedGoogle Scholar
  13. Chafee MV, Goldman-Rakic PS (2000) Inactivation of parietal and prefrontal cortex reveals interdependence of neural activity during memory-guided saccades. J Neurophysiol 83(3):1550–1566. CrossRefPubMedGoogle Scholar
  14. Chai XJ, Ofen N, Gabrieli JD, Whitfield-Gabrieli S (2014) Selective development of anticorrelated networks in the intrinsic functional organization of the human brain. J Cogn Neurosci 26(3):501–513. CrossRefPubMedGoogle Scholar
  15. Chandler LJ (2003) Ethanol and brain plasticity: receptors and molecular networks of the postsynaptic density as targets of ethanol. Pharmacol Ther 99(3):311–326. CrossRefPubMedGoogle Scholar
  16. Chen G, Chen G, Xie C, Li SJ (2011) Negative functional connectivity and its dependence on the shortest path length of positive network in the resting-state human brain. Brain connectivity 1(3):195–206. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cohen JD, Perlstein WM, Braver TS, Nystrom LE, Noll DC, Jonides J, Smith EE (1997) Temporal dynamics of brain activation during a working memory task. Nature 386(6625):604–608. CrossRefPubMedGoogle Scholar
  18. Corbetta M, Shulman GL (2002) Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci 3(3):201–215. CrossRefPubMedGoogle Scholar
  19. Cox RW, Jesmanowicz A (1999) Real-time 3D image registration for functional MRI. Magn Reson Med 42(6):1014–1018Google Scholar
  20. Crews FT, Mdzinarishvili A, Kim D, He J, Nixon K (2006) Neurogenesis in adolescent brain is potently inhibited by ethanol. Neuroscience 137(2):437–445. CrossRefPubMedGoogle Scholar
  21. Crews FT, Vetreno RP, Broadwater MA, Robinson DL (2016) Adolescent alcohol exposure persistently impacts adult neurobiology and behavior. Pharmacol Rev 68(4):1074–1109. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Crone EA, Wendelken C, Donohue S, van Leijenhorst L, Bunge SA (2006) Neurocognitive development of the ability to manipulate information in working memory. Proc Natl Acad Sci 103(24):9315–9320. CrossRefPubMedPubMedCentralGoogle Scholar
  23. De Bellis MD, Clark DB, Beers SR, Soloff PH, Boring AM, Hall J, Kersh A, Keshavan MS (2000) Hippocampal volume in adolescent-onset alcohol use disorders. Am J Psychiatry 157(5):737–744. CrossRefPubMedGoogle Scholar
  24. Delis DC, Kaplan E, Kramer JH (2001) The Delis-Kaplan Executive Function System: examiner’s manual. The Psychological Corporation, San Antonio, TXGoogle Scholar
  25. Delis DC, Kramer JH, Kaplan E, Ober BA (2000) California Verbal Learning Test\. The Psychological Corporation, San Antonio, TXGoogle Scholar
  26. Demir B, Ulug BD, Ergun EL, Erbas B (2002) Regional cerebral blood flow and neuropsychological functioning in early and late onset alcoholism. Psychiatry Res Neuroimaging 115(3):115–125. CrossRefPubMedGoogle Scholar
  27. Doremus TL, Brunell SC, Varlinskaya EI, Spear LP (2003) Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats. Pharmacol Biochem Behav 75(2):411–418. CrossRefPubMedGoogle Scholar
  28. Falk DE, Yi HY, Hilton ME (2008) Age of onset and temporal sequencing of lifetime DSM-IV alcohol use disorders relative to comorbid mood and anxiety disorders. Drug Alcohol Depen 94(1-3):234–245. CrossRefGoogle Scholar
  29. Finn PR, Rickert ME, Miller MA, Lucas J, Bogg T, Bobova L, Cantrell H (2009) Reduced cognitive ability in alcohol dependence: examining the role of covarying externalizing psychopathology. J Abnorm Psychol 118(1):100–116. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME (2005) The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A 102(27):9673–9678. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ (1997) Psychophysiological and modulatory interactions in neuroimaging. NeuroImage 6(3):218–229. CrossRefPubMedGoogle Scholar
  32. Gitelman DR, Penny WD, Ashburner J, Friston KJ (2003) Modeling regional and psychophysiologic interactions in fMRI: the importance of hemodynamic deconvolution. NeuroImage 19(1):200–207. CrossRefPubMedGoogle Scholar
  33. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM (2004) Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci 101(21):8174–8179. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Grant JD et al (2005) Adolescent alcohol use is a risk factor for adult alcohol and drug dependence: evidence from a twin design. Psychol Med 36(01):109–118. CrossRefPubMedGoogle Scholar
