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Acta Neuropathologica

, Volume 118, Issue 5, pp 673–684 | Cite as

The anterior cingulate cortex in autism: heterogeneity of qualitative and quantitative cytoarchitectonic features suggests possible subgroups

  • Marissa Leigh Simms
  • Thomas L. Kemper
  • Clare M. Timbie
  • Margaret L. Bauman
  • Gene J. Blatt
Original Paper

Abstract

Autism is a behaviorally defined disorder with deficits in social interaction, communication, atypical behaviors, and restricted areas of interest. Postmortem studies of the brain in autism have shown a broad spectrum of abnormalities in the cerebellum and neocortex, involving limbic regions such as anterior cingulate cortex (ACC, Brodmann’s area 24). Using stereological techniques, we analyzed quantitatively cytoarchitectonic subdomains of the ACC (areas 24a, b, c) with regard to cell packing density and cell size. Microscopic examination of the ACC was also done to identify any neuropathologies. Results showed a significant decrease in cell size in layers I–III and layers V–VI of area 24b and in cell packing density in layers V–VI of area 24c. Direct comparisons revealed irregular lamination in three of nine autism brains and increased density of neurons in the subcortical white matter in the remaining cases. Because previous studies have suggested that von Economo neurons (VENs) may be altered in autism, a preliminary study of their density and size was undertaken. VEN density did not differ between autism and control brains overall. However, among the nine autism cases, there were two subsets; three brains with significantly increased VEN density and the remaining six cases with reduced VEN density compared to controls. Collectively, the findings of this pilot study may reflect the known heterogeneity in individuals with autism and variations in clinical symptomotology. Further neuroanatomic analyses of the ACC, from carefully documented subjects with autism, could substantially expand our understanding of ACC functions and its role in autism.

Keywords

Autism ACC von Economo Neurons Neuropathology 

Notes

Acknowledgments

Tissue was provided by the Harvard Brain Bank Tissue Resource Center, the Autism Tissue Program and the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. Supported by the National Institutes of Health Studies To Advance Autism Research and Treatment (NIH STAART) U54 MH66398 and National Institutes of Neurological Disorders and Stroke (NINDS) NS38975-01A1. We gratefully acknowledge Hillary Kaplan for her help with tissue processing, Dr. Michael Bowley for helpful discussions regarding stereological principles and design, Jerry Skefos for his expert technical assistance, and Dr. Ron Killiany for his statistical expertise.

