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Brain surface contraction mapped in first-episode schizophrenia: a longitudinal magnetic resonance imaging study

Abstract

Schizophrenia is associated with structural brain abnormalities, but the timing of onset and course of these changes remains unclear. Longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive brain volume decreases in patients around and after the onset of illness, although considerable discrepancies exist regarding which brain regions are affected. The anatomical pattern of these progressive changes in schizophrenia is largely unknown. In this study, MRI scans were acquired repeatedly from 16 schizophrenia patients approximately 2 years apart following their first episode of illness, and also from 14 age-matched healthy subjects. Cortical Pattern Matching, in combination with Structural Image Evaluation, using Normalisation, of Atrophy, was applied to compare the rates of cortical surface contraction between patients and controls. Surface contraction in the dorsal surfaces of the frontal lobe was significantly greater in patients with first-episode schizophrenia (FESZ) compared with healthy controls. Overall, brain surface contraction in patients and healthy controls showed similar anatomical patterns, with that of the former group exaggerated in magnitude across the entire brain surface. That the pattern of structural change in the early course of schizophrenia corresponds so closely to that associated with normal development is consistent with the hypothesis that a schizophrenia-related factor interacts with normal adolescent brain developmental processes in the pathophysiology of schizophrenia. The exaggerated progressive changes seen in patients with schizophrenia may reflect an increased rate of synaptic pruning, resulting in excessive loss of neuronal connectivity, as predicted by the late neurodevelopmental hypothesis of the illness.

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References

  1. Pantelis C, Yucel M, Wood SJ, Velakoulis D, Sun D, Berger G et al. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr Bull 2005; 31: 672–696.

    Article  Google Scholar 

  2. Shenton ME, Dickey CC, Frumin M, McCarley RW . A review of MRI findings in schizophrenia. Schizophr Res 2001; 49: 1–52.

    Article  CAS  Google Scholar 

  3. Yucel M, Stuart GW, Maruff P, Velakoulis D, Crowe SF, Savage G et al. Hemispheric and gender-related differences in the gross morphology of the anterior cingulate/paracingulate cortex in normal volunteers: an MRI morphometric study. Cereb Cortex 2001; 11: 17–25.

    Article  CAS  Google Scholar 

  4. Nakamura M, Nestor PG, McCarley RW, Levitt JJ, Hsu L, Kawashima T et al. Altered orbitofrontal sulcogyral pattern in schizophrenia. Brain 2007; 130 (Part 3): 693–707.

    Article  Google Scholar 

  5. Weinberger D . From neuropathology to neurodevelopment. Lancet 1995; 346: 552–557.

    Article  CAS  Google Scholar 

  6. DeLisi LE, Sakuma M, Maurizio AM, Relja M, Hoff AL . Cerebral ventricular change over the first 10 years after the onset of schizophrenia. Psychiatry Res 2004; 130: 57–70.

    Article  Google Scholar 

  7. DeLisi LE, Stritzke P, Riordan H, Holan V, Boccio A, Kushner M et al. The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome. Biol Psychiatry 1992; 31: 241–254.

    Article  CAS  Google Scholar 

  8. DeLisi LE, Tew W, Xie S, Hoff AL, Sakuma M, Kushner M et al. A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biol Psychiatry 1995; 38: 349–360.

    Article  CAS  Google Scholar 

  9. Garver DL, Nair TR, Christensen JD, Holcomb JA, Kingsbury SJ . Brain and ventricle instability during psychotic episodes of the schizophrenias. Schizophr Res 2000; 44: 11–23.

    Article  CAS  Google Scholar 

  10. Nair TR, Christensen JD, Kingsbury SJ, Kumar NG, Terry WM, Garver DL . Progression of cerebroventricular enlargement and the subtyping of schizophrenia. Psychiatry Res 1997; 74: 141–150.

    Article  CAS  Google Scholar 

  11. Nakamura M, Salisbury DF, Hirayasu Y, Bouix S, Pohl KM, Yoshida T et al. Neocortical gray matter volume in first-episode schizophrenia and first-episode affective psychosis: a cross-sectional and longitudinal MRI study. Biol Psychiatry 2007; 62: 773–783.

