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White matter volume changes in people who develop psychosis

  • Mark Walterfang (a1), Philip K. McGuire (a2), Alison R. Yung (a3), Lisa J. Phillips (a4), Dennis Velakoulis (a1), Stephen J. Wood (a5), John Suckling (a6), Edward T. Bullmore (a7), Warrick Brewer (a8), Bridget Soulsby (a5), Patricia Desmond (a9), Patrick D. McGorry (a10) and Christos Pantelis (a11)...



Grey matter changes have been described in individuals who are pre- and peri-psychotic, but it is unclear if these changes are accompanied by changes in white matter structures.


To determine whether changes in white matter occur prior to and with the transition to psychosis in individuals who are pre-psychotic who had previously demonstrated grey matter reductions in frontotemporal regions.


We used magnetic resonance imaging (MRI) to examine regional white matter volume in 75 people with prodromal symptoms. A subset of the original group (n=21) were rescanned at 12–18 months to determine white matter volume changes. Participants were retrospectively categorised according to whether they had or had not developed psychosis at follow-up.


Comparison of the baseline MRI data from these two subgroups revealed that individuals who later developed psychosis had larger volumes of white matter in the frontal lobe, particularly in the left hemisphere. Longitudinal comparison of data in individuals who developed psychosis revealed a reduction in white matter volume in the region of the left fronto-occipital fasciculus. Participants who had not developed psychosis showed no reductions in white matter volume but increases in a region subjacent to the right inferior parietal lobule.


The reduction in volume of white matter near the left fronto-occipital fasciculus may reflect a change in this tract in association with the onset of frank psychosis.


Corresponding author

Correspondence: Dr Mark Walterfang, Melbourne Neuropsychiatry Centre, Level 2, John Cade Building, Royal Melbourne Hospital, 3050 Australia. Email:


