Neurostructural Endophenotypes In Autism Spectrum Disorder

  • Armin Raznahan
  • Jay N. Giedd
  • Patrick F. Bolton

Abstract

Autism Spectrum Disorder (ASD) is a group of behaviourally defi ned neurodevelopmental disorders of childhood onset characterised by impairments in communication and social reciprocity as well as a range of distinctive non-social symptoms. Despite including some of the most heritable disorders in psychiatry, it has proved difficult to identify risk genes for ASD, and to build models for the neurobiological mechanisms through which putative risk factors might operate to give rise to the ASD behavioural phenotype. In this chapter we detail why measures of brain anatomy derived from structural magnetic resonance images have been put forward as potential alternative endophenotypes that might increase our ability to identify risk genes and associated brain mechanisms for ASD. We then examine the progress that has been made so far in identifying neurostructural endophenotypes for ASD, and consider some of the challenges and opportunities presented by this new line of research in ASD neurobiology.

Keywords

Autism spectrum disorder endophenotype structural magnetic resonance imaging MRI development 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    American Psychiatric Organisation. Diagnostic and Statistical Manual of Mental Disorders: Test Revision (DSM-IV-TR), 4th edition. Washington, DC: American Psychiatric Association. 2000.CrossRefGoogle Scholar
  2. 2.
    Ronald A, Happe F, Bolton P, Butcher LM, Price TS, Wheelwright S, Baron-Cohen S, Plomin R. Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Adol Psychiat 2006;45:691–699.CrossRefGoogle Scholar
  3. 3.
    Volkmar FR, Lord C, Bailey A, Schultz RT, Klin A. Autism and pervasive developmental disorders. J Child Psychol Psychiat Allied Disciplines 2004;45:135–170.CrossRefGoogle Scholar
  4. 4.
    Baird G, Simonoff E, Pickles A, Chandler S, Loucas T, Meldrum D, Charman T. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 2006;368(9531):210–215.PubMedCrossRefGoogle Scholar
  5. 5.
    Fombonne E, Zakarian R, Bennett A, Meng L, Lean-Heywood D. Pervasive developmental disorders in Montreal, Quebec, Canada: prevalence and links with immunizations. Pediatrics 2006;118(1):e139–e150.PubMedCrossRefGoogle Scholar
  6. 6.
    Wing L, Yeates SR, Brierley LM, Gould J. The prevalence of early childhood autism: comparison of administrative and epidemiological studies. Psychol Med 1976;6:89–100.PubMedGoogle Scholar
  7. 7.
    Gernsbacher MA, Dawson M, Goldsmith HH. Three reasons not to believe in an autism epidemic. Curr Dir Psychol Sci 2005;14:55–58.CrossRefGoogle Scholar
  8. 8.
    Bailey A, Le Couteur A, Gottesman I, Bolton P. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995;25:63–77.PubMedGoogle Scholar
  9. 9.
    Veenstra-VanderWeele J, Cook EJ. Molecular genetics of autism spectrum disorder. Mol Psychiat 2004;9:819–832.CrossRefGoogle Scholar
  10. 10.
    Tan HY, Callicott JH, Weinberger DR. Intermediate phenotypes in schizophrenia genetics redux: is it a no brainer? Mol Psychiat 2008;13:233–238.CrossRefGoogle Scholar
  11. 11.
    Walters JT, Owen MJ. Endophenotypes in psychiatric genetics. Mol Psychiat 2007;12:886–890.CrossRefGoogle Scholar
  12. 12.
    World Health Organisation. Mental disorders; a glossary and guide to their classification in accordance with the 10th revision of the international classification of diseases-research diagnostic criteria (ICD-10). Geneva: WHO; 1993.Google Scholar
  13. 13.
    Kanner L. Autistic disturbances of affective contact. Nerv Child 1943;2:217–250.Google Scholar
  14. 14.
    Asperger H. Dies “autistischen Psychopathen”. Arch Psychiat Nervenkr 1944;117:76–136.CrossRefGoogle Scholar
  15. 15.
    Bolton P, Macdonald H, Pickles A, Rios P. A case-control family history study of autism. J Child Psychol Psychiat 1994;35:877–900.PubMedCrossRefGoogle Scholar
  16. 16.
    Constantino JN, Lajonchere C, Lutz M, Gray T, Abbacchi A, McKenna K, Singh D, Todd RD. Autistic social impairment in the siblings of children with pervasive developmental disorders. Am J Psychiat 2006;163: 294–296.PubMedCrossRefGoogle Scholar
  17. 17.
    DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, Schultz RT, Crawley J, Young LJ. The developmental neurobiology of autism spectrum disorder. J Neurosci 2006;26:6897–6906.PubMedCrossRefGoogle Scholar
  18. 18.
    Bolton PF, Park RJ, Higgins JN, Griffiths PD, Pickles A. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 2002;125(Pt 6): 1247–1255.PubMedCrossRefGoogle Scholar
  19. 19.
    Bukelis I, Porter FD, Zimmerman AW, Tierney E. Smith-Lemli-Opitz syndrome and autism spectrum disorder. Am J Psychiat 2007;164:1655–1661.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, Law P, Qiu S, Lord C, Sebat J, Ye K, Wigler M. A unified genetic theory for sporadic and inherited autism. Proc Natl Acad Sci USA 2007;104: 12831–12836.PubMedCrossRefGoogle Scholar
  21. 21.
    Kendler KS. “ A gene for…”: the nature of gene action in psychiatric disorders. Am J Psychiat 2005;162:1243–1252.PubMedCrossRefGoogle Scholar
  22. 22.
