Open Access Peer-reviewed

Reduced Capillary Density in the Prefrontal Cortex in Schizophrenia

Natalya Uranova1,, Ivetta Zimina1, Olga Vikhreva1, Valentina Rachmanova1, Anna Klintsova2, Diana Orlovskaya1

1Laboratory of Clinical Neuropathology, Mental Health Research Center of Russian Academy of Medical Sciences, Moscow, Russia

2Beckman Institute, University of Illinois, Urbana-Champaign, Illinois, USA

American Journal of Medical Sciences and Medicine. 2013, 1(3), 45-51. DOI: 10.12691/ajmsm-1-3-3
Published online: August 25, 2017


Neuroimaging studies have shown that the core symptoms of schizophrenia are associated with local changes of cerebral blood flow, particularly in the frontal cortex. Previously we reported ultrastructural damage of capillaries in the upper layers of the prefrontal cortex, Brodmann’s area (BA) 10 and in the visual cortex, BA schizophrenia. An electron microscopic morphometric study was performed to estimate capillary area density (N cap/mm2) in two upper layers of the prefrontal and visual cortices in 26 cases of schizophrenia and 26 normal controls. Capillary area density was lower in the prefrontal cortex in the schizophrenia group (-24%, p < 0.001) and in the subgroup of schizophrenia with predominantly negative symptoms (n=12, -35%, p < 0.001) as compared to controls. Group and subgroup differences were absent in the visual cortex. Dysfunction of neocortical microvasculature in schizophrenia is related to region-specific capillary deficiency in the prefrontal cortex. These changes might contribute to the lowered blood flow, reduced glucose metabolic rates, resting hypofrontality and hypoactivation reported in the prefrontal cortex of patients with schizophrenia.