  35. Greenough WT, Black JE, Wallace CS (1987) Experience and brain-development. Child Dev 58(3):539–559. CrossRefPubMedGoogle Scholar
  36. Hampshire A, Chamberlain SR, Monti MM, Duncan J, Owen AM (2010) The role of the right inferior frontal gyrus: inhibition and attentional control. NeuroImage 50(3):1313–1319. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Hampson M, Driesen NR, Skudlarski P, Gore JC, Constable RT (2006) Brain connectivity related to working memory performance. J Neurosci 26(51):13338–13343. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Hawkins JD, Graham JW, Maguin E, Abbott R, Hill KG, Catalano RF (1997) Exploring the effects of age of alcohol use initiation and psychosocial risk factors on subsequent alcohol misuse. J Stud Alcohol 58(3):280–290. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Herting MM, Fair D, Nagel BJ (2011) Altered fronto-cerebellar connectivity in alcohol-naive youth with a family history of alcoholism. NeuroImage 54(4):2582–2589. CrossRefPubMedGoogle Scholar
  40. Isbell E, Fukuda K, Neville HJ, Vogel EK (2015) Visual working memory continues to develop through adolescence. Front Psychol 6:696. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Jo HJ, Saad ZS, Simmons WK, Milbury LA, Cox RW (2010) Mapping sources of correlation in resting state FMRI, with artifact detection and removal. NeuroImage 52(2):571–582. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Johnston LD, O'Malley PM, Miech RA, Bachman JG, Schulenberg JE (2017) Monitoring the future national survey results on drug use, 1975–2016: overview, key findings on adolescent drug use. Institute for Social Research, The University of Michigan, Ann ArborGoogle Scholar
  43. Kelly AMC, Uddin LQ, Biswal BB, Castellanos FX, Milham MP (2008) Competition between functional brain networks mediates behavioral variability. NeuroImage 39(1):527–537. CrossRefPubMedGoogle Scholar
  44. Kessler RC, Crum RM, Warner LA, Nelson CB, Schulenberg J, Anthony JC (1997) Lifetime co-occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the national comorbidity survey. Arch Gen Psychiatry 54(4):313–321. CrossRefPubMedGoogle Scholar
  45. Lewis R, Rennick P (1979) Manual for the repeatable cognitive-perceptual-motor battery. Axon, Gross Point, MIGoogle Scholar
  46. Lipari RN, Williams MR, Copello EAP, Pemberton MR (2016) Risk and protective factors and estimates of substance use initiation: results from the 2015 national survey on drug use and health. NSDUH Data ReviewGoogle Scholar
  47. Luck SJ, Vogel EK (1997) The capacity of visual working memory for features and conjunctions. Nature 390(6657):279–281. CrossRefPubMedGoogle Scholar
  48. Maurage P, Bestelmeyer PE, Rouger J, Charest I, Belin P (2013) Binge drinking influences the cerebral processing of vocal affective bursts in young adults. NeuroImage 3:218–225. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Medina KL, Nagel BJ, Park A, McQueeny T, Tapert SF (2007) Depressive symptoms in adolescents: associations with white matter volume and marijuana use. J Child Psychol Psychiatry 48(6):592–600. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Morris SA, Eaves DW, Smith AR, Nixon K (2010) Alcohol inhibition of neurogenesis: a mechanism of hippocampal neurodegeneration in an adolescent alcohol abuse model. Hippocampus 20:596–607. PubMedPubMedCentralGoogle Scholar
  51. Newson R (2003) Multiple-test procedures and smile plots. Stata J 3:109–132Google Scholar
  52. Nguyen-Louie TT, Castro N, Matt GE, Squeglia LM, Brumback T, Tapert SF (2015) Effects of emerging alcohol and marijuana use behaviors on adolescents’ neuropsychological functioning over four years. J Stud Alcohol Drugs 76(5):738–748. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Nguyen-Louie TT, Courtney KE, Squeglia LM, Bagot K, Eberson S, Migliorini R, Alcaraz AR, Tapert SF, Pulido C (2017) Prospective changes in neural alcohol cue reactivity in at-risk adolescents. Brain imaging and behavior.