    Rutter M, Moffitt TE, Caspi A. Gene-environment interplay and psychopathology: multiple varieties but real effects. J Child Psychol Psychiat Allied Disciplines 2006;47:226–261.CrossRefGoogle Scholar
  23. 23.
    Stone JL, Merriman B, Cantor RM, Yonan AL, Conrad GT, Geschwind DH, Nelson SF. Evidence for sex-specific risk alleles in autism spectrum disorder. Am J Hum Genet 2004;75:1117–1123.PubMedCrossRefGoogle Scholar
  24. 24.
    Szatmari P, Maziade M, Zwaigenbaum L, Merette C, Roy MA, Joober R, Palmour R. Informative phenotypes for genetic studies of psychiatric disorders. Am J Med Genet B Neuropsychiat Genet 2007;144:581–588.CrossRefGoogle Scholar
  25. 25.
    John B, Lewis K. Chromosome variability and geographical distribution in insects: chromosome rather than gene variation provide the key to differences among populations. Science 1966;152:711–721.PubMedCrossRefGoogle Scholar
  26. 26.
    Gottesman II. Genetic theorizing and schizophrenia. Br J Psychiat 1973;122:15–30.CrossRefGoogle Scholar
  27. 27.
    Gottesman II, Gould TD. The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions. Research advances in genetics and genomics: Implications for psychiatry;2003, pp. 63–84.Google Scholar
  28. 28.
    Gould TD, Gottesman II. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav 2006;5:113–119.PubMedCrossRefGoogle Scholar
  29. 29.
    Doyle AE, Faraone SV, Seidman LJ, Willcutt EG, Nigg JT, Waldman ID, Pennington BF, Peart J, Biederman J. Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD? J Child Psychol Psychiat Allied Disciplines 2005;46(7)774–803.CrossRefGoogle Scholar
  30. 30.
    Doyle AE, Willcutt EG, Seidman LJ, Biederman J, Chouinard VA, Silva J, Faraone S V. Attention-deficit/hyperactivity disorder endophenotypes. Biol Psychiat 2005;57:1324–1335.PubMedCrossRefGoogle Scholar
  31. 31.
    Flint J, Munafo MR. The endophenotype concept in psychiatric genetics. Psychol Med 2007;37(2):163–180.PubMedCrossRefGoogle Scholar
  32. 32.
    Skuse DH. Endophenotypes and child psychiatry. Br J Psychiat 2001;178:395–396.CrossRefGoogle Scholar
  33. 33.
    Viding E, Blakemore SJ. Endophenotype approach to developmental psychopathology: implications for autism research. Behav Genet 2006;37:51–60.PubMedCrossRefGoogle Scholar
  34. 34.
    Waldman ID. Statistical approaches to complex phenotypes: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biol Psychiat 2005;57(11):1347–1356.PubMedCrossRefGoogle Scholar
  35. 35.
    Scherk H, Falkai P. Effects of antipsychotics on brain structure. Curr Opin Psychiat 2006;19:145–150.CrossRefGoogle Scholar
  36. 36.
    Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A, Rapoport JL, Giedd JN. Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol 2007;6:494–500.PubMedCrossRefGoogle Scholar
  37. 37.
    Hariri AR, Weinberger DR. Imaging genomics. Br Med Bull 2003;65:259–270.PubMedCrossRefGoogle Scholar
  38. 38.
    Palmen SJ, van Engeland H. Review on structural neu-roimaging findings in autism. J Neural Trans 2004;111: 903–929.CrossRefGoogle Scholar
  39. 39.
    Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM. Towards a neuroanatomy of autism: a systematic review and meta-analysis of structural magnetic resonance imaging studies. Eur Psychiat 2008;23(4):289–299.CrossRefGoogle Scholar
  40. 40.
    Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci 2008;31:137–145.PubMedCrossRefGoogle Scholar
  41. 41.
    Redcay E, Courchesne E. When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol Psychiat 2005;58:1–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Prince M, Stewart R, Ford T. Practical Psychiatric Epidemiology. Oxford: Oxford University Press; 2003.Google Scholar
  43. 43.
    Brierley B, Shaw P, David AS. The human amygdala: a systematic review and meta-analysis of volumetric magnetic resonance imaging. Brain Res Brain Res Rev 2002;39:84–105.PubMedCrossRefGoogle Scholar
  44. 44.
    Geuze E, Vermetten E, Bremner JD. MR-based in vivo hip-pocampal volumetrics: 1. Review of methodologies currently employed. Mol Psychiat 2004;10:147–159.CrossRefGoogle Scholar
  45. 45.
    Klauschen F, Goldman A, Barra V, Meyer-Lindenberg A, Lundervold A. Evaluation of automated brain MR image segmentation and volumetry methods. Hum Brain Mapp 2008; [Epub ahead of print].Google Scholar
  46. 46.
    Ewers M, Teipel SJ, Dietrich O, Schonberg SO, Jessen F, Heun R, Scheltens P, van de PL, Freymann NR, Moeller HJ, Hampel H. Multicenter assessment of reliability of cranial MRI. Neurobiol Aging 2006;27:1051–1059.PubMedCrossRefGoogle Scholar
  47. 47.
