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Acta Neuropathologica

, Volume 124, Issue 1, pp 67–79 | Cite as

Decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism

  • Sarah Jacot-Descombes
  • Neha Uppal
  • Bridget Wicinski
  • Micaela Santos
  • James Schmeidler
  • Panteleimon Giannakopoulos
  • Helmut Heinsein
  • Christoph Schmitz
  • Patrick R. Hof
Original Paper

Abstract

Autism is a neurodevelopmental disorder characterized by deficits in social interaction and social communication, as well as by the presence of repetitive and stereotyped behaviors and interests. Brodmann areas 44 and 45 in the inferior frontal cortex, which are involved in language processing, imitation function, and sociality processing networks, have been implicated in this complex disorder. Using a stereologic approach, this study aims to explore the presence of neuropathological differences in areas 44 and 45 in patients with autism compared to age- and hemisphere-matched controls. Based on previous evidence in the fusiform gyrus, we expected to find a decrease in the number and size of pyramidal neurons as well as an increase in volume of layers III, V, and VI in patients with autism. We observed significantly smaller pyramidal neurons in patients with autism compared to controls, although there was no difference in pyramidal neuron numbers or layer volumes. The reduced pyramidal neuron size suggests that a certain degree of dysfunction of areas 44 and 45 plays a role in the pathology of autism. Our results also support previous studies that have shown specific cellular neuropathology in autism with regionally specific reduction in neuron size, and provide further evidence for the possible involvement of the mirror neuron system, as well as impairment of neuronal networks relevant to communication and social behaviors, in this disorder.

Keywords

Autism Brodmann area 44 Brodmann area 45 Inferior frontal gyrus Neuropathology Stereology 

