Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Research
  • Published:
Behavior Genetics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders: DSM-5. Am Psychiatr Assoc, Arlington

    Book  Google Scholar 

  • Angold A, Costello EJ, Erkanli A (1999) Comorbidity. J Child Psychol Psychiatry 40(1):57–87

    Article  PubMed  Google Scholar 

  • Back S, Rosenberg P (2014) Pathophysiology of glia in perinatal white matter injury. Glia 62(11):1790

    Article  PubMed  PubMed Central  Google Scholar 

  • Barbaresi WJ, Colligan RC, Weaver AL, Voigt RG, Killian JM, Katusic SK (2013) Mortality, ADHD, and psychosocial adversity in adults with childhood ADHD: a prospective study. Pediatrics 131(4):637–644

    Article  PubMed  PubMed Central  Google Scholar 

  • Barker DJP (2007) The origins of the developmental origins theory. J Intern Med 261(5):412–417

    Article  PubMed  Google Scholar 

  • Bassan H, Kidron D, Bassan M, Rotstein M, Kariv N, Giladi E, Davidson A, Gozes I, Harel S (2010) The effects of vascular intrauterine growth retardation on cortical astrocytes. J Matern Fetal Neonatal Med 23(7):595–600

    Article  PubMed  Google Scholar 

  • Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366(9481):237–248

    Article  PubMed  Google Scholar 

  • Bjelke B, Andersson K, Ogren SO, Bolme P (1991) Asphyctic lesion: proliferation of tyrosine hydroxylase-immunoreactive nerve cell bodies in the rat substantia nigra and functional changes in dopamine neurotransmission. Brain Res 543(1):1–9

    Article  PubMed  Google Scholar 

  • Boksa P, El-Khodor BF (2003) Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: possible implications for schizophrenia and other disorders. Neurosci Biobehav Rev 27(1–2):91–101

    Article  PubMed  Google Scholar 

  • Bosco C, Diaz E (2012) Placental hypoxia and foetal development versus alcohol exposure in pregnancy. Alcohol Alcohol 47(2):109–117

    Article  PubMed  Google Scholar 

  • Boulet SL, Schieve LA, Boyle CA (2011) Birth weight and health and developmental outcomes in US children, 1997–2005. Matern Child Health J 15(7):836–844

    Article  PubMed  Google Scholar 

  • Breslau N, Brown G, DelDotto J, Kumar S, Ezhuthachan S, Andreski P, Hufnagle K (1996) Psychiatric sequelae of low birth weight at 6 years of age. J Abnorm Child Psychol 24(3):385–400

    Article  PubMed  Google Scholar 

  • Brown N, Inder T, Bear M, Hunt R, Anderson P, Doyle L (2009) Neurobehavior at term and white and gray matter abnormalities in very preterm infants. J Pediatr 155(1):32–38

    Article  PubMed  Google Scholar 

  • Bush PG, Mayhew TM, Abramovich DR, Aggett PJ, Burke MD, Page KR (2000) Maternal cigarette smoking and oxygen diffusion across the placenta. Placenta 21(8):824–833

    Article  PubMed  Google Scholar 

  • Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3(8):617–628

    Article  PubMed  Google Scholar 

  • Chen Y, Hillefors-Berglund M, Herrera-Marschitz M, Bjelke B, Gross J, Andersson K, von Euler G (1997) Perinatal asphyxia induces long-term changes in dopamine D1, D2, and D3 receptor binding in the rat brain. Exp Neurol 146(1):74–80

    Article  PubMed  Google Scholar 

  • Class QA, Rickert ME, Larsson H, Lichtenstein P, D’Onofrio BM (2014) Fetal growth and psychiatric and socioeconomic problems: population-based sibling comparison. Br J Psychiatry 205(5):355–361

    Article  PubMed  PubMed Central  Google Scholar 

  • Colantuoni C, Lipska BK, Ye TZ, Hyde TM, Tao R, Leek JT, Colantuoni EA, Elkahloun AG, Herman MM, Weinberger DR, Kleinman JE (2011) Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478:519–524

    Article  PubMed  PubMed Central  Google Scholar 

  • Day K, Waite L, Thalacker-Mercer A, West A, Bamman M, Brooks J, Myers R, Absher D (2013) Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome Biol 14(9):R102

    Article  PubMed  PubMed Central  Google Scholar 

  • Dela Cruz JA, Schmidt-Kastner R, Stevens JA, Steinbusch HW, Rutten BP (2014) Differential distribution of hypoxia-inducible factor 1-beta (ARNT or ARNT2) in mouse substantia nigra and ventral tegmental area. J Chem Neuroanat 61–62:64–71