    Belmonte MK, Mazziotta JC, Minshew NJ, Evans AC, Courchesne E, Dager SR, Bookheimer SY, Aylward EH, Amaral DG, Cantor RM, Chugani DC, Dale AM, Davatzikos C, Gerig G, Herbert MR, Lainhart JE, Murphy DG, Piven J, Reiss AL, Schultz RT, Zeffiro TA, Levi-Pearl S, Lajonchere C, Colamarino SA. Offering to share: how to put heads together in autism neuroimaging. J Autism Dev Disord 2007;38:2–13.PubMedCrossRefGoogle Scholar
  48. 48.
    Myers K, Winters NC. Ten-year review of rating scales. II: Scales for internalizing disorders. J Am Acad Child Adol Psychiat 2002;41:634–659.CrossRefGoogle Scholar
  49. 49.
    Collett BR, Ohan JL, Myers KM. Ten-year review of rating scales. V: Scales assessing attention-deficit/hyperactivity disorder. J Am Acad Child Adol Psychiat 2003;42:1015–1037.CrossRefGoogle Scholar
  50. 50.
    Schmitt JE, Eyler LT, Giedd JN, Kremen WS, Kendler KS, Neale MC. Review of twin and family studies on neuroanatomic phenotypes and typical neurodevelopment. Twin Res Hum Genet 2007;10:683–694.PubMedCrossRefGoogle Scholar
  51. 51.
    Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Hulshoff Pol HE. Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Mapp 2007; 28:464–473.PubMedCrossRefGoogle Scholar
  52. 52.
    Wallace GL, Eric SJ, Lenroot R, Viding E, Ordaz S, Rosenthal MA, Molloy EA, Clasen LS, Kendler KS, Neale MC, Giedd JN. A pediatric twin study of brain morphometry. J Child Psychol Psychiat Allied Disciplines 2006; 47(10):987–993.CrossRefGoogle Scholar
  53. 53.
    Pfefferbaum A, Sullivan E V, Swan GE, Carmelli D. Brain structure in men remains highly heritable in the seventh and eighth decades of life. Neurobiol Aging 2000; 21:63–74.PubMedCrossRefGoogle Scholar
  54. 54.
    Baare WF, Hulshoff Pol HE, Boomsma DI, Posthuma D, De Geus EJ, Schnack HG, van Haren NE, van Oel CJ, Kahn RS. Quantitative genetic modeling of variation in human brain morphology. Cereb Cortex 2001; 11(9):816–824.PubMedCrossRefGoogle Scholar
  55. 55.
    Posthuma D, De Geus EJ, Neale MC, Hulshoff Pol HE, Baare WF, Kahn RS, Boomsma DI. Multivariate genetic analysis of brain structure in an extended twin design. Behav Genet 2000; 30:311–319.PubMedCrossRefGoogle Scholar
  56. 56.
    Wright-I-C, Sham P, Murray RM, Weinberger DR, Ballmore ET. Genetic contributions to regional variability in human brain structure: methods and preliminary results. Neroimage 2002; 17(1):256–271.CrossRefGoogle Scholar
  57. 57.
    Hulshoff Pol HE, Schnack HG, Posthuma D, Mandl RC, Baare WF, van OC, van Haren NE, Collins DL, Evans AC, Amunts K, Burgel U, Zilles K, de GE, Boomsma DI, Kahn RS. Genetic contributions to human brain morphology and intelligence. J Neurosci 2006; 26(40):10235–10242.PubMedCrossRefGoogle Scholar
  58. 58.
    Lenroot RK, Schmitt JE, Ordaz SJ, Wallace GL, Neale MC, Lerch JP, Kendler KS, Evans AC, Giedd JN. Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence. Hum Brain Mapp 2009;30(1): 163–174.PubMedCrossRefGoogle Scholar
  59. 59.
    Thompson PM, Cannon TD, Narr KL, van ET, Poutanen VP, Huttunen M, Lonnqvist J, Standertskjold-Nordenstam CG, Kaprio J, Khaledy M, Dail R, Zoumalan CI, Toga AW. Genetic influences on brain structure. Nat Neurosci 2001; 4:1253–1258.PubMedCrossRefGoogle Scholar
  60. 60.
    Kates WR, Burnette CP, Eliez S, Strunge LA, Kaplan D, Landa R, Reiss AL, Pearlson GD. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. Am J Psychiat 2004; 161(3):539–546.PubMedCrossRefGoogle Scholar
  61. 61.
    Schmitt JE, Wallace GL, Rosenthal MA, Molloy EA, Ordaz S, Lenroot R, Clasen LS, Blumenthal JD, Kendler KS, Neale MC, Giedd JN. A multivariate analysis of neu-roanatomic relationships in a genetically informative pediatric sample. Neuroimage 2007; 35(1):70–82.PubMedCrossRefGoogle Scholar
  62. 62.
    Rakic P. A small step for the cell, a giant leap for mankind: a hypothesis of neocortical expansion during evolution. Trends Neurosci 1995; 18:383–388.PubMedCrossRefGoogle Scholar
  63. 63.
    Dawson G, Munson J, Webb SJ, Nalty T, Abbott R, Toth K. Rate of head growth decelerates and symptoms worsen in the second year of life in autism. Biol Psychiat 2007; 61(4):458–464.PubMedCrossRefGoogle Scholar
  64. 64.
    Webb SJ, Nalty T, Munson J, Brock C, Abbott R, Dawson G. Rate of head circumference growth as a function of autism diagnosis and history of autistic regression. J Child Neurol 2007; 22:1182–1190.PubMedCrossRefGoogle Scholar
  65. 65.
    Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, Gilmore J, Piven J. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiat 2005; 62(12):1366–1376.PubMedCrossRefGoogle Scholar
  66. 66.