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1 Shenton, M, Dickey, C, Frumin, M, McCarley, R. A review of MRI findings in schizophrenia. Schizophr Res 2001; 49: 152.
2 Weinberger, D, McClure, R. Neurotoxicity, neuroplasticity and magnetic resonance imaging morphometry: what is happening in the schizophrenic brain? Arch Gen Psychiatry 2002; 59: 553–8.
3 Velakoulis, D, Pantelis, C, McGorry, PD, Dudgeon, P, Brewer, W, Cook, M, Desmond, P, Bridle, N, Tierney, P, Murrie, V, Singh, B, Copolov, D. Hippocampal volume in first-episode psychosis and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Arch Gen Psychiatry 1999; 56: 133–40.
4 Roy, PD, Zipursky, RB, Saint-Cyr, JA, Bury, A, Langevin, R, Seeman, MV. Temporal horn enlargement is present in schizophrenia and bipolar disorder. Biol Psychiatry 1998; 44: 418–22.
5 Cahn, W, Hulshoff Pol, HE, Lems, EB, van Haren, NE, Schnack, HG, van der Linden, JA, Schothorst, PF, van Engeland, H, Kahn, RS. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatr 2002; 59: 1002–10.
6 Kasai, K, Shenton, ME, Salisbury, DF, Hirayasu, Y, Lee, CU, Ciszewski, AA, Yurgelun-Todd, D, Kikinis, R, Jolesz, FA, McCarley, RW. Progressive decrease of left superior temporal gyrus gray matter volume in patients with first-episode schizophrenia. Am J Psychiatry 2003; 160: 156–64.
7 van Haren, NE, Hulshoff Pol, HE, Schnack, HG, Cahn, W, Mandl, RC, Collins, DL, Evans, AC, Kahn, RS. Focal gray matter changes in schizophrenia across the course of the illness: a 5-year follow-up study. Neuropsychopharmacol 2007; 32: 2057–66.
8 Pantelis, C, Velakoulis, D, McGorry, PD, Wood, SJ, Suckling, J, Phillips, LJ, Yung, AR, Bullmore, ET, Brewer, W, Soulsby, B, Desmond, P, McGuire, PK. Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison. Lancet 2003; 361: 281–8.
9 Job, D, Whalley, H, Mcintosh, A, Owens, D, Johnstone, E, Lawrie, S. Grey matter changes can improve the prediction of schizophrenia in subjects at high risk. BMC Med 2006; 4: 29.
10 Job, D, Whalley, H, Johnstone, E, Lawrie, S. Grey matter changes over time in high risk subjects developing schizophrenia. Neuroimage 2005; 25: 1023–30.
11 Friston, K. Schizophrenia and the disconnection hypothesis. Acta Psychiatr Scand Suppl 1999; 99: 6879.
12 Friston, K, Frith, C. Schizophrenia: a disconnection syndrome? Clin Neurosci 1995; 3: 8997.
13 McGuire, P, Frith, C. Disordered functional connectivity in schizophrenia. Psychol Med 1996; 26: 663–7.
14 Breir, A, Buchanan, R, Elkashef, A, Munson, R, Kirkpatrick, B, Gellad, F. Brain morphology and schizophrenia: a magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures. Arch Gen Psychiatry 1992; 49: 921–6.
15 Buchanan, R, Vladar, K, Barta, P, Pearlson, G. Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry 1998; 155: 1049–55.
16 Hulshoff Pol, HE, Schnack, HG, Bertens, MG, van Haren, NE, van der Tweel, I, Staal, WG, Baaré, WF, Kahn, RS. Volume changes in gray matter in patients with schizophrenia. Am J Psychiatry 2002; 159: 244–50.
17 Paillère-Martinot, M, Caclin, A, Artiges, E, Poline, JB, Joliot, M, Mallet, L, Recasens, C, Attar-Lévy, D, Martinot, JL. Cerebral gray and white matter reductions and clinical correlates in patients with early onset schizophrenia. Schizophr Res 2001; 50: 1926.
18 Sanfilipo, M, Lafargue, T, Rusinek, H, Arena, L, Loneragan, C, Lautin, A, Feiner, D, Rotrosen, J, Wolkin, A. Volumetric measure of the frontal and temporal lobe regions in schizophrenia: relationship to negative symptoms. Arch Gen Psychiatry 2000; 57: 471–80.
19 Sigmundsson, T, Suckling, J, Maier, M, Williams, S, Bullmore, E, Greenwood, K, Fukuda, R, Ron, M, Toone, B. Structural abnormalities in frontal, temporal and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms. Am J Psychiatry 2001; 158: 234–43.
20 Wible, CG, Anderson, J, Shenton, ME, Kricun, A, Hirayasu, Y, Tanaka, S, Levitt, JJ, O'Donnell, BF, Kikinis, R, Jolesz, FA, McCarley, RW. Prefrontal cortex, negative symptoms, and schizophrenia: an MRI study. Psychiatry Res 2001; 108: 6578.
21 Okugawa, G, Sedvallo, G, Agartz, I. Reduced grey and white matter volumes in the temporal lobe of male patients with chronic schizophrenia. Eur Arch Psychiatry Clin Neurosci 2002; 252: 120–3.
22 Takahashi, K, Suzuki, M, Kawasaki, Y, Hagino, H, Yamashita, I, Nohara, S, Nakamura, K, Seto, H, Kurachi, M. Perigenual cingulate gyrus volume in patients with schizophrenia: a magnetic resonance imaging study. Biol Psychiatry 2003; 53: 593600.
23 Kanaan, R, Kim, J, Kaufmann, W, Pearlson, G, Barker, G, McGuire, P. Diffusion tensor imaging in schizophrenia. Biol Psychiatry 2005; 58: 921–9.
24 Walterfang, M, Wood, S, Velakoulis, D, Pantelis, C. Neuropathological, neurogenetic and neuroimaging evidence for white matter pathology in schizophrenia. Neurosci Biobehav Rev 2006; 30: 918–48.
25 Yung, AR, Phillips, LJ, McGorry, PD, McFarlane, CA, Francey, S, Harrigan, S, Patton, GC, Jackson, HJ. Prediction of psychosis. A step towards indicated prevention of schizophrenia. Br J Psychiatry 1998; 172(suppl 33): 1420.
26 Yung, AR, Stanford, C, Cosgrave, E, Killackey, E, Phillips, L, Nelson, B, McGorry, PD. Testing the ultra-high risk (prodromal) criteria for the prediction of psychosis in a clinical sample of young people. Schizophr Res 2006; 84: 5766.
27 Bullmore, ET, Suckling, J, Overmeyer, S, Rabe-Hesketh, S, Taylor, E, Brammer, MJ. Global, voxel and cluster tests, by theory and permutation for a difference between two groups of structural MR images of the brain. IEEE Trans Med Imaging 1999; 18: 3242.