    Article  PubMed  Google Scholar 

  • Derrick M, Drobyshevsky A, Ji X, Tan S (2007) A model of cerebral palsy from fetal hypoxia-ischemia. Stroke 38(2 Suppl):731–735

    Article  PubMed  Google Scholar 

  • Dick DM, Agrawal A, Keller MC, Adkins A, Aliev F, Monroe S, Hewitt JK, Kendler KS, Sher KJ (2015) Candidate gene-environment interaction research: reflections and recommendations. Perspect Psychol Sci 10(1):37–59

    Article  PubMed  PubMed Central  Google Scholar 

  • Doshi JA, Hodgkins P, Kahle J, Sikirica V, Cangelosi MJ, Setyawan J, Erder MH, Neumann PJ (2012) Economic impact of childhood and adult attention-deficit/hyperactivity disorder in the United States. J Am Acad Child Adolesc Psychiatry 51(10):990–1002

    Article  PubMed  Google Scholar 

  • Elgen I, Sommerfelt K, Markestad T (2003) Population based, controlled study of behavioural problems and psychiatric disorders in low birthweight children at 11 years of age. Obstet Gynecol Surv 58(2):103

    Article  Google Scholar 

  • Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, Sleiman PM, Zhang H, Kim CE, Robison R (2012) Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44(1):78–84

    Article  PubMed Central  Google Scholar 

  • Ellison VJ, Mocatta TJ, Winterbourn CC, Darlow BA, Volpe JJ, Inder TE (2005) The relationship of CSF and plasma cytokine levels to cerebral white matter injury in the premature newborn. Pediatr Res 57(2):282–286

    Article  PubMed  Google Scholar 

  • Ficks CA, Waldman ID (2009) Gene-environment interactions in attention-deficit/hyperactivity disorder. Curr Psychiatry Rep 11(5):387–392

    Article  PubMed  Google Scholar 

  • Ficks C, Lahey B, Waldman I (2013) Does low birth weight share common genetic or environmental risk with childhood disruptive disorders? J Abnorm Psychol 122(3):842–853

    Article  PubMed  PubMed Central  Google Scholar 

  • Filipek PA, Semrud-Clikeman M, Steingard RJ, Renshaw PF, Kennedy DN, Biederman J (1997) Volumetric MRI analysis comparing subjects having attention-deficit hyperactivity disorder with normal controls. Neurology 48(3):589–601

    Article  PubMed  Google Scholar 

  • Froehlich TE, Anixt JS, Loe IM, Chirdkiatgumchai V, Kuan L, Gilman RC (2011) Update on environmental risk factors for attention-deficit/hyperactivity disorder. Curr Psychiatry Rep 13(5):333–344

    Article  PubMed  PubMed Central  Google Scholar 

  • Fu J, Olofsson P (2006) Restrained cerebral hyperperfusion in response to superimposed acute hypoxemia in growth-restricted human fetuses with established brain-sparing blood flow. Early Hum Dev 82(3):211–216

    Article  PubMed  Google Scholar 

  • Fu J, Olofsson P (2011) Relations between fetal brain-sparing circulation, oxytocin challenge test, mode of delivery and fetal outcome in growth-restricted term fetuses. Acta Obstet Gyn Scan 90(3):227–230

    Google Scholar 

  • Gardener H, Spiegelman D, Buka SL (2009) Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry 195(1):7–14

    Article  PubMed  PubMed Central  Google Scholar 

  • Gau SS, Tseng WL, Tseng WY, Wu YH, Lo YC (2015) Association between microstructural integrity of frontostriatal tracts and school functioning: ADHD symptoms and executive function as mediators. Psychol Med 45(3):529–543

    Article  PubMed  Google Scholar 

  • Getahun D, Rhoads GG, Demissie K, Lu SE, Quinn VP, Fassett MJ, Wing DA, Jacobsen SJ (2013) In utero exposure to ischemic-hypoxic conditions and attention-deficit/hyperactivity disorder. Pediatrics 131(1):e53–e61

    Article  PubMed  Google Scholar 

  • Gluckman PD, Hanson MA (2004) Living with the past: evolution, development, and patterns of disease. Science 305(5691):1733–1736

    Article  PubMed  Google Scholar 

  • Groen-Blukhuis MM, Middeldorp CM, van Beijsterveldt CE, Boomsma DI (2011) Evidence for a causal association of low birth weight and attention problems. J Am Acad Child Adolesc Psychiatry 50(12):1247–1254

    Article  Google Scholar 

  • Guvendag GE, Karcaaltincaba D, Kandemir O, Kiykac S, Mentese A (2013) Cord blood oxidative stress markers correlate with umbilical artery pulsatility in fetal growth restriction. J Matern Fetal Neonatal Med 26(6):576