    Lainhart JE, Piven J, Wzorek M, Landa R, Santangelo SL, Coon H, Folstein SE. Macrocephaly in children and adults with autism. J Am Acad Child Adol Psychiat 1997; 36(2):282–290.CrossRefGoogle Scholar
  67. 67.
    Aylward EH, Minshew NJ, Field K, Sparks BF, Singh N. Effects of age on brain volume and head circumference in autism. Neurology 2002; 59:175–183.PubMedGoogle Scholar
  68. 68.
    Stevenson RE, Schroer RJ, Skinner C, Fender D, Simensen RJ. Autism and macrocephaly. Lancet 1997; 349(9067): 1744–1745.PubMedCrossRefGoogle Scholar
  69. 69.
    Fidler DJ, Bailey JN, Smalley SL. Macrocephaly in autism and other pervasive developmental disorders. Dev Med Child Neurol 2000; 42:737–740.PubMedCrossRefGoogle Scholar
  70. 70.
    Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G, Deutsch CK, Dunn M, Estes A, Tager-Flusberg H, Folstein S, Hepburn S, Hyman S, McMahon W, Minshew N, Munson J, Osann K, Ozonoff S, Rodier P, Rogers S, Sigman M, Spence MA, Stodgell CJ, Volkmar F. Head circumference and height in autism: a study by the collaborative program of excellence in autism. Am J Med Genet A 2006; 140:2257–2274.PubMedGoogle Scholar
  71. 71.
    Elder LM, Dawson G, Toth K, Fein D, Munson J. Head circumference as an early predictor of autism symptoms in younger siblings of children with autism spectrum disorder. J Autism Dev Disord 2008; 38:1104–1111.PubMedCrossRefGoogle Scholar
  72. 72.
    Conciatori M, Stodgell CJ, Hyman SL, O'Bara M, Militerni R, Bravaccio C, Trillo S, Montecchi F, Schneider C, Melmed R, Elia M, Crawford L, Spence SJ, Muscarella L, Guarnieri V, D'Agruma L, Quattrone A, Zelante L, Rabinowitz D, Pascucci T, Puglisi-Allegra S, Reichelt KL, Rodier PM, Persico AM. Association between the HOXA1 A218G polymorphism and increased head circumference in patients with autism. (References). Biol Psychiat 2004; 55:413–419.PubMedCrossRefGoogle Scholar
  73. 73.
    Sacco R, Papaleo V, Hager J, Rousseau F, Moessner R, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Curatolo P, Manzi B, Pascucci T, Puglisi-Allegra S, Reichelt KL, Persico AM. Case-control and family-based association studies of candidate genes in autistic disorder and its endophenotypes: TPH2 and GLO1. BMC Med Genet 2007; 8:11.PubMedCrossRefGoogle Scholar
  74. 74.
    Muscarella LA, Guarnieri V, Sacco R, Militerni R, Bravaccio C, Trillo S, Schneider C, Melmed R, Elia M, Mascia ML, Rucci E, Piemontese MR, D'Agruma L, Persico AM. HOXA1 gene variants influence head growth rates in humans. Am J Med Genet B Neuropsychiat Genet 2007; 144B:388–390.CrossRefGoogle Scholar
  75. 75.
    Sacco R, Militerni R, Frolli A, Bravaccio C, Gritti A, Elia M, Curatolo P, Manzi B, Trillo S, Lenti C, Saccani M, Schneider C, Melmed R, Reichelt KL, Pascucci T, Puglisi-Allegra S, Persico AM. Clinical, morphological, and biochemical correlates of head circumference in autism. Biol Psychiat 2007; 62:1038–1047.PubMedCrossRefGoogle Scholar
  76. 76.
    Mraz KD, Green J, Dumont-Mathieu T, Makin S, Fein D. Correlates of head circumference growth in infants later diagnosed with autism spectrum disorders. J Child Neurol 2007; 22:700–713.PubMedCrossRefGoogle Scholar
  77. 77.
    Hardan AY, Girgis RR, Adams J, Gilbert AR, Keshavan MS, Minshew NJ. Abnormal brain size effect on the thalamus in autism. Psychiat Res 2006; 147(2–3):145–151.Google Scholar
  78. 78.
    Waiter GD, Williams JH, Murray AD, Gilchrist A, Perrett DI, Whiten A. A voxel-based investigation of brain structure in male adolescents with autistic spectrum disorder. Neuroimage 2004; 22(2):619–625.PubMedCrossRefGoogle Scholar
  79. 79.
    McAlonan GM, Cheung V, Cheung C, Suckling J, Lam GY, Tai KS, Yip L, Murphy DG, Chua SE. Mapping the brain in autism. A voxel-based MRI study of volumetric differences and intercorrelations in autism. Brain 2005; 128(Pt 2):268–276.PubMedGoogle Scholar
  80. 80.
    Hardan AY, Muddasani S, Vemulapalli M, Keshavan MS, Minshew NJ. An MRI study of increased cortical thickness in autism. Am J Psychiat 2006; 163(7):1290–1292.PubMedCrossRefGoogle Scholar
  81. 81.
    Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA, Tigue ZD, Chisum HJ, Moses P, Pierce K, Lord C, Lincoln AJ, Pizzo S, Schreibman L, Haas RH, Akshoomoff NA, Courchesne RY. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology 2001; 57:245–254.PubMedGoogle Scholar
  82. 82.