schizophrenia, capillary, electron microscopy, morphometry, prefrontal cortex, visual cortex
[1]  Weinberger, D.R., Berman, K.F. and Zec, R.F. “Physiology dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence,” Arch Gen Psychiatry, 43(2).114-124. Feb 1986.
[2]  Parellada, E., Catafau, A.M., Bernardo, M., Lomena, F., Catarineu, S. and González-Monclús, E., “The resting and activation issue of hypofrontality: a single photon emission computed tomography study in neuroleptic-naive and neuroleptic-free schizophrenic female patients,” Biol Psychiatry, 44(8).787-790.Oct 1998.
[3]  Ragland, J.D., Gur, R.C., Glahn, D.C., et al. “Frontotemporal cerebral blood flow change during executive and declarative memory tasks in schizophrenia: a positron emission tomography study,” Neuropsychology, 12(3).399-413.Jul 1998.
[4]  Moreno-Iniguez, M., Ortuño, F., Arbizu, J., Millán, M., Soutullo, C. and Cervera-Enguix, S., “Regional cerebral blood flow SPECT study, at rest and during Wisconsin Card Sorting Test [WCST] performance, in schizophrenia naive patients or treated with atypical neuroleptics,” Actas Esp Psiquiatr, 33(6).343-351.Nov-Dec 2005.
[5]  Andreasen, N.C., Calarge, C.A. and O'Leary, D.S., “Theory of mind and schizophrenia: a positron emission tomography study of medication-free patients,” Schizophr Bull, 34(4).708-719.Jul 2008.
[6]  Potkin, S.G., Alva, G., Fleming, K., et al. “A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography,” Am J Psychiatry, 159(2).227-237. Feb 2002.
[7]  Buchsbaum, M.S., Nenadic, I., Hazlett, E.A., et al. Differential metabolic rates in prefrontal and temporal Brodmann areas in schizophrenia and schizotypal personality disorder. Schizophr Res, 54 (1-2).141-150. Mar 2002.
[8]  Hoshi, Y., Shinba, T., Sato, C. and Doi, N., “Resting hypofrontality in schizophrenia: A study using near-infrared time-resolved spectroscopy,” Schizophr Res, 84 (2-3).411-420.Jun 2006.
[9]  Vita, A., Bressi, S., Perani, D., Invernizzi, G., Giobbio, G.M., Dieci, M. Garbarini, M., Del Sole, A. and Fazio, F., “High-resolution SPECT study of regional cerebral blood flow in drug-free and drug-naive schizophrenia patients,” Am J Psychiatry, 152 (6).876-882. Jun 1995.
[10]  Suzuki, M., Nohara, S., Hagino, H., Takahashi, T., Kawasaki, Y., Yamashita, I., Watanabe, N., Seto, H. and Kurachi, M., “Prefrontal abnormalities in patients with simple schizophrenia: structural and functional brain-imaging studies in five cases,” Psychiatry Res, 140 (2).157-171.Nov 2005.
[11]  Wang, C.S., Yang, Y.K., Chen, M., Chiu, N.T., Yeh, T.L. and Lee, I.H., “Negative symptoms and regional cerebral blood flow in patients with schizophrenia: a single photon emission computed tomography study,” Kaohsiung J Med Sci, 19 (9).464-469.Sep. 2003.
[12]  Gonul, A.S., Kula, M., Eşel, E., Tutuş, A. and Sofuoglu, S., “A Tc-99m HMPAO SPECT study of regional cerebral blood flow in drug-free schizophrenia patients with deficit and non-deficit syndrome,” Psychiatry Res, 123 (3).199-205. Jul 2003.
[13]  Li, X., Tang, J., Wu, Z., Zhao, G., Liu, C. and George, M.S., “SPECT study of Chinese schizophrenia patients suggests that cerebral hypoperfusion and laterality exist in different ethnic groups,” World J Biol Psychiatry, 6 (2).98-106.2005.
[14]  Zhao, J., He, X., Liu, Z. and Yang, D., “The effects of clozapine on cognitive function and regional cerebral blood flow in the negative symptom profile schizophrenia,” Inl J Psychiatr Med, 36 (2).171-81.2006.
[15]  Hanson, D.R. and Gottesman, I.I., “Theories of schizophrenia: a genetic-inflammatory-vascular synthesis,” BMC Medical Genetics, 11.6.7. Feb 2005.
[16]  Kreczmanski, P., Schmidt-Kastner, R., Heinsen, H., Steinbusch, H.W., Hof, P.R.and Schmitz, C., “Stereological studies of capillary length density in the frontal cortex of schizophrenics,” Acta Neuropathol, 109 (5), 510-518. May 2005.View Article  PubMed