    Article  Google Scholar 

  • Heinonen K, Räikkönen K, Pesonen A-K, Andersson S, Kajantie E, Eriksson JG, Wolke D, Lano A (2010) Behavioural symptoms of attention deficit/hyperactivity disorder in preterm and term children born small and appropriate for gestational age: a longitudinal study. BMC Pediatr 10:91

    Article  PubMed  PubMed Central  Google Scholar 

  • Henriksen T, Clausen T (2002) The fetal origins hypothesis: placental insufficiency and inheritance versus maternal malnutrition in well-nourished populations. Acta Obstet Gyn Scan 81(2):112–114

    Article  Google Scholar 

  • Horwood L, Mogridge N, Darlow B (1998) Cognitive, educational, and behavioural outcomes at 7 to 8 years in a national very low birthweight cohort. Arch Dis Child Fetal Neonatal Ed 79(1):F12

    Article  PubMed  PubMed Central  Google Scholar 

  • Hultman CM, Torrång A, Tuvblad C, Cnattingius S, Larsson JO, Lichtensetin P (2007) Birth weight and attention-deficit/hyperactivity symptoms in childhood and ealry adolescence: a prospective Swedish twin study. J Am Acad Child Adolesc Psychiatry 46(3):370–377

    Article  PubMed  Google Scholar 

  • Inamura K, Olsson Y, Siesjo BK (1987) Substantia nigra damage induced by ischemia in hyperglycemic rats. A light and electron microscopic study. Acta Neuropathol 75(2):131–139

    Article  PubMed  Google Scholar 

  • Indredavik M, Vik T, Heyerdahl S, Kulseng S, Fayers P, Brubakk A (2004) Psychiatric symptoms and disorders in adolescents with low birth weight. Arch Dis Child Fetal Neonatal Ed 89(5):F445

    Article  PubMed  PubMed Central  Google Scholar 

  • Jellema R, Lima PV, Zwanenburg A, Ophelders D, De Munter S, Vanderlocht J, Germeraad W, Kuypers E, Collins J, Cleutjens J (2013) Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep. J Neuroinflamm 10:13

    Article  Google Scholar 

  • Jesmin S, Togashi H, Mowa CN, Ueno K, Yamaguchi T, Shibayama A, Miyauchi T, Sakuma I, Yoshioka M (2004) Characterization of regional cerebral blood flow and expression of angiogenic growth factors in the frontal cortex of juvenile male SHRSP and SHR. Brain Res 2:172–182

    Article  Google Scholar 

  • Kates WR, Frederikse M, Mostofsky SH, Folley BS, Cooper K, Mazur-Hopkins P, Kofman O, Singer HS, Denckla MB, Pearlson GD, Kaufmann WE (2002) MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome. Psychiatry Res 116(1–2):63–81

    Article  PubMed  Google Scholar 

  • Kaur C, Ling E (2008) Blood brain barrier in hypoxic-ischemic conditions. Curr Neurovasc Res 5(1):71

    Article  PubMed  Google Scholar 

  • Kinzler W, Vintzileos A (2008) Fetal growth restriction: a modern approach. Curr Opin Obstet Gynecol 20(2):125

    Article  PubMed  Google Scholar 

  • Knopik VS (2009) Maternal smoking during pregnancy and child outcomes: real or spurious effect? Dev Neuropsychol 34(1):1–36

    Article  PubMed  PubMed Central  Google Scholar 

  • Knopik VS (2010) Commentary: smoking during pregnancy—genes and environment weigh in. Int J Epidemiol 39(5):1203–1205

    Article  PubMed  PubMed Central  Google Scholar 

  • Knopik VS, Sparrow EP, Madden PA, Bucholz KK, Hudziak JJ, Reich W, Slutske WS, Grant JD, McLaughlin TL, Todoro A, Todd RD, Heath AC (2005) Contributions of parental alcoholism, prenatal substance exposure, and genetic transmission to child ADHD risk: a female twin study. Psychol Med 35(5):625-635

    Article  PubMed  Google Scholar 

  • Knopik VS, Heath AC, Jacob T, Slutske WS, Bucholz KK, Madden PA, Waldron M, Martin NG (2006) Maternal alcohol use disorder and offspring ADHD: disentangling genetic and environmental effects using a children-of-twins design. Psychol Med 36(10):1461–1471

    Article  PubMed  Google Scholar 

  • Knopik VS, Maccani MA, Francazio S, McGeary JE (2012) The epigenetics of maternal cigarette smoking during pregnancy and effects on child development. Dev Psychopathol 24(4):1377–1390

    Article  PubMed  PubMed Central  Google Scholar 

  • Knopik VS, Marceau K, Palmer RHC, Smith TF, Heath AC (2015) Maternal smoking during pregnancy and offspring birth weight: A genetically-informed approach incorporating multiple raters. Behav Genet. doi:10.1007/s10519-015-9750-6