    Lotspeich LJ, Kwon H, Schumann CM, Fryer SL, Goodlin-Jones BL, Buonocore MH, Lammers CR, Amaral DG, Reiss AL. Investigation of neuroanatomical differences between autism and Asperger syndrome. Arch Gen Psychiat 2004; 61:291–298.PubMedCrossRefGoogle Scholar
  83. 83.
    Palmen SJ, Hulshoff Pol HE, Kemner C, Schnack HG, Durston S, Lahuis BE, Kahn RS, van EH. Increased gray-matter volume in medication-naive high-functioning children with autism spectrum disorder. Psychol Med 2005; 35(4):561–570.PubMedCrossRefGoogle Scholar
  84. 84.
    Herbert MR, Ziegler DA, Deutsch CK, O'Brien LM, Lange N, Bakardjiev A, Hodgson J, Adrien KT, Steele S, Makris N, Kennedy D, Harris GJ, Caviness VS, Jr. Dissociations of cerebral cortex, subcortical and cerebral white matter volumes in autistic boys. Brain 2003; 126 (Pt 5):1182–1192.PubMedCrossRefGoogle Scholar
  85. 85.
    Palmen SJMC. Brain anatomy in non-affected parents of autistic probands: a MRI study. Psychol Med 2005; 35:1411–1420.PubMedCrossRefGoogle Scholar
  86. 86.
    Peterson E, Schmidt GL, Tregellas JR, Winterrowd E, Kopelioff L, Hepburn S, Reite M, Rojas DC. A voxel-based morphometry study of gray matter in parents of children with autism. Neuroreport 2006; 17(12):1289–1292.PubMedCrossRefGoogle Scholar
  87. 87.
    Rojas DC, Smith JA, Benkers TL, Camou SL, Reite ML, Rogers SJ. Hippocampus and amygdala volumes in parents of children with autistic disorder. Am J Psychiat 2004; 161(11):2038–2044.PubMedCrossRefGoogle Scholar
  88. 88.
    Wassink TH, Hazlett HC, Epping EA, Arndt S, Dager SR, Schellenberg GD, Dawson G, Piven J. Cerebral cortical gray matter overgrowth and functional variation of the serotonin transporter gene in autism. Arch Gen Psychiat 2007; 64:709–717.PubMedCrossRefGoogle Scholar
  89. 89.
    Sparks BF, Friedman SD, Shaw DW, Aylward EH, Echelard D, Artru AA, Maravilla KR, Giedd JN, Munson J, Dawson G, Dager SR. Brain structural abnormalities in young children with autism spectrum disorder. Neurology 2002; 59(2):184–192.PubMedGoogle Scholar
  90. 90.
    Davis LK, Hazlett HC, Librant AL, Nopoulos P, Sheffield VC, Piven J, Wassink TH. Cortical enlargement in autism is associated with a functional VNTR in the monoamine oxidase A gene. Am J Med Genet B Neuropsychiat Genet 2008; 147B:1145–1151.CrossRefGoogle Scholar
  91. 91.
    Sabol SZ, Hu S, Hamer D. A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 1998; 103:273–279.PubMedCrossRefGoogle Scholar
  92. 92.
    Boylan CB, Blue ME, Hohmann CF. Modeling early cortical serotonergic deficits in autism. Behav Brain Res 2007; 176:94–108.PubMedCrossRefGoogle Scholar
  93. 93.
    Shaw P, Gornick M, Lerch J, Addington A, Seal J, Greenstein D, Sharp W, Evans A, Giedd JN, Castellanos FX, Rapoport JL. Polymorphisms of the dopamine d4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder. Arch Gen Psychiat 2007; 64:921–931.PubMedCrossRefGoogle Scholar
  94. 94.
    Phelps EA, LeDoux JE. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 2005; 48:175–187.PubMedCrossRefGoogle Scholar
  95. 95.
    Schultz RT. Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area. Int J Dev Neurosci 2005 May; 23(2–3):125–141.PubMedCrossRefGoogle Scholar
  96. 96.
    Haznedar MM, Buchsbaum MS, Wei TC, Hof PR, Cartwright C, Bienstock CA, Hollander E. Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiat 2001; 157:1994–2001.CrossRefGoogle Scholar
  97. 97.
    Howard MA, Cowell PE, Boucher J, Broks P, Mayes A, Farrant A, Roberts N. Convergent neuroanatomical and behavioural evidence of an amygdala hypothesis of autism. Neuroreport 2000; 11(13):2931–2935.PubMedCrossRefGoogle Scholar
  98. 98.
    Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, Lammers CR, Reiss AL, Amaral DG. The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages. J Neurosci 2004; 24(28):6392–6401.PubMedCrossRefGoogle Scholar
  99. 99.
    Nacewicz BM, Dalton KM, Johnstone T, Long MT, McAuliff EM, Oakes TR, Alexander AL, Davidson RJ. Amygdala volume and nonverbal social impairment in adolescent and adult males with autism. Arch Gen Psychiat 2006; 63:1417–1428.PubMedCrossRefGoogle Scholar
  100. 100.
    Palmen SJMC, Durston S, Nederveen H, Van England H. No evidence for preferential involvement of medial temporal lobe structures in high-functioning autism. Psychol Med 2006; 36:827–834.PubMedCrossRefGoogle Scholar
  101. 101.
    Munson J, Dawson G, Abbott R, Faja S, Webb SJ, Friedman SD, Shaw D, Artru A, Dager SR. Amygdalar volume and behavioral development in autism. Arch Gen Psychiat 2006; 63(6):686–693.PubMedCrossRefGoogle Scholar
  102. 102.
