Acta Neuropathologica

, Volume 109, Issue 5, pp 510–518 | Cite as

Stereological studies of capillary length density in the frontal cortex of schizophrenics

  • Pawel Kreczmanski
  • Rainald Schmidt-Kastner
  • Helmut Heinsen
  • Harry W. M. Steinbusch
  • Patrick R. Hof
  • Christoph SchmitzEmail author
Regular Paper


The presence of microvasculature abnormalities in the prefrontal cortex of schizophrenics was proposed in a recent study of molecular signatures of schizophrenia [Prabakaran et al (2004) Mol Psychiat 9:684–697]. To assess this possibility further, we investigated capillary length densities in prefrontal cortex area 9 and anterior cingulate cortex area 24 in postmortem brains from 13 schizophrenics and 13 age- and sex-matched controls. To check that our sample of brains shared cardinal neuropathological features of schizophrenia with previously reported case studies, we also measured cortical gray matter volumes and cortical thickness in areas 9 and 24. The mean cortical gray matter volume was significantly reduced in brains from schizophrenics compared to controls. Mean cortical thickness was significantly reduced in area 24, but not in area 9, in schizophrenics. There were no differences in mean capillary length densities in either area 9 or 24 between the two groups. Thus, alterations in capillary length density in the prefrontal cortex cannot be considered a general feature of schizophrenia. Compromised brain metabolism and occurrence of oxidative stress in the brain of schizophrenics are likely caused by other mechanisms.


Schizophrenia Stereology Cortical thickness Cortical gray matter Microvasculature 



The authors thank G. Greene and B. Boehringer (MicroBrightField, Williston, VT) for valuable help in implementing the “Space balls” method. This study was supported by the Stanley Medical Research Institute (grant no. 02R-258 to H.H., P.R.H. and C.S.), by the European Community (Quality of Life and Management of Living Resources, QLK6-CT-2000-60042, QLK6-GH-00-60042-46, to P.K.), and NIH grant MH66392 (to P.R.H.). R.S.K. was an investigator at the Cerebral Vascular Disease Research Center (NIH grant NS05820). P.R.H. is the Regenstreif Professor of Neuroscience.


