Orbitofrontal cortex thickness and substance use disorders in emerging adulthood: causal inferences from a co-twin control/discordant twin study

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Background/aims: Research linking orbitofrontal cortex (OFC) structure and substance use disorders (SUDs) is largely correlational and often implies a causal effect of addiction/substance exposure on the brain, but familial risk factors (e.g. genetic liability) may confound these associations. We tested whether associations between alcohol, cannabis and tobacco use disorders and OFC thickness reflected the potential causal effects of familial risk or SUDs-related consequences (e.g. substance exposure). Design: A co-twin control/discordant twin design separated familial risk confounding from SUD-related consequences. Setting/participants: A population-based sample of 436 24-year-old twins (62% monozygotic) from the Minnesota Twin Family Study, USA. Measurements: Alcohol, cannabis and tobacco use disorders were assessed using the Composite International Diagnostic Interview—Substance Abuse Module. Cortical thickness of the medial and lateral OFC (mOFC and lOFC, respectively) was assessed using magnetic resonance imaging (MRI). Findings: Lower mOFC (P-values ≤ 0.006) but not lOFC (P-values ≥ 0.190) thickness was observed in diagnosed individuals (n = 185) relative to non-SUD controls (n = 251). Co-twin control analyses offered evidence that mOFC associations were consistent with familial risk across SUDs (between-pair effect: P-values ≤ 0.047) and the independent consequences of having an alcohol or cannabis use disorder (within-pair effect: P-values ≤ 0.024). That is, within alcohol/cannabis discordant twin pairs, affected twins had significantly lower mOFC thickness compared with their unaffected co-twins. Conclusions: A confounder-adjusted analysis of the Minnesota Twin Family Study appeared to indicate that, beyond a substance use disorders general familial risk effect, the experience of an alcohol or cannabis use disorder in emerging adulthood reduces the thickness of the medial orbitofrontal cortex, a region associated with value-guided decision-making.

Original languageEnglish (US)
Early online dateFeb 23 2021
StateE-pub ahead of print - Feb 23 2021

Bibliographical note

Funding Information:
This work was supported by National Institute on Drug Abuse grants R01DA036216 and K01DA037280 and National Institute on Alcohol Abuse and Alcoholism grants R21AA026632 and R21AA026919. J.H. was supported by National Institute on Drug Abuse grant T32DA037183, the University of Minnesota College of Liberal Arts Eva O. Miller Fellowship, and the National Science Foundation Graduate Research Fellowship under Grant no. 00039202. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The authors acknowledge the Minnesota Supercomputing Institute (MSI; http://www.msi.umn.edu ) and the Center for Magnetic Resonance Research (supported by grants NIBIB P41 EB027061 and 1S10OD017974‐01) at the University of Minnesota for providing resources that contributed to the research results reported within this paper.

Publisher Copyright:
© 2021 Society for the Study of Addiction

Copyright 2021 Elsevier B.V., All rights reserved.


  • Addiction
  • alcohol
  • cannabis
  • co-twin control analysis
  • discordant twin design
  • emerging adulthood
  • endophenotype
  • orbitofrontal cortex
  • substance use disorders
  • tobacco

PubMed: MeSH publication types

  • Journal Article

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