28 Suckling, J, Sigmundsson, T, Greenwood, K, Bullmore, E. A modified fuzzy clustering algorithm for operated independent tissue classification of dual echo MR images. Magn Reson Imaging 1999; 17: 1065–76.
29 Suckling, J, Davis, MH, Ooi, C, Wink, AM, Fadili, J, Salvador, R, Welchew, D, Sendur, L, Maxim, V, Bullmore, ET. Permutation testing of orthogonal factorial effects in a language processing experiment using fMRI. Hum Brain Mapp 2006; 27: 425–33.
30 Suckling, J, Bullmore, E. Permutation tests for factorially designed neuroimaging experiments. Hum Brain Mapp 2004; 22: 193205.
31 Schmahmann, JD, Doyon, J, McDonald, D, Holmes, C, Lavoie, K, Hurwitz, AS, Kabani, N, Toga, A, Evans, A, Petrides, M. Three-dimensional MRI atlas of the human cerebellum in proportional stereotaxic space. Neuroimage 1999; 10: 233–60.
32 Gloor, P. The Temporal Lobe and Limbic System. Oxford University Press, 1997.
33 Petrides, M, Pandya, D. Association fiber pathways to the frontal cortex from the superior temporal region in the rhesus monkey. J Comp Neurol 1988; 273: 5266.
34 Crosby, E. Correlative Anatomy of the Nervous System. Macmillan, 1962.
35 Catani, M, Howard, R, Pajevic, S, Jones, D. Virtual in vivo interactive dissection of white matter fasciculi in the human brain. Neuroimage 2002; 17: 7794.
36 McGuire, P, Bates, J, Goldman-Rakic, P. Interhemispheric integration: I. Symmetry and convergence of the corticocortical connections of the left and the right principal sulcus (PS) and the left and the right supplementary motor area (SMA) in the rhesus monkey. Cereb Cortex 1991; 1: 390407.
37 Yeterian, E, Pandya, D. Thalamic connections of the cortex of the superior temporal sulcus in the rhesus monkey. J Comp Neurol 1989; 282: 8097.
38 Harris, J, Whalley, H, Yates, S, Miller, P, Johnstone, EC, Lawrie, SM. Abnormal cortical folding in high-risk individuals: a predictor of the development of schizophrenia. Biol Psychiatry 2004; 56: 182–9.
39 Vogeley, K, Tepest, R, Pfeiffer, U, Schneider-Axmann, T, Maier, W, Honer, WG, Falkai, P. Right frontal hypergyria differentiation in affected and unaffected siblings of families multiply affected with schizophrenia: a morphometric MRI stdy. Am J Psychiatry 2001; 158: 494–6.
40 Harris, J, Moorhead, T, Miller, P, McIntosh, A, Bonnici, H, Owens, D, Johnstone, EC, Lawrie, SM. Increased prefrontal gyrification in a large high-risk cohort characterizes those who develop schizophrenia and reflects abnormal prefrontal development. Biol Psychiatry 2007; 62: 722–9.
41 Sowell, E, Peterson, B, Thompson, P, Welcome, S, Henkenius, A, Toga, A. Mapping cortical change across the human life span. Nat Neurosci 2003; 6: 309–15.
42 Bartzokis, G, Beckson, M, Lu, PH, Nuechterlein, KH, Edwards, N, Mintz, J. Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. Arch Gen Psychiatry 2001; 58: 461–5.
43 Thompson, PM, Vidal, C, Giedd, JN, Gochman, P, Blumenthal, J, Nicolson, R, Toga, AW, Rapoport, JL. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci USA 2001; 98: 11650–5.
44 Lieberman, JA, Tollefson, GD, Charles, C, Zipursky, R, Sharma, T, Kahn, RS, Keefe, RS, Green, AI, Gur, RE, McEvoy, J, Perkins, D, Hamer, RM, Gu, H, Tohen, M; HGDH Study Group. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatr 2005; 62: 361–70.
45 Molina, V, Reig, S, Sanz, J, Palomo, T, Benito, C, Sánchez, J, Sarramea, F, Pascau, J, Desco, M. Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia. Schizophr Res 2005; 80: 6171.
46 Bartzokis, G, Lu, PH, Nuechterlein, KH, Gitlin, M, Doi, C, Edwards, N, Lieu, C, Altshuler, LL, Mintz, J. Differential effects of typical and atypical antipsychotics on brain myelination in schizophrenia. Schizophr Res 2007; 93: 1322.
47 Potash, J. Carving chaos: genetics and the classification of mood and psychotic syndromes. Harv Rev Psychiatry 2006; 14: 4763.
48 Velakoulis, D, Wood, SJ, Wong, MT, McGorry, PD, Yung, A, Phillips, L, Smith, D, Brewer, W, Proffitt, T, Desmond, P, Pantelis, C. Hippocampal and amygdala volumes differ according to psychosis stage and diagnosis: an MRI study of chronic schizophrenia, first-episode psychosis and ultra-high risk subjects. Arch Gen Psychiatry 2006; 63: 139–49.
49 Bookstein, F. Voxel-based morphometry should not be used with imperfectly registered images. Neuroimage 2001; 14: 1454–62.
50 Crum, W, Griffin, L, Hill, D, Hawkes, D. Zen and the art of medical image registration: correspondence, homology, and quality. Neuroimage 2003; 20: 1425–37.
51 Jones, D, Symms, M, Cercignani, M, Howard, R. The effect of filter size on VBM analyses of DT-MRI data. Neuroimage 2005; 26: 546–54.
52 Burgel, U, Amunts, K, Hoemke, L, Mohlberg, H, Gilsbach, J, Zilles, K. White matter fiber tracts of the human brain: three-dimensional mapping at microscopic resolution, topography and intersubject variability. Neuroimage 2005; 29: 1092–105.
53 Cogan, D, Chu, F, Reingold, D, Barranger, J. Ocular motor signs in some metabolic diseases. Arch Opthalmol 1981; 99: 1802–8.
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White matter volume changes in people who develop psychosis

  • Mark Walterfang (a1), Philip K. McGuire (a2), Alison R. Yung (a3), Lisa J. Phillips (a4), Dennis Velakoulis (a1), Stephen J. Wood (a5), John Suckling (a6), Edward T. Bullmore (a7), Warrick Brewer (a8), Bridget Soulsby (a5), Patricia Desmond (a9), Patrick D. McGorry (a10) and Christos Pantelis (a11)...
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