Notes

Acknowledgments

The authors thank Autism Speaks (the Autism Celloidin Library Project, PRH), the James S. MacDonnell Foundation (PRH), the Seaver Foundation (NU), and the Vachoux Foundation (SJD, MS), Drs J. Wegiel, D. Lightfoot, and J. Pickett, as well as Ms E. Xiu for their generous support. We would also like to acknowledge the Bronx VA Medical Center Brain Bank, Harvard Brain Tissue Resource Center, National Institute of Child Health and Human Development Brain Tissue Bank, New York State Institute for Basic Research in Developmental Disabilities, Oxford Brain Bank, University of Maryland Brain and Tissue Bank, University of Wuerzburg Morphologic Brain Research Unit, and the Autism Tissue Program for providing the materials used in this study. We are especially grateful to the families who donated tissue to make this study possible.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    American Psychiatric Association (2000) ASM-IV-TR: diagnostic and statistical manual of mental disorders text revision. American Psychiatric Association, Washington, DCGoogle Scholar
  2. 2.
    Amunts K, Schleicher A, Burgel U, Mohlberg H, Uylings HB, Zilles K (1999) Broca’s region revisited: cytoarchitecture and intersubject variability. J Comp Neurol 412:319–341PubMedCrossRefGoogle Scholar
  3. 3.
    Baillargeon R, Scott RM, He Z (2010) False-belief understanding in infants. Trends Cogn Sci 14:110–118PubMedCrossRefGoogle Scholar
  4. 4.
    Barbas H (1986) Pattern in the laminar origin of corticocortical connections. J Comp Neurol 252:415–422PubMedCrossRefGoogle Scholar
  5. 5.
    Baron-Cohen S, Leslie AM, Frith U (1985) Does the autistic child have a “theory of mind”? Cognition 21:37–46PubMedCrossRefGoogle Scholar
  6. 6.
    Bookheimer S (2002) Functional MRI of language: new approaches to understanding the cortical organization of semantic processing. Annu Rev Neurosci 25:151–188PubMedCrossRefGoogle Scholar
  7. 7.
    Broca P (1861) Remarques sur le siège de la faculté du langage articulé; suivies d’une observation d’aphémie (perte de la parole). Bull Mem Soc Anat Paris 36:330–357Google Scholar
  8. 8.
    Brodmann K (1909) Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Johann Ambrosius Barth, LeipzigGoogle Scholar
  9. 9.
    Carey DP (1996) ‘Monkey see, monkey do’ cells. Neurophysiology. Curr Biol 6:1087–1088PubMedCrossRefGoogle Scholar
  10. 10.
    Casanova MF, El-Baz A, Vanbogaert E, Narahari P, Switala A (2010) A topographic study of minicolumnar core width by lamina comparison between autistic subjects and controls: possible minicolumnar disruption due to an anatomical element in-common to multiple laminae. Brain Pathol 20:451–458PubMedCrossRefGoogle Scholar
  11. 11.
    Catani M, Jones DK, ffytche DH (2005) Perisylvian language networks of the human brain. Ann Neurol 57:8–16PubMedCrossRefGoogle Scholar
  12. 12.
    Coleman PD, Romano J, Lapham L, Simon W (1985) Cell counts in cerebral cortex of an autistic patient. J Autism Dev Disord 15:245–255PubMedCrossRefGoogle Scholar
  13. 13.
    Council on Child and Adolescent Health, (1988) American Academy of Pediatrics Council on Child and Adolescent Health: age limits of pediatrics. Pediatrics 81:736Google Scholar
  14. 14.
    Courchesne E, Campbell K, Solso S (2011) Brain growth across the life span in autism: age-specific changes in anatomical pathology. Brain Res 1380:138–145PubMedCrossRefGoogle Scholar
  15. 15.
    Courchesne E, Mouton PR, Calhoun ME et al (2011) Neuron number and size in prefrontal cortex of children with autism. J Am Med Assoc 306:2001–2010CrossRefGoogle Scholar
  16. 16.
    Courchesne E, Pierce K (2005) Why the frontal cortex in autism might be talking only to itself: local over-connectivity but long-distance disconnection. Curr Opin Neurobiol 15:225–230PubMedCrossRefGoogle Scholar
  17. 17.
    di Pellegrino G, Fadiga L, Fogassi L, Gallese V, Rizzolatti G (1992) Understanding motor events: a neurophysiological study. Exp Brain Res 91:176–180PubMedCrossRefGoogle Scholar
  18. 18.
    Dinstein I, Pierce K, Eyler L et al (2011) Disrupted neural synchronization in toddlers with autism. Neuron 70:1218–1225PubMedCrossRefGoogle Scholar