[17]  Kreczmanski, P., Heinsen,H., Mantua,V., et al. “Microvessel length density, total length, and length per neuron in five subcortical regions in schizophrenia,”. Acta Neuropathol, 117(4). 409-421.Apr 2009.View Article  PubMed
[18]  Kut'ko, I.I., Frolov, V.M., Rachkauskas, G.S., Pavlenko, V.V. and Petrunia, A.M., “Microhemodynamics and energy metabolism in schizophrenia patients,” Lik Sprava, 1, 61-65. Jan-Feb 1997. (Russian). PubMed
[19]  Orlovskaya, D.D. and Solov'eva, Zh.V., “Changes in the ultrafine structure of capillaries of the embryonic brain in the presence of schizophrenia in the mother,” Zh Nevropatol Psikhiatr Im S S Korsakova., 76(7),1043-1046. 1976 (Russian).
[20]  Senitz, D. and Winkelmann, E., “Neuronal structure abnormality in the orbito-frontal cortex of schizophrenics,” J Hirnforsch, 32 (2). 149-158.1991. (German)
[21]  Webster, M.J., Knable, M.B., Johnston-Wilson, N., Nagata, K., Inagaki, M. and Yolken, R.H., “Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression,” Brain, Behav Immunol, 15(4), 388-400. Dec 2001.View Article  PubMed
[22]  Vostrikov, V., Orlovskaya, D. and Uranova, N., “Deficit of pericapillary oligodendrocytes in the prefrontal cortex in schizophrenia,” World J Biol Psychiatry, 9 (1), 34-42. 2008.View Article  PubMed
[23]  Harris, L.W., Wayland, M., Lan, M., et al. “The cerebral microvasculature in schizophrenia: a laser capture microdissection study,” PLoS One, 3 (12), e3964. 2008.View Article  PubMed
[24]  Fulzele, S. and Pillai, A., “Decreased VEGF mRNA expression in the dorsolateral prefrontal cortex of schizophrenia subject,” Schizophr Res, 115 (2-3), 372-373. Dec 2009.View Article  PubMed
[25]  Uranova, N.A., Zimina, I.S., Vikhreva, O.V., Krukov, N.O., Rachmanova, V.I. and Orlovskaya, D.D., “Ultrastructural damage of capillaries in the neocortex in schizophrenia,” World J Biol Psychiatry, 11(3), 567-578. Apr 2010.View Article  PubMed
[26]  Peters, A., The fine structure of the nervous system. The neurons and supporting cells. Philadelphia, London, Toronto: WB Saunders, 1976. 296-302.
[27]  Davis, J.M., Dose equivalence of the antipsychotic drugs. J Psychiatr Res 11, 65-69. 1974.View Article
[28]  Sinka, L., Kovari, E., Santos, M., Herrmann, F.R., Gold, G., Hof, P.R., Bouras, C. and Giannakopoulos, P., “Microvascular changes in late-life schizophrenia and mood disorders: stereological assessment of capillary diameters in anterior cingulate cortex”. Neuropathol Appl Neurobiol, 38(7):696-709. Dec 2012.View Article  PubMed
[29]  Ertugrul, A., Volkan-Salanci, B., Basar, K., et al., “The effect of clozapine on regional cerebral blood flow and brain metabolite ratios in schizophrenia: relationship with treatment response,” Psychiatry Res, 174 (2), 121-129.Nov 2009.View Article  PubMed
[30]  Newton, S.S. and Duman, R.S., “Neurogenic actions of atypical antipsychotic drugs and therapeutic implications,” CNS Drugs, 21 (9), 715-725. 2007.View Article  PubMed
[31]  Uranova, N.A., Vikhreva, O.V., Zimina, I.S., et al. “Abnormal patterns of cortical synaptic connectivity in schizophrenia,” Vest. Ross. Akad. Med. Nauk, 3. 8-14.2007 (Russian).
[32]  Guidotti, A., Auta, J., Davis, J.M., et al. “Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder: a postmortem brain study,” Arch Gen Psychiatry, 57 (11), 1061-1069. Nov 2000.View Article  PubMed
[33]  Uranova, N., Orlovskaya, D., Zimina, I., Vikhreva, O., Rachmanova, V., Klintsova, A., Black, J. and Greenough, W.T., “Decreased synaptic size in schizophrenic cortex: a postmortem morphometric electron microscopic study,” 30th Annual Meeting of the Society for Neuroscience Abstracts 26: 1558-1558. 2000.
[34]  Glantz, L.A. and Lewis, D.A., “Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity,” Arch Gen Psychiatry, 54 (10), 943-952. Oct 1997.View Article  PubMed
[35]  Peters, A., Moss, M.B. and Sethares, C., “The effects of aging on layer 1 of primary visual cortex in the rhesus monkey,” Cereb Cortex, 11 (2), 93-103. Feb 2001.View Article  PubMed