    Google Scholar 

  • Knopik VS, Marceau K, Bidwell LC, Palmer RHC, Smith TF, Todorov A, Evans AS, Heath AC (2016) Smoking during pregnancy and ADHD risk: a genetically-informed, multiple-rater approach. Am J Med Genet Part B. doi:10.1002/ajmg.b.32421

    PubMed  Google Scholar 

  • Kolevzon A, Gross R, Reichenberg A (2007) Prenatal and perinatal risk factors for autism: a review and integration of findings. Arch Pediatr Adolesc Med 161(4):326–333

    Article  PubMed  Google Scholar 

  • Krakowiak P, Goines PE, Tancredi DJ, Ashwood P, Handen RL, Hertz-Picciotto I, Van de Water J (2015) Neonatal cytokine profiles associated with autism spectrum disorder. Biol Psychiatry. doi:10.1016/jbiopsych.2015.08.007

    PubMed  Google Scholar 

  • Lahti J, Raikkonen K, Kajantie E, Heinonen K, Pesonen AK, Jarvenpaa AL, Strandberg T (2006) Small body size at birth and behavioural symptoms of ADHD in children aged five to six years. J Child Psychol Psychiatry 47(11):1167–1174

    Article  PubMed  Google Scholar 

  • Laplante F, Brake WG, Chehab SL, Sullivan RM (2012) Sex differences in the effects of perinatal anoxia on dopamine function in rats. Neurosci Lett 506(1):89–93

    Article  PubMed  Google Scholar 

  • Larroque B, Marret S, Ancel P, Arnaud C, Marpeau L, Supernant K, Pierrat V, Rozé J, Matis J, Cambonie G (2003) White matter damage and intraventricular hemorrhage in very preterm infants: the EPIPAGE study. J Pediatr 143(4):477–483

    Article  PubMed  Google Scholar 

  • Lasky-Su J (2013) A network medicine approach to psychiatric genetics. Am J Med Genet B Neuropsychiatr Genet 162(7):579

    Article  Google Scholar 

  • Lee DW, Rajagopalan S, Siddiq A, Gwiazda R, Yang L, Beal MF, Ratan RR, Andersen JK (2009) Inhibition of prolyl hydroxylase protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: model for the potential involvement of the hypoxia-inducible factor pathway in Parkinson disease. J Biol Chem 284(42):29065–29076

    Article  PubMed  PubMed Central  Google Scholar 

  • Lesch KP, Merker S, Reif A, Novak M (2013) Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD. Eur Neuropsychopharmacol 23(6):479–491

    Article  PubMed  Google Scholar 

  • Lewis S, Murray R (1987) Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia. J Psychiatr Res 21(4):413

    Article  PubMed  Google Scholar 

  • Linnet KM, Dalsgaard S, Obel C, Wisborg K, Henriksen TB, Rodriguez A, Kotimaa A, Moilanen I, Thomsen PH, Olsen J, Jarvelin MR (2003) Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence. Am J Psychiatry 160(6):1028–1040

    Article  PubMed  Google Scholar 

  • Linnet K, Wisborg K, Agerbo E, Secher N, Thomsen P, Henriksen T (2006) Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch Dis Child 91(8):655–660

    Article  PubMed  PubMed Central  Google Scholar 

  • Lou HC (1996) Etiology and pathogenesis of attention-deficit hyperactivity disorder (ADHD): significance of prematurity and perinatal hypoxic-haemodynamic encephalopathy. Acta Paediatr 85(11):1266–1271

    Article  PubMed  Google Scholar 

  • Lou HC, Rosa P, Pryds O, Karrebaek H, Lunding J, Cumming P, Gjedde A (2004) ADHD: increased dopamine receptor availability linked to attention deficit and low neonatal cerebral blood flow. Dev Med Child Neurol 46(3):179–183

    Article  PubMed  Google Scholar 

  • Mac Gabhann F, Popel AS (2008) Systems biology of vascular endothelial growth factors. Microcirculation 15(8):715–738

    Article  PubMed  PubMed Central  Google Scholar 

  • Maccani MA, Marsit CJ (2009) Epigenetics in the placenta. Am J Reprod Immunol 62(2):78–89

    Article  PubMed  PubMed Central  Google Scholar 

  • Mallard E, Rehn A, Rees S, Tolcos M, Copolov D (1999) Ventriculomegaly and reduced hippocampal volume following intrauterine growth-restriction: implications for the aetiology of schizophrenia. Schizophr Res 40(1):11–21

    Article  PubMed  Google Scholar 

  • Maulik D (2006) Fetal growth compromise: definitions, standards, and classification. Clin Obstet Gynecol 49(2):214–218