  19. 19.
    Fatemi SH, Earle J, Kanodia R et al (2002) Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol 22:25–33PubMedCrossRefGoogle Scholar
  20. 20.
    Fogassi L, Ferrari PF, Gesierich B, Rozzi S, Chersi F, Rizzolatti G (2005) Parietal lobe: from action organization to intention understanding. Science 308:662–667PubMedCrossRefGoogle Scholar
  21. 21.
    Ford A, McGregor KM, Case K, Crosson B, White KD (2010) Structural connectivity of Broca’s area and medial frontal cortex. Neuroimage 52:1230–1237PubMedCrossRefGoogle Scholar
  22. 22.
    Frith U (2001) Mind blindness and the brain in autism. Neuron 32:969–979PubMedCrossRefGoogle Scholar
  23. 23.
    Gallese V (2003) The roots of empathy: the shared manifold hypothesis and the neural basis of intersubjectivity. Psychopathology 36:171–180PubMedCrossRefGoogle Scholar
  24. 24.
    Gallese V, Fadiga L, Fogassi L, Rizzolatti G (1996) Action recognition in the premotor cortex. Brain 119:593–609PubMedCrossRefGoogle Scholar
  25. 25.
    Gilbert CD, Kelly JP (1975) The projections of cells in different layers of the cat’s visual cortex. J Comp Neurol 163:81–105PubMedCrossRefGoogle Scholar
  26. 26.
    Goines P, Van de Water J (2010) The immune system’s role in the biology of autism. Curr Opin Neurol 23:111–117PubMedCrossRefGoogle Scholar
  27. 27.
    Grezes J, Armony JL, Rowe J, Passingham RE (2003) Activations related to “mirror” and “canonical” neurones in the human brain: an fMRI study. Neuroimage 18:928–937PubMedCrossRefGoogle Scholar
  28. 28.
    Hadjikhani N, Joseph RM, Snyder J, Tager-Flusberg H (2006) Anatomical differences in the mirror neuron system and social cognition network in autism. Cereb Cortex 16:1276–1282PubMedCrossRefGoogle Scholar
  29. 29.
    Hamilton AF (2009) Goals, intentions and mental states: challenges for theories of autism. J Child Psychol Psychiatry 50:881–892PubMedCrossRefGoogle Scholar
  30. 30.
    Hamilton AF, Brindley RM, Frith U (2007) Imitation and action understanding in autistic spectrum disorders: how valid is the hypothesis of a deficit in the mirror neuron system? Neuropsychologia 45:1859–1868PubMedCrossRefGoogle Scholar
  31. 31.
    Hampshire A, Chamberlain SR, Monti MM, Duncan J, Owen AM (2010) The role of the right inferior frontal gyrus: inhibition and attentional control. Neuroimage 50:1313–1319PubMedCrossRefGoogle Scholar
  32. 32.
    Happe F, Frith U (1996) The neuropsychology of autism. Brain 119(Pt 4):1377–1400PubMedCrossRefGoogle Scholar
  33. 33.
    Hari R, Kujala MV (2009) Brain basis of human social interaction: from concepts to brain imaging. Physiol Rev 89:453–479PubMedCrossRefGoogle Scholar
  34. 34.
    Haxby JV, Hoffman EA, Gobbini MI (2000) The distributed human neural system for face perception. Trends Cogn Sci 4:223–233PubMedCrossRefGoogle Scholar
  35. 35.
    Hayes TL, Lewis DA (1993) Hemispheric differences in layer III pyramidal neurons of the anterior language area. Arch Neurol 50:501–505PubMedCrossRefGoogle Scholar
  36. 36.
    Hazlett HC, Poe MD, Gerig G et al (2011) Early brain overgrowth in autism associated with an increase in cortical surface area before age 2 years. Arch Gen Psychiatry 68:467–476PubMedCrossRefGoogle Scholar
  37. 37.
    Heinsen H, Arzberger T, Schmitz C (2000) Celloidin mounting (embedding without infiltration)—a new, simple and reliable method for producing serial sections of high thickness through complete human brains and its application to stereological and immunohistochemical investigations. J Chem Neuroanat 20:49–59PubMedCrossRefGoogle Scholar
  38. 38.
    Heinsen H, Heinsen YL (1991) Serial thick, frozen, gallocyanin stained sections of human central nervous system. J Histotechnol 14:167–173Google Scholar
  39. 39.
    Heiser M, Iacoboni M, Maeda F, Marcus J, Mazziotta JC (2003) The essential role of Broca’s area in imitation. Eur J Neurosci 17:1123–1128PubMedCrossRefGoogle Scholar
  40. 40.
    Iacoboni M, Woods RP, Brass M, Bekkering H, Mazziotta JC, Rizzolatti G (1999) Cortical mechanisms of human imitation. Science 286:2526–2528PubMedCrossRefGoogle Scholar