  54. Østby Y, Tamnes CK, Fjell AM, Westlye LT, Due-Tønnessen P, Walhovd KB (2009) Heterogeneity in subcortical brain development: a structural magnetic resonance imaging study of brain maturation from 8 to 30 years. J Neurosci 29(38):11772–11782. CrossRefPubMedGoogle Scholar
  55. Paulus MP, Tapert SF, Pulido C, Schuckit MA (2006) Alcohol attenuates load-related activation during a working memory task: relation to level of response to alcohol. Alcohol Clin Exp Res 30(8):1363–1371. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Pechansky F, Szobot CM, Scivoletto S (2004) Alcohol use among adolescents: concepts, epidemiological characteristics and etiopatogenic factors. Revista Brasileira de Psiquiatria 26:14-17 doi:/S1516-44462004000500005Google Scholar
  57. Peeters M, Monshouwer K, Janssen T, Wiers RW, Vollebergh WAM (2014) Working memory and alcohol use in at-risk adolescents: a 2-year follow-up. Alcohol Clin Exp Res 38:1176–1183 doi:10.1111/acer.12339Google Scholar
  58. Rey A, Osterrieth PA (1993) Translations of excerpts from Andre Rey's "Psychological examination of traumatic encephalopathy" and P.A. Osterrieth's "The complex figure copy test" vol 7. Clin NeuropsycholGoogle Scholar
  59. Rohde P, Lewinsohn PM, Seeley JR (1996) Psychiatric comorbidity with problematic alcohol use in high school students. J Am Acad Child Adolesc Psychiatry 35(1):101–109. CrossRefPubMedGoogle Scholar
  60. SAMHSA (2013) Results from the 2012 National Survey on Drug Use and Health: summary of national findings. NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services AdministrationGoogle Scholar
  61. Schweinsburg AD, Schweinsburg BC, Nagel BJ, Eyler LT, Tapert SF (2011) Neural correlates of verbal learning in adolescent alcohol and marijuana users. Addiction 106(3):564–573. CrossRefPubMedGoogle Scholar
  62. Shokri-Kojori E, Tomasi D, Wiers CE, Wang GJ, Volkow ND (2016) Alcohol affects brain functional connectivity and its coupling with behavior: greater effects in male heavy drinkers. Mol Psychiatry 22(8):1185–1195. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Shrier LA, Emans J, Woods ER, DuRant RH (1997) The association of sexual risk behaviors and problem drug behaviors in high school students. J Adolesc Health 20(5):377–383. CrossRefPubMedGoogle Scholar
  64. Shulman GL, Astafiev SV, Franke D, Pope DL, Snyder AZ, McAvoy MP, Corbetta M (2009) Interaction of stimulus-driven reorienting and expectation in ventral and dorsal frontoparietal and basal ganglia-cortical networks. J Neurosci 29(14):4392–4407. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Silveri MM, Spear LP (1998) Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny. Alcohol Clin Exp Res 22(3):670–676. CrossRefPubMedGoogle Scholar
  66. Singh-Curry V, Husain M (2009) The functional role of the inferior parietal lobe in the dorsal and ventral stream dichotomy. Neuropsychologia 47(6):1434–1448. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Sobell L, Sobell M (1992) Timeline Follow-Back. In: Litten R, Allen J (eds) Measuring alcohol consumption. Humana Press, pp 41–72.