  1. 1.
    Andreasen NC, Rezai K, Alliger R, Swayze VW, Flaum M, Kirchner P, et al (1992) Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch Gen Psychiatry 49:943–958PubMedGoogle Scholar
  2. 2.
    Arnold SE, Trojanowski JQ (1996) Recent advances in defining the neuropathology of schizophrenia. Acta Neuropathol 92:217–231CrossRefPubMedGoogle Scholar
  3. 3.
    Berman KF, Zec RF, Weinberger DR (1986) Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. II. Role of neuroleptic treatment, attention, and mental effort. Arch Gen Psychiatry 43:126–135PubMedGoogle Scholar
  4. 4.
    Bouras C, Kövari E, Hof PR, Riederer BM, Giannakopoulos P (2001) Anterior cingulate cortex pathology in schizophrenia and bipolar disorder. Acta Neuropathol 102:373–379PubMedGoogle Scholar
  5. 5.
    Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278CrossRefPubMedGoogle Scholar
  6. 6.
    Brodmann K (1909) Vergleichende Lokalisationslehre der Großhirnrinde. Barth, LeipzigGoogle Scholar
  7. 7.
    Calhoun ME, Mouton PR (2000) Length measurement: new developments in neurostereology and 3D imagery. J Chem Neuroanat 21:257–265CrossRefGoogle Scholar
  8. 8.
    Catafau AM, Parellada E, Lomeña FJ, Bernardo M, Pavía J, Ros D, et al (1994) Prefrontal and temporal blood flow in schizophrenia: resting and activation technetium-99m-HMPAO-SPECT patterns in young neuroleptic-naive patients with acute disease. J Nucl Med 35:935–941PubMedGoogle Scholar
  9. 9.
    Cavalieri B (1635) Geometria indivisibilibus continuorum. Typis Clementis Ferronij, Bononiae (reprinted 1966 as Geometria Degli Indivisibili. Unione Tipografico-Editrice Torinese, Torino)Google Scholar
  10. 10.
    Cohen BM, Yurgelun-Todd D, English CD, Renshaw PF (1995) Abnormalities of regional distribution of cerebral vasculature in schizophrenia detected by dynamic susceptibility contrast MRI. Am J Psychiatry 152:1801–1803PubMedGoogle Scholar
  11. 11.
    Curtis CE, Iacono WG, Beiser M (1999) Relationship between nailfold plexus visibility and clinical, neuropsychological, and brain structural measures in schizophrenia. Biol Psychiatry 46:102–109CrossRefPubMedGoogle Scholar
  12. 12.
    Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, Buxbaum J, Haroutunian V (2003) White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 60:443–456CrossRefPubMedGoogle Scholar
  13. 13.
    Falkai P, Honer WG, David S, Bogerts B, Majtenyi C, Bayer TA (1999) No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study. Neuropathol Appl Neurobiol 25:48–53CrossRefPubMedGoogle Scholar
  14. 14.
    Gittins R, Harrison PJ (2004) A quantitative morphometric study of the human anterior cingulate cortex. Brain Res 1013:212–222CrossRefPubMedGoogle Scholar
  15. 15.
    Gundersen HJG, Jensen EB (1987) The efficiency of systematic sampling and its prediction. J Microsc 147:229–263PubMedGoogle Scholar
  16. 16.
    Hakak Y, Walker JR, Li C, Wong WH, Davis KL, Buxbaum JD, Haroutunian V, Fienberg AA (2001) Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci USA 98:4746–4751CrossRefPubMedGoogle Scholar
  17. 17.
    Harrison PJ (1999) The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122:593–624CrossRefPubMedGoogle Scholar
  18. 18.
    Harrison PJ, Owen MJ (2003) Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361:417–419CrossRefPubMedGoogle Scholar
  19. 19.
    Harrison PJ, Weinberger DR (2004) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry: advance online publication, 20 July 2004, doi:10.1038/ Scholar
  20. 20.
    Heinsen H, Heinsen YL (1991) Serial thick, frozen, gallocyanin stained sections of human central nervous system. J Histotechnol 14:167–173Google Scholar
  21. 21.
    Heinsen H, Beckmann H, Heinsen YL, Gallyas F, Haas S, Scharff G (1989) Laminar neuropathology in Alzheimer’s disease by a modified Gallyas impregnation. Psychiatry Res 29:463–465CrossRefPubMedGoogle Scholar
  22. 22.
    Heinsen H, Henn R, Eisenmenger W, Gotz M, Bohl J, Bethke B, et al (1994) Quantitative investigations on the human entorhinal area: left—right asymmetry and age-related changes. Anat Embryol (Berl) 190:181–194Google Scholar
  23. 23.
    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 20:49–59CrossRefPubMedGoogle Scholar
  24. 24.
    Hill K, Mann L, Laws KR, Stephenson CM, Nimmo-Smith I, McKenna PJ (2004) Hypofrontality in schizophrenia: a meta-analysis of functional imaging studies. Acta Psychiatr Scand 110:243–256CrossRefPubMedGoogle Scholar
  25. 25.
    Hof PR, Haroutunian V, Copland C, Davis KL, Buxbaum JD (2002) Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochem Res 27:1193–1200CrossRefPubMedGoogle Scholar
  26. 26.
    Hof PR, Haroutunian V, Friedrich VL Jr, Byne W, Buitron C, Perl DP, Davis KL (2003) Loss and altered spatial distribution of oligodendrocytes in the superior frontal gyrus in schizophrenia. Biol Psychiatry 53:1075–1085CrossRefPubMedGoogle Scholar
  27. 27.
    Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360CrossRefPubMedGoogle Scholar
  28. 28.
    Kety SS (1959) Biochemical theories of schizophrenia. I. Science 129:1528–1532PubMedGoogle Scholar
  29. 29.
    Kety SS (1959) Biochemical theories of schizophrenia. II. Science 129:1590–1596PubMedGoogle Scholar
  30. 30.
    LaManna JC, Chavez JC, Pichiule P (2004) Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol 207:3163–3169CrossRefPubMedGoogle Scholar
  31. 31.