  41. 41.
    Jacobs B, Driscoll L, Schall M (1997) Life-span dendritic and spine changes in areas 10 and 18 of human cortex: a quantitative Golgi study. J Comp Neurol 386:661–680PubMedCrossRefGoogle Scholar
  42. 42.
    Johnson-Frey SH, Maloof FR, Newman-Norlund R, Farrer C, Inati S, Grafton ST (2003) Actions or hand-object interactions? Human inferior frontal cortex and action observation. Neuron 39:1053–1058PubMedCrossRefGoogle Scholar
  43. 43.
    Jones EG (1984) Laminar distribution of cortical efferent cells. In: Peters A, Jones EG (eds) Cellular components of the cerebral cortex. Plenum, New York, pp 521–553Google Scholar
  44. 44.
    Just MA, Cherkassky VL, Keller TA, Minshew NJ (2004) Cortical activation and synchronization during sentence comprehension in high-functioning autism: evidence of underconnectivity. Brain 127:1811–1821PubMedCrossRefGoogle Scholar
  45. 45.
    Kana RK, Keller TA, Cherkassky VL, Minshew NJ, Just MA (2006) Sentence comprehension in autism: thinking in pictures with decreased functional connectivity. Brain 129:2484–2493PubMedCrossRefGoogle Scholar
  46. 46.
    Keller SS, Deppe M, Herbin M, Gilissen E (2012) Variability and asymmetry of the sulcal contours defining Broca’s area homologue in the chimpanzee brain. J Comp Neurol 520:1165–1180PubMedCrossRefGoogle Scholar
  47. 47.
    Kelly C, Uddin LQ, Shehzad Z et al (2010) Broca’s region: linking human brain functional connectivity data and non-human primate tracing anatomy studies. Eur J Neurosci 32:383–398PubMedCrossRefGoogle Scholar
  48. 48.
    Keuken MC, Hardie A, Dorn BT et al (2011) The role of the left inferior frontal gyrus in social perception: an rTMS study. Brain Res 1383:196–205PubMedCrossRefGoogle Scholar
  49. 49.
    Kobayashi C, Glover GH, Temple E (2007) Children’s and adults’ neural bases of verbal and nonverbal ‘theory of mind’. Neuropsychologia 45:1522–1532PubMedCrossRefGoogle Scholar
  50. 50.
    Kosaka H, Omori M, Munesue T et al (2010) Smaller insula and inferior frontal volumes in young adults with pervasive developmental disorders. Neuroimage 50:1357–1363PubMedCrossRefGoogle Scholar
  51. 51.
    Koshino H, Carpenter PA, Minshew NJ, Cherkassky VL, Keller TA, Just MA (2005) Functional connectivity in an fMRI working memory task in high-functioning autism. Neuroimage 24:810–821PubMedCrossRefGoogle Scholar
  52. 52.
    Lai G, Pantazatos SP, Schneider H, Hirsch J (2012) Neural systems for speech and song in autism. Brain 135:961–975PubMedCrossRefGoogle Scholar
  53. 53.
    Liakakis G, Nickel J, Seitz RJ (2011) Diversity of the inferior frontal gyrus—a meta-analysis of neuroimaging studies. Behav Brain Res 225:341–347PubMedCrossRefGoogle Scholar
  54. 54.
    Lund JS, Lund RD, Hendrickson AE, Bunt AH, Fuchs AF (1975) The origin of efferent pathways from the primary visual cortex, area 17, of the macaque monkey as shown by retrograde transport of horseradish peroxidase. J Comp Neurol 164:287–303PubMedCrossRefGoogle Scholar
  55. 55.
    Ono M, Kubik S, Abernathey CD (1990) Atlas of the cerebral sulci. Thieme Medical Publishers, New York, pp 54–58Google Scholar
  56. 56.
    Palmen SJ, van Engeland H, Hof PR, Schmitz C (2004) Neuropathological findings in autism. Brain 127:2572–2583PubMedCrossRefGoogle Scholar
  57. 57.
    Patterson PH (2011) Maternal infection and immune involvement in autism. Trends Mol Med 17:389–394PubMedCrossRefGoogle Scholar
  58. 58.
    Premack D, Woodruff G (1978) Does the chimpanzee have a ‘theory of mind’? Behav Brain Sci 4:515–526CrossRefGoogle Scholar
  59. 59.
    Rice C (2009) Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill Summ 58:1–20Google Scholar
  60. 60.
    Rizzolatti G, Fadiga L, Gallese V, Fogassi L (1996) Premotor cortex and the recognition of motor actions. Brain Res Cogn Brain Res 3:131–141PubMedCrossRefGoogle Scholar
  61. 61.
    Rizzolatti G, Fogassi L, Gallese V (2001) Neurophysiological mechanisms underlying the understanding and imitation of action. Nat Rev Neurosci 2:661–670PubMedCrossRefGoogle Scholar
  62. 62.