References

  1. 1.
    Abe N, Suzuki M, Tsukiura T, Mori E, Yamaguchi K, Itoh M, Fujii T (2006) Dissociable roles of prefrontal and anterior cingulate cortices in deception. Cereb Cortex 16:192–199CrossRefPubMedGoogle Scholar
  2. 2.
    Akbarian S, Kim JJ, Potkin SG, Hetrick WP, Bunney WE Jr, Jones EG (1996) Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients. Arch Gen Psychiatry 53:425–436PubMedGoogle Scholar
  3. 3.
    Allman J, Hakeem A, Watson K (2002) Two phylogenetic specializations in the human brain. Neuroscientist 8:335–346CrossRefPubMedGoogle Scholar
  4. 4.
    Allman JM, Hakeem A, Erwin JM, Nimchinsky E, Hof P (2001) The anterior cingulate cortex. The evolution of an interface between emotion and cognition. Ann N Y Acad Sci 935:107–117PubMedCrossRefGoogle Scholar
  5. 5.
    Allman JM, Watson KK, Tetreault NA, Hakeem AY (2005) Intuition and autism: a possible role for von Economo neurons. Trends Cogn Sci 9:367–373CrossRefPubMedGoogle Scholar
  6. 6.
    American Psychiatric Association (1994) Diagnostic criteria from DSM-IV. The Association Washington, DCGoogle Scholar
  7. 7.
    Arber S (2004) Subplate neurons: bridging the gap to function in the cortex. Trends Neurosci 27:111–113CrossRefPubMedGoogle Scholar
  8. 8.
    Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M (1995) Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 25:63–77CrossRefPubMedGoogle Scholar
  9. 9.
    Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, Rutter M, Lantos P (1998) A clinicopathological study of autism. Brain 121(Pt 5):889–905CrossRefPubMedGoogle Scholar
  10. 10.
    Barnea-Goraly N, Kwon H, Menon V, Eliez S, Lotspeich L, Reiss AL (2004) White matter structure in autism: preliminary evidence from diffusion tensor imaging. Biol Psychiatry 55:323–326CrossRefPubMedGoogle Scholar
  11. 11.
    Butti C, Sherwood CC, Hakeem AY, Allman JM, Hof PR (2009) Total number and volume of von Economo neurons in the brains of cetaceans. J Comp Neurol (in press)Google Scholar
  12. 12.
    Carper RA, Moses P, Tigue ZD, Courchesne E (2002) Cerebral lobes in autism: early hyperplasia and abnormal age effects. Neuroimage 16:1038–1051CrossRefPubMedGoogle Scholar
  13. 13.
    Casanova MF, Buxhoeveden DP, Switala AE, Roy E (2002) Minicolumnar pathology in autism. Neurology 58:428–432PubMedGoogle Scholar
  14. 14.
    Cohen MX, Heller AS, Ranganath C (2005) Functional connectivity with anterior cingulate and orbitofrontal cortices during decision-making. Brain Res Cogn Brain Res 23:61–70CrossRefPubMedGoogle Scholar
  15. 15.
    Courchesne E, Pierce K (2005) Brain overgrowth in autism during a critical time in development: implications for frontal pyramidal neuron and interneuron development and connectivity. Int J Dev Neurosci 23:153–170CrossRefPubMedGoogle Scholar
  16. 16.
    Devinsky O, Morrell MJ, Vogt BA (1995) Contributions of anterior cingulate cortex to behaviour. Brain 118(Pt 1):279–306CrossRefPubMedGoogle Scholar
  17. 17.
    Eastwood SL, Harrison PJ (2003) Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis. Mol Psychiatry 8:769, 821–831Google Scholar
  18. 18.
    Eastwood SL, Harrison PJ (2005) Interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal gyrus in schizophrenia. Schizophr Res 79:181–188CrossRefPubMedGoogle Scholar
  19. 19.
    Fan J, Hof PR, Guise KG, Fosella JA, Posner MI (2008) The functional integration of the anterior cingulate cortex during conflict processing. Cereb Cortex 18:796–805CrossRefPubMedGoogle Scholar
  20. 20.
    Folstein S, Rutter M (1977) Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry 18:297–321CrossRefPubMedGoogle Scholar
  21. 21.
    Frith U, Frith C (2001) The biological basis of social interaction. Curr Direct Psycholog Sci 10:151–155CrossRefGoogle Scholar
  22. 22.
    Gehring WJ, Taylor SF (2004) When the going gets tough, the cingulate gets going. Nat Neurosci 7:1285–1287CrossRefPubMedGoogle Scholar
  23. 23.
    Gittins R, Harrison PJ (2004) A quantitative morphometric study of the human anterior cingulate cortex. Brain Res 1013:212–222CrossRefPubMedGoogle Scholar
  24. 24.
    Hakeem AY, Sherwood CC, Bonar CJ, Butti C, Hof PR, Allman JM (2009) Von Economo neurons in the elephant brain. Anat Rec 292:242–248CrossRefGoogle Scholar
  25. 25.
    Harding B, Copp AJ (1997) Malformations. In: Graham D, Lantos P (eds) Greenfield’s neuropathology. Arnold, London, pp 397–536Google Scholar
  26. 26.