    Dalton KM, Nacewicz BM, Alexander AL, Davidson RJ. Gaze-fixation, brain activation, and amygdala volume in unaffected siblings of individuals with autism. Biol Psychiat 2007; 61:512–520.PubMedCrossRefGoogle Scholar
  103. 103.
    Schmahmann JD, Weilburg JB, Sherman JC. The neurop-sychiatry of the cerebellum — insights from the clinic. Cerebellum 2007; 6:254–267.PubMedCrossRefGoogle Scholar
  104. 104.
    Riva D, Giorgi C. The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours. Brain 2000; 123 (Pt 5):1051–1061.PubMedCrossRefGoogle Scholar
  105. 105.
    Desmond JE, Chen SH, DeRosa E, Pryor MR, Pfefferbaum A, Sullivan E V. Increased frontocerebellar activation in alcoholics during verbal working memory: an fMRI study. Neuroimage 2003; 19:1510–1520.PubMedCrossRefGoogle Scholar
  106. 106.
    Middleton FA, Strick PL. Cerebellar projections to the prefrontal cortex of the primate. J Neurosci 2001; 21: 700–712.PubMedGoogle Scholar
  107. 107.
    MacLeod CE, Zilles K, Schleicher A, Rilling JK, Gibson KR. Expansion of the neocerebellum in Hominoidea. J Hum Evol 2003; 44:401–429.PubMedCrossRefGoogle Scholar
  108. 108.
    Courchesne E, Hesselink JR, Jernigan TL, Yeung-Courchesne R. Abnormal neuroanatomy in a nonretarded person with autism. Unusual findings with magnetic resonance imaging. Arch Neurol 1987; 44(3):335–341.Google Scholar
  109. 109.
    Hardan AY, Minshew NJ, Harenski K, Keshavan MS. Posterior fossa magnetic resonance imaging in autism. J Am Acad Child Adol Psychiat 2001; 40(6):666–672.CrossRefGoogle Scholar
  110. 110.
    Cleavinger HB, Bigler ED, Johnson JL, Lu J, McMahon W, Lainhart JE. Quantitative magnetic resonance image analysis of the cerebellum in macrocephalic and normocephalic children and adults with autism. J Int Neuropsychol Soc 2008; 14:401–413.PubMedCrossRefGoogle Scholar
  111. 111.
    Kato T. Genetic and epigenic differences causing discordance between monozygotic twins as clue to molecular basis of mental disorders. Mol Psychiat 2005; 10:622–630.CrossRefGoogle Scholar
  112. 112.
    Aron AR, Durston S, Eagle DM, Logan GD, Stinear CM, Stuphorn V. Converging evidence for a fronto-basal-gan-glia network for inhibitory control of action and cognition. J Neurosci 2007; 27:11860–11864.PubMedCrossRefGoogle Scholar
  113. 113.
    Balleine BW, Delgado MR, Hikosaka O. The role of the dorsal striatum in reward and decision-making. J Neurosci 2007; 27:8161–8165.PubMedCrossRefGoogle Scholar
  114. 114.
    Graybiel AM. Habits, rituals, and the evaluative brain. Ann Rev Neurosci 2008; 31:359–387.PubMedCrossRefGoogle Scholar
  115. 115.
    Hardan AY, Kilpatrick M, Keshavan MS, Minshew NJ. Motor performance and anatomic magnetic resonance imaging (MRI) of the basal ganglia in autism. J Child Neurol 2003; 18(5):317–324.PubMedCrossRefGoogle Scholar
  116. 116.
    Sears LL, Vest C, Mohamed S, Bailey J, Ranson BJ, Piven J. An MRI study of the basal ganglia in autism. Prog Neuro-Psychopharmacol Biol Psychiat 1999; 23(4):613–624.CrossRefGoogle Scholar
  117. 117.
    Voelbel GT, Bates ME, Buckman JF, Pandina G, Hendren RL. Caudate nucleus volume and cognitive performance: are they related in childhood psychopathology? Biol Psychiat 2006; 60:942–950.PubMedCrossRefGoogle Scholar
  118. 118.
    Langen M, Durston S, Staal WG, Palmen SJ, van EH. Caudate nucleus is enlarged in high-functioning medication-naive subjects with autism. Biol Psychiat 2007; 62:262–266.PubMedCrossRefGoogle Scholar
  119. 119.
    Hollander E, Anagnostou E, Chaplin W, Esposito K, Haznedar MM, Licalzi E, Wasserman S, Soorya L, Buchsbaum M. Striatal volume on magnetic resonance imaging and repetitive behaviors in autism. Biol Psychiat 2005; 58:226–232.PubMedCrossRefGoogle Scholar
  120. 120.
    Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 2007; 17:103–111.PubMedCrossRefGoogle Scholar
  121. 121.
    Egaas B, Courchesne E, Saitoh O. Reduced size of corpus callosum in autism. Arch Neurol 1995; 52(8):794–801.PubMedGoogle Scholar
  122. 122.
    Elia M, Ferri R, Musumeci SA, Panerai S, Bottitta M, Scuderi C. Clinical correlates of brain morphometric features of subjects with low-functioning autistic disorder. J Child Neurol 2000; 15(8):504–508.PubMedCrossRefGoogle Scholar
  123. 123.
    Gaffney GR, Kuperman S, Tsai LY, Minchin S, Hassanein KM. Midsagittal magnetic resonance imaging of autism. Br J Psychiat 1987; 151:831–833.CrossRefGoogle Scholar
  124. 124.