    Article  PubMed  Google Scholar 

  • McClendon E, Chen K, Gong X, Sharifnia E, Hagen M, Cai V, Shaver DC, Riddle A, Dean JM, Gunn AJ, Mohr C, Kaplan JS, Rossi DJ, Kroenke CD, Hohimer AR, Back SA (2014) Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons. Ann Neurol 75(4):508–524

    Article  PubMed  PubMed Central  Google Scholar 

  • Mick E, Biederman J, Prince J, Fischer MJ, Faraone SV (2002) Impact of low birth weight on attention-deficit hyperactivity disorder. J Dev Behav Pediatr 23(1):16–22

    Article  PubMed  Google Scholar 

  • Mill J, Petronis A (2008) Pre- and peri-natal environmental risks for attention-deficit hyperactivity disorder (ADHD): the potential role of epigenetic processes in mediating susceptibility. J Child Psychol Psychiatry 49(10):1020–1030

    Article  PubMed  Google Scholar 

  • Milosevic J, Maisel M, Wegner F, Leuchtenberger J, Wenger RH, Gerlach M, Storch A, Schwarz J (2007) Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling. J Neurosci 27(2):412–421

    Article  PubMed  Google Scholar 

  • Mimura I, Nangaku M, Kanki Y, Tsutsumi S, Inoue T, Kohro T, Yamamoto S, Fujita T, Shimamura T, Suehiro J, Taguchi A, Kobayashi M, Tanimura K, Inagaki T, Tanaka T, Hamakubo T, Sakai J, Aburatani H, Kodama T, Wada Y (2012) Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol 32(15):3018–3032

    Article  PubMed  PubMed Central  Google Scholar 

  • Mittal VA, Ellman LM, Cannon TD (2008) Gene-environment interaction and covariation in schizophrenia: the role of obstetric complications. Schizophr Bull 34(6):1083–1094

    Article  PubMed  PubMed Central  Google Scholar 

  • Moffitt TE, Caspi A, Rutter M (2005) Strategy for investigating interactions between measured genes and measured environments. Arch Gen Psychiatry 62(5):473–481

    Article  PubMed  Google Scholar 

  • Mostofsky SH, Cooper KL, Kates WR, Denckla MB, Kaufmann WE (2002) Smaller prefrontal and premotor volumes in boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 52(8):785–794

    Article  PubMed  Google Scholar 

  • Mueller BR, Bale TL (2008) Sex-specific programming of offspring emotionality after stress early in pregnancy. J Neurosci 28(36):9055–9065

    Article  PubMed  PubMed Central  Google Scholar 

  • Murray AJ (2012) Oxygen delivery and fetal-placental growth: beyond a question of supply and demand? Placenta 33(Suppl 2):e16–e22

    Article  PubMed  Google Scholar 

  • Mwaniki MK, Atieno M, Lawn JE, Newton CR (2012) Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet 379(9814):445–452

    Article  PubMed  PubMed Central  Google Scholar 

  • Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98(1–2):143–151

    Article  PubMed  Google Scholar 

  • Nigg JT (2005) Neuropsychologic theory and findings in attention-deficit/hyperactivity disorder: the state of the field and salient challenges for the coming decade. Biol Psychiatry 57(11):1424–1435

    Article  PubMed  Google Scholar 

  • Nigg JT (2006) What causes ADHD? Understanding what goes wrong and why. Guilford Press, New York

    Google Scholar 

  • Nigg J (2012) Environment, developmental origins, and attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 166(4):387–388

    Article  PubMed  PubMed Central  Google Scholar 

  • Nigg J, Nikolas M, Burt SA (2010) Measured gene-by-environment interaction in relation to attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49(9):863–873

    Article  PubMed  PubMed Central  Google Scholar 

  • Oades RD (2011) An exploration of the associations of pregnancy and perinatal features with cytokines and tryptophan/kynurenine metabolism in children with attention-deficit hyperactivity disorder (ADHD). Atten Defic Hyperact Disord 3(4):301–318

    Article  PubMed  Google Scholar 

  • Oades RD, Myint AM, Dauvermann MR, Schimmelmann BG, Schwarz MJ (2010) Attention-deficit hyperactivity disorder (ADHD) and glial integrity: an exploration of associations of cytokines and kynurenine metabolites with symptoms and attention. Behav Brain Funct 6:32

    Article  PubMed  PubMed Central  Google Scholar 

  • Overmeyer S, Bullmore ET, Suckling J, Simmons A, Williams SC, Santosh PJ, Taylor E (2001) Distributed grey and white matter deficits in hyperkinetic disorder: MRI evidence for anatomical abnormality in an attentional network. Psychol Med 31(8):1425–1435