    Haznedar MM, Buchsbaum MS, Wei TC, Hof PR, Cartwright C, Bienstock CA, Hollander E (2000) Limbic circuitry in patients with autism spectrum disorders studied with positron emission tomography and magnetic resonance imaging. Am J Psychiatry 157:1994–2001CrossRefPubMedGoogle Scholar
  27. 27.
    Herbert MR, Ziegler DA, Makris N, Filipek PA, Kemper TL, Normandin JJ, Sanders HA, Kennedy DN, Caviness VS Jr (2004) Localization of white matter volume increase in autism and developmental language disorder. Ann Neurol 55:530–540CrossRefPubMedGoogle Scholar
  28. 28.
    Hof PR, Van der Gucht E (2007) Structure of the cerebral cortex of the humpback whale, Megaptera novaeangliae (Cetacea, Mysticeti, Balaenopteridae). Anat Rec 290:1–31CrossRefGoogle Scholar
  29. 29.
    Huster RJ, Westerhausen R, Kreuder F, Schweiger E, Wittling W (2007) Morphologic asymmetry of the human anterior cingulate cortex. Neuroimage 34:888–895CrossRefPubMedGoogle Scholar
  30. 30.
    Hutsler JJ, Love T, Zhang H (2007) Histological and magnetic resonance imaging assessment of cortical layering and thickness in autism spectrum disorders. Biol Psychiatry 61:449–457CrossRefPubMedGoogle Scholar
  31. 31.
    Joseph R (1996) Neuropsychiatry, neurophysiology, and clinical neuroscience, 2nd edn. Williams and Wilkins, BaltimoreGoogle Scholar
  32. 32.
    Kanold PO, Kara P, Reid RC, Shatz CJ (2003) Role of subplate neurons in functional maturation of visual cortical columns. Science 301:521–525CrossRefPubMedGoogle Scholar
  33. 33.
    Kaufman JA, Paul LK, Manaye KF, Granstedt AE, Hof PR, Hakeem AY, Allman JM (2008) Selective reduction of von Economo neuron number in agenesis of the corpus callosum. Acta Neuropathol 116:479–489CrossRefPubMedGoogle Scholar
  34. 34.
    Kemper TL (1988) Neuroanatomic studies of dyslexia and autism. In: Disorders of the developing nervous system. In: Swann JW, Messer A (eds) Changing views on their origins, diagnoses, and treatment. Alan R. Liss, New York, pp 125–154Google Scholar
  35. 35.
    Kemper TL, Bauman M (1998) Neuropathology of infantile autism. J Neuropathol Exp Neurol 57:645–652CrossRefPubMedGoogle Scholar
  36. 36.
    Kemper TL, Bauman ML (1993) The contribution of neuropathologic studies to the understanding of autism. Neurol Clin 11:175–187PubMedGoogle Scholar
  37. 37.
    Kennedy DP, Semendeferi K, Courchesne E (2007) No reduction of spindle neuron number in frontoinsular cortex in autism. Brain Cogn 64:124–129CrossRefPubMedGoogle Scholar
  38. 38.
    Kerns JG, Cohen JD, MacDonald AW 3rd, Cho RY, Stenger VA, Carter CS (2004) Anterior cingulate conflict monitoring and adjustments in control. Science 303:1023–1026CrossRefPubMedGoogle Scholar
  39. 39.
    Kostovic I, Rakic P (1990) Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J Comp Neurol 297:441–470CrossRefPubMedGoogle Scholar
  40. 40.
    Kuehn BM (2007) CDC: autism spectrum disorders common. J Am Med Assoc 297:940CrossRefGoogle Scholar
  41. 41.
    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 (2006) Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism. Am J Med Genet A 140:2257–2274PubMedGoogle Scholar
  42. 42.
    Luders E, Narr KL, Thompson PM, Rex DE, Jancke L, Toga AW (2006) Hemispheric asymmetries in cortical thickness. Cereb Cortex 16:1232–1238CrossRefPubMedGoogle Scholar
  43. 43.
    Marin-Padilla M (1988) Early ontogenesis of the human cerebral cortex In: Peters A JE (ed) Cerebral cortex, vol 7. Plenum Press, New York, pp 1–34Google Scholar
  44. 44.
    Matsumoto K, Tanaka K (2004) Neuroscience. Conflict and cognitive control. Science 303:969–970CrossRefPubMedGoogle Scholar
  45. 45.
    Mundy P (2003) Annotation: the neural basis of social impairments in autism: the role of the dorsal medial-frontal cortex and anterior cingulate system. J Child Psychol Psychiatry 44:793–809CrossRefPubMedGoogle Scholar
  46. 46.
    Murphy DG, Daly E, Schmitz N, Toal F, Murphy K, Curran S, Erlandsson K, Eersels J, Kerwin R, Ell P, Travis M (2006) Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger’s syndrome: an in vivo SPECT study. Am J Psychiatry 163:934–936CrossRefPubMedGoogle Scholar
  47. 47.
    Nimchinsky EA, Gilissen E, Allman JM, Perl DP, Erwin JM, Hof PR (1999) A neuronal morphologic type unique to humans and great apes. Proc Natl Acad Sci USA 96:5268–5273CrossRefPubMedGoogle Scholar
  48. 48.
    Nimchinsky EA, Vogt BA, Morrison JH, Hof PR (1995) Spindle neurons of the human anterior cingulate cortex. J Comp Neurol 355:27–37CrossRefPubMedGoogle Scholar
  49. 49.