    Hardan AY, Minshew NJ, Keshavan MS. Corpus callosum size in autism. Neurology 2000; 55:1033–1036.PubMedGoogle Scholar
  125. 125.
    Vidal CN, Nicolson R, DeVito TJ, Hayashi KM, Geaga JA, Drost DJ, Williamson PC, Rajakumar N, Sui Y, Dutton RA, Toga AW, Thompson PM. Mapping corpus callosum deficits in autism: an index of aberrant cortical connectivity. Biol Psychiat 2006; 60:218–225.PubMedCrossRefGoogle Scholar
  126. 126.
    Boger-Megiddo I, Shaw DW, Friedman SD, Sparks BF, Artru AA, Giedd JN, Dawson G, Dager SR. Corpus callo-sum morphometrics in young children with autism spectrum disorder. J Autism Dev Disord 2006; 36(6):733–739.PubMedCrossRefGoogle Scholar
  127. 127.
    Kilian S, Brown WS, Hallam BJ, McMahon W, Lu J, Johnson M, Bigler ED, Lainhart J. Regional callosal morphology in autism and macrocephaly. Dev Neuropsychol 2008; 33:74–99.PubMedGoogle Scholar
  128. 128.
    Witelson SF. Hand and sex differences in the isthmus and genu of the human corpus callosum. A postmortem morphological study. Brain 1989; 112(Pt 3):799–835.PubMedCrossRefGoogle Scholar
  129. 129.
    Piven J, Bailey J, Ranson BJ, Arndt S. An MRI study of the corpus callosum in autism. Am J Psychiat 1997; 154(8):1051–1056.PubMedGoogle Scholar
  130. 130.
    Just MA, Cherkassky VL, Keller TA, Kana RK, Minshew NJ. Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry. Cereb Cortex 2007; 17:951–961.PubMedCrossRefGoogle Scholar
  131. 131.
    Sowell ER, Peterson BS, Kan E, Woods RP, Yoshii J, Bansal R, Xu D, Zhu H, Thompson PM, Toga AW. Sex differences in cortical thickness mapped in 176 healthy individuals between 7 and 87 years of age. Cereb Cortex 2007; 17:1550–1560.PubMedCrossRefGoogle Scholar
  132. 132.
    Herve PY, Crivello F, Perchey G, Mazoyer B, Tzourio-Mazoyer N. Handedness and cerebral anatomical asymmetries in young adult males. Neuroimage 2006; 29: 1066–1079.PubMedCrossRefGoogle Scholar
  133. 133.
    Craig MC, Zaman SH, Daly EM, Cutter WJ, Robertson DMW, Hallahan B, Toal F, Reed S, Ambikapathy A, Brammer M, Murphy CM, Murphy DGM. Women with autistic-spectrum disorder: magnetic resonance imaging study of brain anatomy. Br J Psychiat 2007; 191:224–228.CrossRefGoogle Scholar
  134. 134.
    Szatmari P, Zwaigenbaum L, Bryson S. Conducting genetic epidemiology studies of autism spectrum disorders: issues in matching. J Autism Dev Disord 2004; 34:49–57.PubMedCrossRefGoogle Scholar
  135. 135.
    Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adol Psychiat 2008; 47:921–929.CrossRefGoogle Scholar
  136. 136.
    Carper RA, Moses P, Tigue ZD, Courchesne E. Cerebral lobes in autism: early hyperplasia and abnormal age effects. Neuroimage 2002; 16(4):1038–1051.PubMedCrossRefGoogle Scholar
  137. 137.
    Raznahan A, Toro R, Dale E, Paus T, Bolton PF, Murphy D. Cortical Dysmaturation in Autism Spectrum Disorder. Oral presentation at 7th annual meeting for autism research london. 2008. Ref Type: Internet Communication.Google Scholar
  138. 138.
    Giedd JN, Lenroot RK, Shaw P, Lalonde F, Celano M, White S, Tossell J, Addington A, Gogtay N. Trajectories of anatomic brain development as a phenotype. Novartis Found Symp 2008; 289:101–112.PubMedCrossRefGoogle Scholar
  139. 139.
    Knickmeyer RC, Wheelwright S, Hoekstra R, Baron-Cohen S. Age of menarche in females with autism spectrum conditions. Dev Med Child Neurol 2006; 48:1007–1008.PubMedCrossRefGoogle Scholar
  140. 140.
    Rojas DC, Peterson E, Winterrowd E, Reite ML, Rogers SJ, Tregellas JR. Regional gray matter volumetric changes in autism associated with social and repetitive behavior symptoms. BMC Psychiat 2006; 6:56.CrossRefGoogle Scholar
  141. 141.
    Murphy M, Bolton PF, Pickles A, Fombonne E, Piven J, Rutter M. Personality traits of the relatives of autistic probands. Psychol Med 2000; 30(6):1411–1424.PubMedCrossRefGoogle Scholar
  142. 142.
    Pickles A, Starr E, Kazak S, Bolton P, Papanikolaou K, Bailey A, Goodman R, Rutter M. Variable expression of the autism broader phenotype: findings from extended pedigrees. J Child Psychol Psychiat Allied Disciplines 2000; 41(4):491–502.CrossRefGoogle Scholar
  143. 143.
    Losh M, Childress D, Lam K, Piven J. Defining key features of the broad autism phenotype: a comparison across parents of multiple- and single-incidence autism families. Am J Med Genet B Neuropsychiat Genet 2008; 147B:424–433.CrossRefGoogle Scholar
  144. 144.