    Article  Google Scholar 

  12. Gur RE, Cowell P, Turetsky BI, Gallacher F, Cannon T, Bilker W et al. A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry 1998; 55: 145–152.

    Article  CAS  Google Scholar 

  13. van Haren NE, Hulshoff Pol HE, Schnack HG, Cahn W, Mandl RC, Collins DL et al. Focal gray matter changes in schizophrenia across the course of the illness: a 5-year follow-up study. Neuropsychopharmacology 2007; 32: 2057–2066.

    Article  Google Scholar 

  14. Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005; 62: 361–370.

    Article  CAS  Google Scholar 

  15. Rapoport JL, Giedd JN, Blumenthal J, Hamburger S, Jeffries N, Fernandez T et al. Progressive cortical change during adolescence in childhood-onset schizophrenia. A longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 1999; 56: 649–654.

    Article  CAS  Google Scholar 

  16. Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci USA 2001; 98: 11650–11655.

    Article  CAS  Google Scholar 

  17. Ho BC, Andreasen NC, Nopoulos P, Arndt S, Magnotta V, Flaum M . Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Arch Gen Psychiatry 2003; 60: 585–594.

    Article  Google Scholar 

  18. Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A . Progressive brain volume changes and the clinical course of schizophrenia in men: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2001; 58: 148–157.

    Article  CAS  Google Scholar 

  19. Kasai K, Shenton ME, Salisbury DF, Hirayasu Y, Lee CU, Ciszewski AA et al. Progressive decrease of left superior temporal gyrus gray matter volume in patients with first-episode schizophrenia. Am J Psychiatry 2003; 160: 156–164.

    Article  Google Scholar 

  20. Kasai K, Shenton ME, Salisbury DF, Hirayasu Y, Onitsuka T, Spencer MH et al. Progressive decrease of left Heschl gyrus and planum temporale gray matter volume in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Arch Gen Psychiatry 2003; 60: 766–775.

    Article  Google Scholar 

  21. Vidal CN, Rapoport JL, Hayashi KM, Geaga JA, Sui Y, McLemore LE et al. Dynamically spreading frontal and cingulate deficits mapped in adolescents with schizophrenia. Arch Gen Psychiatry 2006; 63: 25–34.

    Article  Google Scholar 

  22. Weinberger DR, McClure RK . Neurotoxicity, neuroplasticity, and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry 2002; 59: 553–558.

    Article  Google Scholar 

  23. Cahn W, Pol HEH, Lems E, van Haren NEM, Schnack HG, van der Linden JA et al. Brain volume changes in first-episode schizophrenia—A 1-year follow-up study. Arch Gen Psychiatry 2002; 59: 1002–1010.

    Article  Google Scholar 

  24. Thompson PM, Hayashi KM, Sowell ER, Gogtay N, Giedd JN, Rapoport JL et al. Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia. Neuroimage 2004; 23 (Suppl 1): S2–S18.

    Article  Google Scholar 

  25. Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S et al. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 1489–1496.

    Article  CAS  Google Scholar 

  26. Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004; 23 (Suppl 1): S208–S219.

    Article  Google Scholar 

  27. Smith SM, Zhang YY, Jenkinson M, Chen J, Matthews PM, Federico A et al. Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 2002; 17: 479–489.

    Article  Google Scholar 

  28. Mazziotta JC, Toga AW, Evans A, Fox P, Lancaster J . A probabilistic atlas of the human brain: theory and rationale for its development. The International Consortium for Brain Mapping (ICBM). Neuroimage 1995; 2: 89–101.

    Article  CAS  Google Scholar 

  29. Genovese CR, Lazar NA, Nichols T . Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage 2002; 15: 870–878.

    Article  Google Scholar 

  30. Pearson K . On lines and planes of closest fit to systems of points in space. Philosophical Magazine 1901; 2: 559–572.

    Google Scholar 

  31. Huttenlocher PR, Dabholkar AS . Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997; 387: 167–178.

    Article  CAS  Google Scholar 

  32. Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA 2004; 101: 8174–8179.