    Ohnishi T, Matsuda H, Hashimoto T, Kunihiro T, Nishikawa M, Uema T, Sasaki M (2000) Abnormal regional cerebral blood flow in childhood autism. Brain 123(Pt 9):1838–1844CrossRefPubMedGoogle Scholar
  50. 50.
    Palmen SJ, van Engeland H, Hof PR, Schmitz C (2004) Neuropathological findings in autism. Brain 127:2572–2583CrossRefPubMedGoogle Scholar
  51. 51.
    Paus T, Tomaiuolo F, Otaky N, MacDonald D, Petrides M, Atlas J, Morris R, Evans AC (1996) Human cingulate and paracingulate sulci: pattern, variability, asymmetry, and probabilistic map. Cereb Cortex 6:207–214CrossRefPubMedGoogle Scholar
  52. 52.
    Paulus MP, Frank LR (2006) Anterior cingulate activity modulates nonlinear decision weight function of uncertain prospects. Neuroimage 30:668–677CrossRefPubMedGoogle Scholar
  53. 53.
    Phillips ML, Drevets WC, Rauch SL, Lane R (2003) Neurobiology of emotion perception I: the neural basis of normal emotion perception. Biol Psychiatry 54:504–514CrossRefPubMedGoogle Scholar
  54. 54.
    Phillips ML, Drevets WC, Rauch SL, Lane R (2003) Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 54:515–528CrossRefPubMedGoogle Scholar
  55. 55.
    Rakic P (1988) Defects of neuronal migration and the pathogenesis of cortical malformations. Prog Brain Res 73:15–37CrossRefPubMedGoogle Scholar
  56. 56.
    Ramón Y, Cajal S, DeFelipe J, Jones EG (1988) Cajal on the cerebral cortex : an annotated translation of the complete writings. Oxford University Press, New YorkGoogle Scholar
  57. 57.
    Redcay E, Courchesne E (2005) When is the brain enlarged in autism? A meta-analysis of all brain size reports. Biol Psychiatry 58:1–9Google Scholar
  58. 58.
    Schmitz C, Hof PR (2000) Recommendations for straightforward and rigorous methods of counting neurons based on a computer simulation approach. J Chem Neuroanat 20:93–114CrossRefPubMedGoogle Scholar
  59. 59.
    Schumann CM, Amaral DG (2006) Stereological analysis of amygdala neuron number in autism. J Neurosci 26:7674–7679CrossRefPubMedGoogle Scholar
  60. 60.
    Seeley WW, Carlin DA, Allman JM, Macedo MN, Bush C, Miller BL, Dearmond SJ (2006) Early frontotemporal dementia targets neurons unique to apes and humans. Ann Neurol 60:660–667CrossRefPubMedGoogle Scholar
  61. 61.
    Sidman RL, Rakic P (1982) Development of the human central nervous system. In: Haymaker W, Adams S (eds) Histology and histopathology of the nervous system, C. C. Thomas, SpringfieldGoogle Scholar
  62. 62.
    Super H, Soriano E, Uylings HB (1998) The functions of the preplate in development and evolution of the neocortex and hippocampus. Brain Res Brain Res Rev 27:40–64CrossRefPubMedGoogle Scholar
  63. 63.
    van Kooten IA, Palmen SJ, von Cappeln P, Steinbusch HW, Korr H, Heinsen H, Hof PR, van Engeland H, Schmitz C (2008) Neurons in the fusiform gyrus are fewer and smaller in autism. Brain 131:987–999CrossRefPubMedGoogle Scholar
  64. 64.
    Vogt BA, Nimchinsky EA, Vogt LJ, Hof PR (1995) Human cingulate cortex: surface features, flat maps, and cytoarchitecture. J Comp Neurol 359:490–506CrossRefPubMedGoogle Scholar
  65. 65.
    Welchew DE, Ashwin C, Berkouk K, Salvador R, Suckling J, Baron-Cohen S, Bullmore E (2005) Functional disconnectivity of the medial temporal lobe in Asperger’s syndrome. Biol Psychiatry 57:991–998CrossRefPubMedGoogle Scholar
  66. 66.
    Wenderoth N, Debaere F, Sunaert S, Swinnen SP (2005) The role of anterior cingulate cortex and precuneus in the coordination of motor behaviour. Eur J NeuroSci 22:235–246CrossRefPubMedGoogle Scholar
  67. 67.
    West MJ (1993) New stereological methods for counting neurons. Neurobiol Aging 14:275–285CrossRefPubMedGoogle Scholar
  68. 68.
    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 231:482–497CrossRefPubMedGoogle Scholar
  69. 69.
    Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ (2008) Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains: a stereological experiment using calbindin-D28k. Cerebellum 7:406–416CrossRefPubMedGoogle Scholar
  70. 70.
    Williams ZM, Bush G, Rauch SL, Cosgrove GR, Eskandar EN (2004) Human anterior cingulate neurons and the integration of monetary reward with motor responses. Nat Neurosci 7:1370–1375CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Marissa Leigh Simms
    • 1
  • Thomas L. Kemper
    • 1
  • Clare M. Timbie
    • 1
  • Margaret L. Bauman
    • 1
  • Gene J. Blatt
    • 1
  1. 1.Department of Anatomy and NeurobiologyBoston University School of MedicineBostonUSA

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