    Article  PubMed  Google Scholar 

  • Owens EB, Hinshaw SP (2013) Perinatal problems and psychiatric comorbidity among children with ADHD. J Clin Child Adolesc Psychol 42(6):762–768

    Article  PubMed  Google Scholar 

  • Peterson B, Anderson A, Ehrenkranz R, Staib L, Tageldin M, Colson E, Gore J, Duncan C, Makuch R, Ment L (2003) Regional brain volumes and their later neurodevelopmental correlates in term and preterm infants. Pediatrics 111(5):939

    Article  PubMed  Google Scholar 

  • Phua DY, Rifkin-Graboi A, Saw SM, Meaney MJ, Qiu A (2012) Executive functions of six-year-old boys with normal birth weight and gestational age. PLoS One 7(4):e36502

    Article  PubMed  PubMed Central  Google Scholar 

  • Pineda DA, Palacio LG, Puerta IC, Merchan V, Arango CP, Galvis AY, Gomez M, Aguirre DC, Lopera F, Arcos-Burgos M (2007) Environmental influences that affect attention deficit/hyperactivity disorder: study of a genetic isolate. Eur Child Adolesc Psychiatry 16(5):337–346

    Article  PubMed  Google Scholar 

  • Poelmans G, Pauls D, Buitelaar J, Franke B (2011) Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. Am J Psychiatry 168(4):365

    Article  PubMed  Google Scholar 

  • Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164(6):942–948

    Article  PubMed  Google Scholar 

  • Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, Wayland M, Freeman T, Dudbridge F, Lilley KS, Karp NA, Hester S, Tkachev D, Mimmack ML, Yolken RH, Webster MJ, Torrey EF, Bahn S (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatr 9(7):684–697

    Article  Google Scholar 

  • Rehn A, Van Den Buuse M, Copolov D, Briscoe T, Lambert G, Rees S (2004) An animal model of chronic placental insufficiency: relevance to neurodevelopmental disorders including schizophrenia. Neuroscience 129(2):381–391

    Article  PubMed  Google Scholar 

  • Ribases M, Hervas A, Ramos-Quiroga JA, Bosch R, Bielsa A, Gastaminza X, Fernandez-Anguiano M, Nogueira M, Gomez-Barros N, Valero S, Gratacos M, Estivill X, Casas M, Cormand B, Bayes M (2008) Association study of 10 genes encoding neurotrophic factors and their receptors in adult and child attention-deficit/hyperactivity disorder. Biol Psychiatry 63(10):935–945

    Article  PubMed  Google Scholar 

  • Roza SJ, Steegers EA, Verburg BO, Jaddoe VW, Moll HA, Hofman A, Verhulst FC, Tiemeier H (2008) What is spared by fetal brain-sparing? Fetal circulatory redistribution and behavioral problems in the general population. Am J Epidemiol 168(10):1145–1152

    Article  PubMed  Google Scholar 

  • Salmaso N, Jablonska B, Scafidi J, Vaccarino FM, Gallo V (2014) Neurobiology of premature brain injury. Nat Neurosci 17(3):341–346

    Article  PubMed  PubMed Central  Google Scholar 

  • Sanchez-Mora C, Ribases M, Ramos-Quiroga JA, Casas M, Bosch R, Boreatti-Hummer A, Heine M, Jacob CP, Lesch KP, Fasmer OB, Knappskog PM, Kooij JJ, Kan C, Buitelaar JK, Mick E, Asherson P, Faraone SV, Franke B, Johansson S, Haavik J, Reif A, Bayes M, Cormand B (2010) Meta-analysis of brain-derived neurotrophic factor p.Val66Met in adult ADHD in four European populations. Am J Med Genet B Neuropsychiatr Genet 153B(2):512–523

    PubMed  Google Scholar 

  • Schmidt-Kastner R, van Os J, Steinbusch H, Schmitz C (2006) Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr Res 84(2–3):253–271

    Article  PubMed  Google Scholar 

  • Schmidt-Kastner R, van Os J, Esquivel G, Steinbusch HW, Rutten BP (2012) An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model. Mol Psychiatr 17(12):1194–1205

    Article  Google Scholar 

  • Sharp FR, Bernaudin M (2004) HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5(6):437–448

    Article  PubMed  Google Scholar 

  • Shibuya M (2008) Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis. BMB Rep 41(4):278–286

    Article  PubMed  Google Scholar 

  • Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312(5):549–560

    Article  PubMed  Google Scholar 

  • Skowronski K, Dubey S, Rodenhiser D, Coomber B (2010) Ischemia dysregulates DNA methyltransferases and p16INK4a methylation in human colorectal cancer cells. Epigenetics 5(6):547–556