[36]  Peters, A., Sethares, C. and Luebke, J.I., “Synapses are lost during aging in the primate prefrontal cortex,” Neurosci, 152 (4) 970-981. Apr 2008.View Article  PubMed
[37]  Andreasen, N.C., O'Leary, D.S., Flaum, M., Nopoulos, P., Watkins, G.L., Boles Ponto, L.L. and Hichwa, R.D., “Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naive patients,” Lancet, 349 (9067). 1730-1734.Jun 1997.View Article
[38]  Schultz, S.K., O'Leary, D.S., Boles Ponto, et al. “Age and regional cerebral blood flow in schizophrenia: age effects in anterior cingulate, frontal, and parietal cortex,” J Neuropsychiatry Clin Neurosci, 14 (1).19-24.Winter 2002.
[39]  Kanahara, N., Shimizu, E., Sekine, Y., et al. “Does hypofrontality expand to global brain area in progression of schizophrenia?: a cross-sectional study between first-episode and chronic schizophrenia,” Prog Neuropsychopharmacol Biol Psychiatry, 33 (3), 410-415. Apr 2009.View Article  PubMed
[40]  Sonntag, W., Eckman, D., Ingraham, J. and Riddle, D., Regulation of Cerebrovascular Aging, In: Riddle DR, editor. Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL], CRC Press, 2007, Chapter 12.
[41]  Kuschinsky, W. and Paulson, O.B., “Capillary circulation in the brain,” Cerebrovasc Brain Metab Rev, 4 (3), 261-286. 1992. PubMed
[42]  Black, J.E., Sirevaag, A.M. and Greenough, W.T., “Complex experience promotes capillary formation in young rat visual cortex,” Neurosci Lett, 83 (3).351-355. Dec1987.
[43]  Sirevaag, A.M. and Greenough, W.T., “Differential rearing effects on rat visual cortex synapses. III. Neuronal and glial nuclei, boutons, dendrites, and capillaries,” Brain Res, 424 (2). 320-332. Oct 1987.View Article
[44]  Argandoña, E.G. and Lafuente, J.V., “Effects of dark-rearing on the vascularization of the developmental rat visual cortex,” Brain Res, 732 (1-2), 43-51.Sep1996.View Article
[45]  Argandoña, E.G. and Lafuente. J.V., “Influence of visual experience deprivation on the postnatal development of the microvascular bed in layer IV of the rat visual cortex,” Brain Res, 855 (1)137-142.Feb 2000.View Article
[46]  Greenberg,D.A. and Jin, K., “From angiogenesis to neuropathology,” Nature, 438 (7070), 954-959. Dec 2005.View Article  PubMed
[47]  Higashima, M., Kawasaki, Y., Urata, K., et al. “Regional cerebral blood flow in male schizophrenic patients performing an auditory discrimination task,” Schizophr Res, 42 (1), 29-39. Mar 2000.View Article
[48]  Crespo-Facorro, B., Paradiso, S., Andreasen, N.C., et al. “Neural mechanisms of anhedonia in schizophrenia: a PET study of response to unpleasant and pleasant odors,” JAMA, 286 (4). 427-435. Jul 2001.View Article  PubMed
[49]  Sabri, O., Owega, A., Schreckenberger, M., et al. “A truly simultaneous combination of functional transcranial Doppler sonography and H[2][15]O PET adds fundamental new information on differences in cognitive activation between schizophrenics and healthy control subjects,” J Nucl Med, 44 (5), 671-681. May 2003. PubMed
[50]  Selemon, L.D., Rajkowska, G. and Goldman-Rakic, P.S. “Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17”. Arch Gen Psychiatry, 52 (10). 805-818. Oct 1995.View Article  PubMed
[51]  Selemon, L.D., Rajkowska, G. and Goldman-Rakic, P.S., “Elevated neuronal density in prefrontal area brains from schizophrenic patients: application of a three-dimensional, stereologic counting method,” J Comp Neurol, 392 (3), 402-412. Mar1998.View Article
[52]  Black, J.E., Kodish, I.M, Grossman, A.W, et al. “Pathology of layer V pyramidal neurons in the prefrontal cortex of patients with schizophrenia,” Am J Psychiatry, 161(4), 742-744.Apr 2004.View Article  PubMed
[53]  Brown, W.R., Moody, D.M., Thore, C.R., Challa, V.R. and Anstrom, J.A., “Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well,” J Neurol Sci, 257 (1-2), 62-66. Jun 2007.View Article  PubMed
[54]  Brown, W.R. and Thore, C.R., “Review: cerebral microvascular pathology in ageing and neurodegeneration,” Neuropathol Appl Neurobiol, 37 (1), 56-74. Feb 2011.