Behavior Genetics

, Volume 46, Issue 3, pp 467–477 | Cite as

Pre- and Perinatal Ischemia-Hypoxia, the Ischemia-Hypoxia Response Pathway, and ADHD Risk

  • Taylor F. Smith
  • Rainald Schmidt-Kastner
  • John E. McGeary
  • Jessica A. Kaczorowski
  • Valerie S. Knopik
Original Research


This review focuses on how measured pre- and perinatal environmental and (epi)genetic risk factors are interrelated and potentially influence one, of many, common developmental pathway towards ADHD. Consistent with the Developmental Origins of Health and Disease hypothesis, lower birth weight is associated with increased ADHD risk. Prenatal ischemia-hypoxia (insufficient blood and oxygen supply in utero) is a primary pathway to lower birth weight and produces neurodevelopmental risk for ADHD. To promote tissue survival in the context of ischemia-hypoxia, ischemia-hypoxia response (IHR) pathway gene expression is altered in the developing brain and peripheral tissues. Although altered IHR gene expression is adaptive in the context of ischemia-hypoxia, lasting IHR epigenetic modifications may lead to increased ADHD risk. Taken together, IHR genetic vulnerability to ischemia-hypoxia and IHR epigenetic alterations following prenatal ischemia-hypoxia may result in neurodevelopmental vulnerability for ADHD. Limitations of the extant literature and future directions for genetically-informed research are discussed.


ADHD Prenatal Ischemia Hypoxia Epigenetic Developmental pathway 



Authors were supported by the following sources: T32MH19927 and RSCA award California Polytechnic State University (Smith) and DA023134 (Knopik). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veteran Affairs.

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 review article does not contain any studies with human or animal subjects performed by any of the authors.

Supplementary material

10519_2016_9784_MOESM1_ESM.docx (1.1 mb)
Basal expression of CCBL1, CCBL2, IL16, NRP1, NRP2, NTRK1, and NTRK3 (see Smith et al. 2014) probes in the prefrontal cortex across development. Developmental expression profiles were created using BrainCloud (Colantuoni et al. 2011; Supplementary material 1 (DOCX 1167 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Psychology and Child DevelopmentCalifornia Polytechnic State UniversitySan Luis ObispoUSA
  2. 2.Division of Behavioral Genetics, Rhode Island Hospital and Department of Psychiatry and Human BehaviorWarren Alpert Medical School of Brown UniversityProvidenceUSA
  3. 3.Integrated Medical Science Department, CE Schmidt College of MedicineFlorida Atlantic University (FAU)Boca RatonUSA
  4. 4.Providence VA Medical CenterProvidenceUSA

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