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith TF, Anastopoulos AD, Garrett ME, Arias-Vasquez A, Franke B, Oades RD, Sonuga-Barke E, Asherson P, Gill M, Buitelaar JK, Sergeant JA, Kollins SH, Faraone SV, Ashley-Koch A, Consortium I (2014) Angiogenic, neurotrophic, and inflammatory system SNPs moderate the association between birth weight and ADHD symptom severity. Am J Med Genet B Neuropsychiatr Genet 165B(8):691–704

    Article  PubMed  Google Scholar 

  • Sonuga-Barke EJ (2002) Psychological heterogeneity in AD/HD—A dual pathway model of behaviour and cognition. Behav Brain Res 130(1–2):29–36

    Article  PubMed  Google Scholar 

  • Swanson JD, Wadhwa PM (2008) Developmental origins of child mental health disorders. J Child Psychol Psychiatry 49(10):1009–1019

    Article  PubMed  PubMed Central  Google Scholar 

  • Swanson JM, Kinsbourne M, Nigg J, Lanphear B, Stefanatos GA, Volkow N, Taylor E, Casey BJ, Castellanos FX, Wadhwa PD (2007) Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol Rev 17(1):39–59

    Article  PubMed  Google Scholar 

  • Thapar A, Rice F, Hay D, Boivin J, Langley K, van den Bree M, Rutter M, Harold G (2009) Prenatal smoking might not cause attention-deficit/hyperactivity disorder: evidence from a novel design. Biol Psychiatry 66(8):722–727

    Article  PubMed  PubMed Central  Google Scholar 

  • Thapar A, Cooper M, Eyre O, Langley K (2013) What have we learnt about the causes of ADHD? J Child Psychol Psychiatry 54(1):3–16

    Article  PubMed  PubMed Central  Google Scholar 

  • Thuring A, Maršál K, Laurini R (2012) Placental ischemia and changes in umbilical and uteroplacental arterial and venous hemodynamics. J Matern Fetal Neonatal Med 25(6):750

    Article  PubMed  Google Scholar 

  • Todd RD, Botteron KN (2001) Is attention-deficit/hyperactivity disorder an energy deficiency syndrome? Biol Psychiatry 50(3):151–158

    Article  PubMed  Google Scholar 

  • Toft P (1999) Prenatal and perinatal striatal injury: a hypothetical cause of attention-deficit–hyperactivity disorder? Pediatr Neurol 21(3):602–610

    Article  PubMed  Google Scholar 

  • Tolsa C, Zimine S, Warfield S, Freschi M, Sancho R, Lazeyras F, Hanquinet S, Pfizenmaier M, Huppi P (2004) Early alteration of structural and functional brain development in premature infants born with intrauterine growth restriction. Pediatr Res 56(1):132

    Article  PubMed  Google Scholar 

  • Tomita S, Ueno M, Sakamoto M, Kitahama Y, Ueki M, Maekawa N, Sakamoto H, Gassmann M, Kageyama R, Ueda N, Gonzalez FJ, Takahama Y (2003) Defective brain development in mice lacking the Hif-1alpha gene in neural cells. Mol Cell Biol 23(19):6739–6749

    Article  PubMed  PubMed Central  Google Scholar 

  • Tsai YP, Wu KJ (2013) Epigenetic regulation of hypoxia-responsive gene expression: focusing on chromatin and DNA modifications. Int J Cancer 134(2):249–256

    Article  PubMed  Google Scholar 

  • Tylee D, Kawaguchi D, Glatt S (2013) On the outside, looking in: A review and evaluation of the comparability of blood and brain-“omes”. Am J Med Genet B Neuropsychiatr Genet 162(7):595–603

    Article  Google Scholar 

  • Ungethum U, Chen Y, Gross J, Bjelke B, Bolme P, Eneroth P, Heldt J, Loidl CF, Herrera-Marschitz M, Andersson K (1996) Effects of perinatal asphyxia on the mesostriatal/mesolimbic dopamine system of neonatal and 4-week-old male rats. Exp Brain Res 112(3):403–410

    Article  PubMed  Google Scholar 

  • van Os J, Wichers M, Danckaerts M, Van Gestel S, Derom C, Vlietinck R (2001) A prospective twin study of birth weight discordance and child problem behavior. Biol Psychiatry 50(8):593–599

    Article  PubMed  Google Scholar 

  • Viswanathan G, Seto J, Patil S, Nudelman G, Sealfon S (2008) Getting started in biological pathway construction and analysis. PLoS Comput Biol 4(2):e16

    Article  PubMed  PubMed Central  Google Scholar 

  • Wadhwa PD, Buss C, Entringer S, Swanson JM (2009) Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med 27(5):358–368