  68. Sobell LC, Maisto SA, Sobell MB, Cooper AM (1979) Reliability of alcohol abusers’ self-reports of drinking behavior. Behav Res Ther 17(2):157–160. CrossRefPubMedGoogle Scholar
  69. Somerville LH (2016) Searching for signatures of brain maturity: what are we searching for? Neuron 92(6):1164–1167. CrossRefPubMedGoogle Scholar
  70. Spadoni AD, Simmons AN, Yang TT, Tapert SF (2013) Family history of alcohol use disorders and neuromaturation: a functional connectivity study with adolescents. Am J Drug Alcohol Abuse 39(6):356–364. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Squeglia LM, Schweinsburg AD, Pulido C, Tapert SF (2011) Adolescent binge drinking linked to abnormal spatial working memory brain activation: differential gender effects. Alcohol Clin Exp Res 35(10):1831–1841. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Squeglia LM, Spadoni AD, Infante MA, Myers MG, Tapert SF (2009) Initiating moderate to heavy alcohol use predicts changes in neuropsychological functioning for adolescent girls and boys. Psychol Addict Behav 23(4):715–722. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Stevens MC, Pearlson GD, Calhoun VD (2009) Changes in the interaction of resting-state neural networks from adolescence to adulthood. Hum Brain Mapp 30(8):2356–2366. CrossRefPubMedGoogle Scholar
  74. Strauss E, Sherman EM, Spreen O (2006) A compendium of neuropsychological tests: administration, norms, and commentary. American Chemical SocietyGoogle Scholar
  75. Talairach J, Tournoux P (1988) Three-dimensional coplanar stereotaxic atlas of the human brain proportional system: an approach to cerebral imaging. Thieme, New YorkGoogle Scholar
  76. Tapert SF, Schweinsburg AD, Barlett VC, Brown SA, Frank LR, Brown GG, Meloy MJ (2004) Blood oxygen level dependent response and spatial working memory in adolescents with alcohol use disorders. Alcohol Clin Exp Res 28(10):1577–1586. CrossRefPubMedGoogle Scholar
  77. Thiel CM, Zilles K, Fink GR (2004) Cerebral correlates of alerting, orienting and reorienting of visuospatial attention: an event-related fMRI study. NeuroImage 21:318–328.
  78. Varlinskaya EI, Spear LP (2002) Acute effects of ethanol on social behavior of adolescent and adult rats: role of familiarity of the test situation. Alcohol Clin Exp Res 26(10):1502–1511. CrossRefPubMedGoogle Scholar
  79. Wager TD, Smith EE (2003) Neuroimaging studies of working memory: a meta-analysis. Cogn Affect Behav Neurosci 3(4):255–274. CrossRefPubMedGoogle Scholar
  80. Wechsler D (1997) Wechsler Adult Intelligence Scale, 3rd edn. The Psychological Corporation, New YorkGoogle Scholar
  81. Wechsler D (1999) Wechsler Abbreviated Scale of Intelligence. The Psychological Corporation, San Antonio, TXGoogle Scholar
  82. Weissman DG et al (2015) Earlier adolescent substance use onset predicts stronger connectivity between reward and cognitive control brain networks. Dev Cogn Neurosci 16:121–129. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Wetherill RR, Bava S, Thompson WK, Boucquey V, Pulido C, Yang TT, Tapert SF (2012) Frontoparietal connectivity in substance-naive youth with and without a family history of alcoholism. Brain Res 1432:66–73. CrossRefPubMedGoogle Scholar
  84. Wetherill RR, Castro N, Squeglia LM, Tapert SF (2013) Atypical neural activity during inhibitory processing in substance-naive youth who later experience alcohol-induced blackouts. Drug Alcohol Depen 128(3):243–249. CrossRefGoogle Scholar
  85. White AM, Truesdale MC, Bae JG, Ahmad S, Wilson WA, Best PJ, Swartzwelder HS (2002) Differential effects of ethanol on motor coordination in adolescent and adult rats. Pharmacol Biochem Behav 73(3):673–677. CrossRefPubMedGoogle Scholar
  86. Zhou Y, Liang M, Jiang T, Tian L, Liu Y, Liu Z, Liu H, Kuang F (2007) Functional dysconnectivity of the dorsolateral prefrontal cortex in first-episode schizophrenia using resting-state fMRI. Neurosci Lett 417(3):297–302. CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.San Diego State University/University of California San Diego Joint Doctoral Program in Clinical PsychologySan DiegoUSA
  2. 2.Department of PsychiatryUniversity of California San DiegoSan DiegoUSA
  3. 3.Department of Psychiatry and Behavioral SciencesMedical University of South CarolinaCharlestonUSA

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