    Hall MH, Schulze K, Sham P, Kalidindi S, McDonald C, Bramon E, Levy DL, Murray RM, Rijsdijk F. Further evidence for shared genetic effects between psychotic bipolar disorder and P50 suppression: a combined twin and family study. Am J Med Genet B Neuropsychiat Genet 2008;147B(5):619–627.CrossRefGoogle Scholar
  145. 145.
    Pezawas L, Meyer-Lindenberg A, Goldman AL, Verchinski BA, Chen G, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger DR. MET BDNF protects against morphological S allele effects of 5-HTTLPR. Mol Psychiat 2008; 13:654.CrossRefGoogle Scholar
  146. 146.
    Hadjikhani N, Joseph R, Snyder J, Tager-Flusberg H. Anatomical differences in the mirror neuron system and social cognition network in autism. Cereb Cortex 2006; 16(9):1276–1282. Epub 2005.PubMedCrossRefGoogle Scholar
  147. 147.
    Nordahl CW, Dierker D, Mostafavi I, Schumann CM, Rivera SM, Amaral DG, van Essen DC. Cortical folding abnormalities in autism revealed by surface-based mor-phometry. J Neurosci 2007; 27:11725–11735.PubMedCrossRefGoogle Scholar
  148. 148.
    Levitt JG, Blanton RE, Smalley S, Thompson PM, Guthrie D, McCracken JT, Sadoun T, Heinichen L, Toga AW. Cortical sulcal maps in autism. Cereb Cortex 2003; 13:728–735.PubMedCrossRefGoogle Scholar
  149. 149.
    Vidal CN, Nicolson R, Boire J Y, Barra V, DeVito TJ, Hayashi KM, Geaga JA, Drost DJ, Williamson PC, Rajakumar N, Toga AW, Thompson PM. Three-dimensional mapping of the lateral ventricles in autism. Psychiat Res 2008; 163:106–115.CrossRefGoogle Scholar
  150. 150.
    Rubenstein JL, Rakic P. Genetic control of cortical development. (Review) (40 refs). Cereb Cortex 1999; 9(6):521–523.PubMedCrossRefGoogle Scholar
  151. 151.
    Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 2002; 297:365–369.PubMedCrossRefGoogle Scholar
  152. 152.
    Armstrong E, Schleicher A, Omran H, Curtis M, Zilles K. The ontogeny of human gyrification. Cereb Cortex 1995; 5:56–63.PubMedCrossRefGoogle Scholar
  153. 153.
    Sowell ER, Thompson PM, Leonard CM, Welcome SE, Kan E, Toga AW. Longitudinal mapping of cortical thickness and brain growth in normal children. J Neurosci 24(38):8223–8231, 2004.PubMedCrossRefGoogle Scholar
  154. 154.
    Huttenlocher PR. Morphometric study of human cerebral cortex development. Neuropsychol 1990; 28(6):517–527.CrossRefGoogle Scholar
  155. 155.
    Thompson PM, Lee AD, Dutton RA, Geaga JA, Hayashi KM, Eckert MA, Bellugi U, Galaburda AM, Korenberg JR, Mills DL, Toga AW, Reiss AL. Abnormal cortical complexity and thickness profiles mapped in Williams syndrome. J Neurosci 2005; 25:4146–4158.PubMedCrossRefGoogle Scholar
  156. 156.
    Shaw P, Eckstrand K, Sharp W, Blumenthal J, Lerch JP, Greenstein D, Clasen L, Evans A, Giedd J, Rapoport JL. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc Natl Acad Sci USA 2007; 104:19649–19654.PubMedCrossRefGoogle Scholar
  157. 157.
    Zwaigenbaum L, Thurm A, Stone W, Baranek G, Bryson S, Iverson J, Kau A, Klin A, Lord C, Landa R, Rogers S, Sigman M. Studying the emergence of autism spectrum disorders in high-risk infants: methodological and practical issues. J Autism Dev Disord 2007; 37(3):466–480.PubMedCrossRefGoogle Scholar
  158. 158.
    Osterling J, Dawson G. Early recognition of children with autism: a study of first birthday home videotapes. J Autism Dev Disord 1994; 24:247–257.PubMedCrossRefGoogle Scholar
  159. 159.
    Pickles A. Latent-class analysis of recurrence risk for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am J Hum Genet 1995; 57:717–726.PubMedGoogle Scholar
  160. 160.
    Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 2008; 9:341–355.PubMedCrossRefGoogle Scholar
  161. 161.
    Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW. Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 2007; 81:1289–1297.PubMedCrossRefGoogle Scholar
  162. 162.
    Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W et al. Strong association of de novo copy number mutations with autism. Science 2007;316:445–449.PubMedCrossRefGoogle Scholar
  163. 163.
    O'Callaghan FJ, Shiell AW, Osborne JP, Martyn CN. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 1998;351:1490.PubMedCrossRefGoogle Scholar
  164. 164.
    Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13(12):624–628.PubMedCrossRefGoogle Scholar
  165. 165.
    Raznahan A, Pugliese L, Barker G, Daly E, Powell J, Bolton P, Murphy DGM. Serotonin transporter genotype and Neuroanatomy in autism spectrum disorders. Psychiat gen, 2008 (in press).Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Armin Raznahan
    • 1
  • Jay N. Giedd
    • 2
  • Patrick F. Bolton
    • 1
  1. 1.Department of Child and Adolescent PsychiatryKing's College London, Institute of PsychiatryLondonUK
  2. 2.Child Psychiatry Branch, National Institute of Mental HealthUSA

Personalised recommendations