    Rogers SJ, Pennington BF (1991) A theoretical approach to the deficits in infantile autism. Dev Psychopathol 3:137–162CrossRefGoogle Scholar
  63. 63.
    Rossignol DA, Frye RE (2012) A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures. Mol Psychiatry 17:389–401Google Scholar
  64. 64.
    Santos M, Uppal N, Butti C et al (2011) Von economo neurons in autism: a stereologic study of the frontoinsular cortex in children. Brain Res 1380:206–217PubMedCrossRefGoogle Scholar
  65. 65.
    Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130:813–831PubMedCrossRefGoogle Scholar
  66. 66.
    Schumann CM, Amaral DG (2006) Stereological analysis of amygdala neuron number in autism. J Neurosci 26:7674–7679PubMedCrossRefGoogle Scholar
  67. 67.
    Senju A (2011) Spontaneous theory of mind and its absence in autism spectrum disorders. Neuroscientist. doi: 10.1177/1073858410397208 PubMedGoogle Scholar
  68. 68.
    Sherwood CC, Broadfield DC, Holloway RL, Gannon PJ, Hof PR (2003) Variability of Broca’s area homologue in african great apes: implications for language evolution. Anat Rec 271:276–285CrossRefGoogle Scholar
  69. 69.
    Terry RD, DeTeresa R, Hansen LA (1987) Neocortical cell counts in normal human adult aging. Ann Neurol 21:530–539PubMedCrossRefGoogle Scholar
  70. 70.
    Theoret H, Halligan E, Kobayashi M, Fregni F, Tager-Flusberg H, Pascual-Leone A (2005) Impaired motor facilitation during action observation in individuals with autism spectrum disorder. Curr Biol 15:R84–R85PubMedCrossRefGoogle Scholar
  71. 71.
    Turella L, Pierno AC, Tubaldi F, Castiello U (2009) Mirror neurons in humans: consisting or confounding evidence? Brain Lang 108:10–21PubMedCrossRefGoogle Scholar
  72. 72.
    Tyler LK, Marslen-Wilson WD, Randall B et al (2011) Left inferior frontal cortex and syntax: function, structure and behaviour in patients with left hemisphere damage. Brain 134:415–431PubMedCrossRefGoogle Scholar
  73. 73.
    van Kooten IA, Palmen SJ, von Cappeln P et al (2008) Neurons in the fusiform gyrus are fewer and smaller in autism. Brain 131:987–999PubMedCrossRefGoogle Scholar
  74. 74.
    Villalobos ME, Mizuno A, Dahl BC, Kemmotsu N, Muller RA (2005) Reduced functional connectivity between V1 and inferior frontal cortex associated with visuomotor performance in autism. Neuroimage 25:916–925PubMedCrossRefGoogle Scholar
  75. 75.
    von Economo C (1927) L’architecture cellulaire normale de l’écorce cérébrale. Masson, ParisGoogle Scholar
  76. 76.
    Wegiel J, Kuchna I, Nowicki K et al (2010) The neuropathology of autism: defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathol 119:755–770PubMedCrossRefGoogle Scholar
  77. 77.
    West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497PubMedCrossRefGoogle Scholar
  78. 78.
    Williams JH (2008) Self-other relations in social development and autism: Multiple roles for mirror neurons and other brain bases. Autism Res 1:73–90PubMedCrossRefGoogle Scholar
  79. 79.
    Williams JH, Whiten A, Suddendorf T, Perrett DI (2001) Imitation, mirror neurons and autism. Neurosci Biobehav Rev 25:287–295PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Sarah Jacot-Descombes
    • 1
    • 4
  • Neha Uppal
    • 1
    • 3
  • Bridget Wicinski
    • 1
  • Micaela Santos
    • 1
    • 4
  • James Schmeidler
    • 2
  • Panteleimon Giannakopoulos
    • 4
    • 5
  • Helmut Heinsein
    • 6
  • Christoph Schmitz
    • 7
  • Patrick R. Hof
    • 1
  1. 1.Fishberg Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA
  2. 2.Department of PsychiatryMount Sinai School of MedicineNew YorkUSA
  3. 3.Seaver Autism CenterMount Sinai School of MedicineNew YorkUSA
  4. 4.Department of Mental Health and PsychiatryUniversity Hospitals and School of MedicineGenevaSwitzerland
  5. 5.Department of PsychiatryUniversity of Lausanne School of MedicineLausanneSwitzerland
  6. 6.Morphological Brain Research Unit, Department of Psychiatry, Psychosomatics, and PsychotherapyUniversity of WuerzburgWuerzburgGermany
  7. 7.Department of Neuroanatomy, School of MedicineLudwig-Maximilians UniversityMunichGermany

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