    Article  CAS  Google Scholar 

  33. Sowell ER, Peterson BS, Thompson PM, Welcome SE, Henkenius AL, Toga AW . Mapping cortical change across the human life span. Nat Neurosci 2003; 6: 309–315.

    Article  CAS  Google Scholar 

  34. Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 1999; 2: 861–863.

    Article  CAS  Google Scholar 

  35. Huttenlocher PR . Synaptic density in human frontal cortex—developmental changes and effects of aging. Brain Res 1979; 163: 195–205.

    Article  CAS  Google Scholar 

  36. Sowell ER, Thompson PM, Tessner KD, Toga AW . Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: inverse relationships during postadolescent brain maturation. J Neurosci 2001; 21: 8819–8829.

    Article  CAS  Google Scholar 

  37. Feinberg I . Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Phychiatr Res 1982-83; 17: 319–334.

    Article  Google Scholar 

  38. van Haren NE, Pol HE, Schnack HG, Cahn W, Brans R, Carati I et al. Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood. Biol Psychiatry 2007; 63: 106–113.

    Article  Google Scholar 

  39. Selemon LD, Rajkowska G, Goldman-Rakic PS . Abnormally high neuronal density in the schizophrenic cortex. A morphometric analysis of prefrontal area 9 and occipital area 17. Arch Gen Psychiatry 1995; 52: 805–818; discussion 819–820.

    Article  CAS  Google Scholar 

  40. Selemon LD, Rajkowska G, Goldman-Rakic PS . Elevated neuronal density in prefrontal area 46 in brains from schizophrenic patients: application of a three-dimensional, stereologic counting method. J Comp Neurol 1998; 392: 402–412.

    Article  CAS  Google Scholar 

  41. Glantz LA, Lewis DA . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. [comment]. Arch Gen Psychiatry 2000; 57: 65–73.

    Article  CAS  Google Scholar 

  42. Cannon TD, Thompson PM, van Erp TG, Toga AW, Poutanen VP, Huttunen M et al. Cortex mapping reveals regionally specific patterns of genetic and disease-specific gray-matter deficits in twins discordant for schizophrenia. Proc Natl Acad Sci USA 2002; 99: 3228–3233.

    Article  CAS  Google Scholar 

  43. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  Google Scholar 

  44. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 2005; 62: 1205–1213.

    Article  CAS  Google Scholar 

  45. Sporn AL, Greenstein DK, Gogtay N, Jeffries NO, Lenane M, Gochman P et al. Progressive brain volume loss during adolescence in childhood-onset schizophrenia. Am J Psychiatry 2003; 160: 2181–2189.

    Article  Google Scholar 

  46. Greenstein D, Lerch J, Shaw P, Clasen L, Giedd J, Gochman P et al. Childhood onset schizophrenia: cortical brain abnormalities as young adults. J Child Psychol Psychiatry 2006; 47: 1003–1012.

    Article  Google Scholar 

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Acknowledgements

This research was supported by project grants from the Australian National Health and Medical Research Council (NHMRC; Grant IDs: 145627, 145737, 970598, 981112, 970391), NHMRC Program Grant (ID: 350241), Victorian Health Promotion Foundation, the Stanley Foundation and Ian Potter Foundation. Drs Velakoulis and Wood were supported as Research Officers with funding from the NHMRC. Dr McGorry was supported by a NARSAD Distinguished Investigator Award. Dr Wood is currently supported by a Clinical Career Development Award from the NHMRC (ID: 359223) and a NARSAD Young Investigator Award. Dr Thompson is supported by NIH Grants AG016570, LM05639, EB01651 and RR019771. Image analysis and statistical analysis were supported by NIH Grants MH65078 to Dr Cannon and RR021813 (Center for Computational Biology) to Dr Toga.

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Correspondence to T D Cannon.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Sun, D., Stuart, G., Jenkinson, M. et al. Brain surface contraction mapped in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Mol Psychiatry 14, 976–986 (2009). https://doi.org/10.1038/mp.2008.34

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