    Lewis DA, Lewitt P (2002) Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 25:409–432CrossRefPubMedGoogle Scholar
  32. 32.
    Lieberman JA (1999) Is schizophrenia a neurodegenerative disorder? A clinical and neurobiological perspective. Biol Psychiatry 46:729–739CrossRefPubMedGoogle Scholar
  33. 33.
    Malaspina D, Harkavy-Friedman J, Corcoran C, Mujica-Parodi L, Printz D, Gorman JM, Van Heertum R (2004) Resting neural activity distinguishes subgroups of schizophrenia patients. Biol Psychiatry 56:931–937CrossRefPubMedGoogle Scholar
  34. 34.
    Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–271CrossRefPubMedGoogle Scholar
  35. 35.
    Middleton FA, Mirnics K, Pierri JN, Lewis DA, Levitt P (2002) Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J Neurosci 22:2718–2729PubMedGoogle Scholar
  36. 36.
    Mouton PR, Gokhale AM, Ward NL, West MJ (2002) Stereological length estimation using spherical probes. J Microsc 206:54–64CrossRefPubMedMathSciNetGoogle Scholar
  37. 37.
    Mueser KT, McGurk SR (2004) Schizophrenia. Lancet 363:2063–2072CrossRefPubMedGoogle Scholar
  38. 38.
    Nimchinsky EA, Vogt BA, Morrison JH, Hof PR (1997) Neurofilament and calcium-binding proteins in the human cingulate cortex. J Comp Neurol 384:597–620CrossRefPubMedGoogle Scholar
  39. 39.
    Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, et al (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9:684–697CrossRefPubMedGoogle Scholar
  40. 40.
    Rajkowska G, Goldman-Rakic PS (1995) Cytoarchitectonic definition of prefrontal areas in the normal human cortex. I. Remapping of areas 9 and 46 using quantitative criteria. Cereb Cortex 5:307–322PubMedGoogle Scholar
  41. 41.
    Rajkowska G, Goldman-Rakic PS (1995) Cytoarchitectonic definition of prefrontal areas in the normal human cortex. II. Variability in locations of areas 9 and 46 and relationship to the Talairach Coordinate System. Cereb Cortex 5:323–337PubMedGoogle Scholar
  42. 42.
    Ross BM, Hughes B, Turenne S, Seeman M, Warsh JJ (2004) Reduced vasodilatory response to methylnicotinate in schizophrenia as assessed by laser Doppler flowmetry. Eur Neuropsychopharmacol 14:191–197CrossRefPubMedGoogle Scholar
  43. 43.
    Schleicher A, Amunts K, Geyer S, Kowalski T, Schormann T, Palomero-Gallagher N, Zilles K (2000) A stereological approach to human cortical architecture: identification and delineation of cortical areas. J Chem Neuroanat 20:31–47CrossRefPubMedGoogle Scholar
  44. 44.
    Schmitz C, Hof PR (2005) Design-based stereology in neuroscience. Neuroscience 130:813–831CrossRefPubMedGoogle Scholar
  45. 45.
    Schultz SK, O’Leary DS, Boles Ponto LL, Arndt S, Magnotta V, Watkins GL, et al (2002) Age and regional cerebral blood flow in schizophrenia: age effects in anterior cingulate, frontal, and parietal cortex. J Neuropsychiatry Clin Neurosci 14:19–24PubMedGoogle Scholar
  46. 46.
    Selemon LD, Goldman-Rakic PS (1999) The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45:17–25CrossRefPubMedGoogle Scholar
  47. 47.
    Selemon LD, Rajkowska G, Goldman-Rakic PS (1995) Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 52:805–818PubMedGoogle Scholar
  48. 48.
    Siever LJ, Davis KL (2004) The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry 161:398–413CrossRefPubMedGoogle Scholar
  49. 49.
    Sofroniew MV (2000) Astrocyte failure as a cause of CNS dysfunction. Mol Psychiatry 5:230–232CrossRefPubMedGoogle Scholar
  50. 50.
    Tkachev D, Mimmack ML, Ryan MM, Wayland M, Freeman T, Jones PB, Starkey M, Webster MJ, Yolken RH, Bahn S (2003) Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362:798–805CrossRefPubMedGoogle Scholar
  51. 51.
    Tsuang M (2000) Schizophrenia: genes and environment. Biol Psychiatry 47:210–220CrossRefPubMedGoogle Scholar
  52. 52.
    Vogel J, Gehrig M, Kuschinsky W, Marti HH (2004) Massive inborn angiogenesis in the brain scarcely raises cerebral blood flow. J Cereb Blood Flow Metab 24:849–859CrossRefPubMedGoogle Scholar
  53. 53.
    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
  54. 54.
    Von Economo C, Koskinas GN (1925) Die Cytoarchitekonik der Hirnrinde des erwachsenen Menschen. Julius Springer, Wien, BerlinGoogle Scholar
  55. 55.
    West MJ, Slomianka L (1998) Total number of neurons in the layers of the human entorhinal cortex (Erratum). Hippocampus 8:426CrossRefGoogle Scholar
  56. 56.
    Wiegand LC, Warfield SK, Levitt JJ, Hirayasu Y, Salisbury DF, Heckers S (2004) Prefrontal cortical thickness in first-episode psychosis: a magnetic resonance imaging study. Biol Psychiatry 55:131–140CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Pawel Kreczmanski
    • 1
    • 2
  • Rainald Schmidt-Kastner
    • 3
  • Helmut Heinsen
    • 4
  • Harry W. M. Steinbusch
    • 1
    • 2
  • Patrick R. Hof
    • 5
  • Christoph Schmitz
    • 1
    • 2
    Email author
  1. 1.Department of Psychiatry and Neuropsychology, Division of Cellular NeuroscienceMaastricht UniversityMaastrichtThe Netherlands
  2. 2.European Graduate School of Neuroscience (EURON)MaastrichtThe Netherlands
  3. 3.Department of NeurologyUniversity of Miami School of MedicineMiamiUSA
  4. 4.Morphologic Brain Research UnitUniversity of WürzburgWürzburgGermany
  5. 5.Department of Neuroscience and Department of Geriatrics and Adult DevelopmentMount Sinai School of MedicineNew YorkUSA

Personalised recommendations