    Article  PubMed  PubMed Central  Google Scholar 

  • Walhovd KB, Fjell AM, Brown TT, Kuperman JM, Chung Y, Hagler DJ Jr, Roddey JC, Erhart M, McCabe C, Akshoomoff N, Amaral DG, Bloss CS, Libiger O, Schork NJ, Darst BF, Casey BJ, Chang L, Ernst TM, Frazier J, Gruen JR, Kaufmann WE, Murray SS, van Zijl P, Mostofsky S, Dale AM, Pediatric Imaging, Neurocognition, Study Group (2012) Long-term influence of normal variation in neonatal characteristics on human brain development. Proc Natl Acad Sci USA 109(49):20089–20094

    Article  PubMed  PubMed Central  Google Scholar 

  • Walker C, Anderson K, Milano K, Ye S, Tancredi D, Pessah I, Hertz-Picciotto I, Kliman H (2013) Trophoblast inclusions are significantly increased in the placentas of children in families at risk for autism. Biol Psychiatry 74(3):204

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Meng FS, Liu ZY, Fan JM, Hao K, Chen XQ, Du JZ (2013) Gestational hypoxia induces sex-differential methylation of Crhr1 linked to anxiety-like behavior. Mol Neurobiol 48(3):544–555

    Article  PubMed  Google Scholar 

  • Watson JA, Watson CJ, McCann A, Baugh J (2010) Epigenetics, the epicenter of the hypoxic response. Epigenetics 5(4):293–296

    Article  PubMed  Google Scholar 

  • Wheaton WW, Chandel NS (2011) Hypoxia 2. Hypoxia regulates cellular metabolism. Am J Physiol Renal Physiol 300(3):C385–C393

    Article  Google Scholar 

  • Whitaker A, Van Rossem R, Feldman J, Schonfeld I, Pinto-Martin J, Tarre C, Shaffer D, Paneth N (1997) Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities. Arch Gen Psychiatry 54(9):847–856

    Article  PubMed  Google Scholar 

  • Whitaker AH, Feldman JF, Lorenz JM, McNicholas F, Fisher PW, Shen S, Pinto-Martin J, Shaffer D, Paneth N (2011) Neonatal head ultrasound abnormalities in preterm infants and adolescent psychiatric disorders. Arch Gen Psychiatry 68(7):742–752

    Article  PubMed  Google Scholar 

  • Wu X, Sun J, Li L (2013) Chronic cerebrovascular hypoperfusion affects global DNA methylation and histone acetylation in rat brain. Neurosci Bull 29(6):685–692

    Article  PubMed  Google Scholar 

  • Yang L, Neale BM, Liu L, Lee SH, Wray NR, Ji N, Li H, Qian Q, Wang D, Li J, Faraone SV, Wang Y, Psychiatric GCAS (2013) Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. Am J Med Genet B Neuropsychiatr Genet 162B(5):419–430

    Article  PubMed  Google Scholar 

  • Yu AY, Shimoda LA, Iyer NV, Huso DL, Sun X, McWilliams R, Beaty T, Sham JS, Wiener CM, Sylvester JT, Semenza GL (1999) Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha. J Clin Invest 103(5):691–696

    Article  PubMed  PubMed Central  Google Scholar 

  • Zubrick S, Kurinczuk J, McDermott B, McKelvey R, Silburn S, Davies L (2000) Fetal growth and subsequent mental health problems in children aged 4 to 13 years. Dev Med Child Neurol 42(01):14–20

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Psychology and Child Development, California Polytechnic State University, 1 Grand Ave., San Luis Obispo, CA, 93407, USA

    Taylor F. Smith & Jessica A. Kaczorowski

  2. Division of Behavioral Genetics, Rhode Island Hospital and Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Taylor F. Smith, John E. McGeary & Valerie S. Knopik

  3. Integrated Medical Science Department, CE Schmidt College of Medicine, Florida Atlantic University (FAU), Boca Raton, FL, USA

    Rainald Schmidt-Kastner

  4. Providence VA Medical Center, Providence, RI, USA

    John E. McGeary

Authors
  1. Taylor F. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rainald Schmidt-Kastner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John E. McGeary
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jessica A. Kaczorowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Valerie S. Knopik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Taylor F. Smith.

Ethics declarations

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10519_2016_9784_MOESM1_ESM.docx

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; http://braincloud.jhmi.edu/plots/). Supplementary material 1 (DOCX 1167 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Smith, T.F., Schmidt-Kastner, R., McGeary, J.E. et al. Pre- and Perinatal Ischemia-Hypoxia, the Ischemia-Hypoxia Response Pathway, and ADHD Risk. Behav Genet 46, 467–477 (2016). https://doi.org/10.1007/s10519-016-9784-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-016-9784-4

Keywords

Search

Navigation