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A longitudinal study of cortical changes and their cognitive correlates in patients followed up after first-episode psychosis

  • L. Gutiérrez-Galve (a1) (a2) (a3), E. M. Chu (a1), V. C. Leeson (a4), G. Price (a1), T. R. E. Barnes (a4), E. M. Joyce (a1) and M. A. Ron (a1)...



Loss of cortical volume in frontotemporal regions occurs in patients with first-episode psychosis (FEP) and longitudinal studies have reported progressive brain volume changes at different stages of the disease, even if cognitive deficits remain stable over time. We investigated cortical changes in patients over the 2 years following their FEP and their associations with clinical and cognitive measures.


Twenty-seven patients after their FEP (20 with schizophrenia, seven with schizo-affective disorder) and 25 healthy controls matched for age and gender participated in this study. Magnetic resonance imaging (MRI) was performed on a 1.5-T scanner both at baseline and after 2 years. Area and thickness of the cortex were measured using surface-based morphometry (SBM). Patients also underwent neuropsychological testing at these two time points.


Progressive cortical thinning in the superior and inferior frontal and, to a lesser extent, superior temporal cortex was observed in patients. Cortical area remained constant. Cortical thinning was associated with duration of treatment at a trend level and was predicted by baseline measures of IQ and working memory. Cortical thinning occurred in the absence of clinical or cognitive deterioration.


The clinical implications of these cortical changes remain uncertain, but patients with less cognitive reserve may be more vulnerable to developing cortical abnormalities when exposed to medication or other disease-related biological factors.


Corresponding author

* Address for correspondence: Dr L. Gutiérrez-Galve, Academic Unit of Child and Adolescent Psychiatry, 3rd floor QEQM Building, Imperial College, St Mary's Campus, Norfolk Place, London W2 1PG, UK. (Email:


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Andreasen, N (1983). The Scale for the Assessment of Negative Symptoms (SANS). The University of Iowa: Iowa City, IA.
Andreasen, N (1984). The Scale for the Assessment of Positive Symptoms (SAPS). The University of Iowa: Iowa City, IA.
Andreasen, NC, Nopoulos, P, Magnotta, V, Pierson, R, Ziebell, S, Ho, BC (2011). Progressive brain change in schizophrenia: a prospective longitudinal study of first-episode schizophrenia. Biological Psychiatry 70, 672679.
Annett, M (1970). A classification of hand preference by association analysis. British Journal of Psychology 61, 303321.
Arango, C, Moreno, C, Martinez, S, Parellada, M, Desco, M, Moreno, D, Fraguas, D, Gogtay, N, James, A, Rapoport, J (2008). Longitudinal brain changes in early-onset psychosis. Schizophrenia Bulletin 34, 341353.
Arango, C, Rapado-Castro, M, Reig, S, Castro-Fornieles, J, Gonzalez-Pinto, A, Otero, S, Baeza, I, Moreno, C, Graell, M, Janssen, J, Parellada, M, Moreno, D, Bargallo, N, Desco, M (2012). Progressive brain changes in children and adolescents with first-episode psychosis. Archives of General Psychiatry 69, 1626.
Asami, T, Bouix, S, Whitford, TJ, Shenton, ME, Salisbury, DF, McCarley, RW (2012). Longitudinal loss of gray matter volume in patients with first-episode schizophrenia: DARTEL automated analysis and ROI validation. NeuroImage 59, 986996.
Boksa, P (2012). Abnormal synaptic pruning in schizophrenia: urban myth or reality? Journal of Psychiatry and Neuroscience 37, 7577.
Brans, RG, van Haren, NE, van Baal, GC, Schnack, HG, Kahn, RS, Hulshoff Pol, HE (2008). Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia. Archives of General Psychiatry 65, 12591268.
Breslow, NE, Clayton, DG (1993). Approximate inference in generalized linear mixed models. Journal of the American Statistical Association 88, 925.
Buckner, RL, Head, D, Parker, J, Fotenos, AF, Marcus, D, Morris, JC, Snyder, AZ (2004). A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. NeuroImage 23, 724738.
Cobia, DJ, Smith, MJ, Wang, L, Csernansky, JG (2012). Longitudinal progression of frontal and temporal lobe changes in schizophrenia. Schizophrenia Research 139, 16.
Dale, AM, Fischl, B, Sereno, MI (1999). Cortical surface-based analysis. I. Segmentation and surface reconstruction. NeuroImage 9, 179194.
Desikan, RS, Segonne, F, Fischl, B, Quinn, BT, Dickerson, BC, Blacker, D, Buckner, RL, Dale, AM, Maguire, RP, Hyman, BT, Albert, MS, Killiany, RJ (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage 31, 968980.
Drake, RE, Osher, FC, Noordsy, DL, Hurlbut, SC, Teague, GB, Beaudett, MS (1990). Diagnosis of alcohol use disorders in schizophrenia. Schizophrenia Bulletin 16, 5767.
Du, AT, Schuff, N, Kramer, JH, Rosen, HJ, Gorno-Tempini, ML, Rankin, K, Miller, BL, Weiner, MW (2007). Different regional patterns of cortical thinning in Alzheimer's disease and frontotemporal dementia. Brain 130, 11591166.
Ellison-Wright, I, Glahn, DC, Laird, AR, Thelen, SM, Bullmore, E (2008). The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. American Journal of Psychiatry 165, 10151023.
Fischl, B, Dale, AM (2000). Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proceedings of the National Academy of Sciences USA 97, 1105011055.
Fischl, B, Sereno, MI, Dale, AM (1999). Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. NeuroImage 9, 195207.
Fusar-Poli, P, Smieskova, R, Kempton, MJ, Ho, BC, Andreasen, NC, Borgwardt, S (2013). Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neuroscience and Biobehavioral Reviews 37, 16801691.
Genovese, CR, Lazar, NA, Nichols, T (2002). Thresholding of statistical maps in functional neuroimaging using the false discovery rate. NeuroImage 15, 870878.
Giedd, JN, Schmitt, JE, Neale, MC (2007). Structural brain magnetic resonance imaging of pediatric twins. Human Brain Mapping 28, 474481.
Goghari, VM, Smith, GN, Honer, WG, Kopala, LC, Thornton, AE, Su, W, Macewan, GW, Lang, DJ (2013). Effects of eight weeks of atypical antipsychotic treatment on middle frontal thickness in drug-naive first-episode psychosis patients. Schizophrenia Research 149, 149155.
Gutiérrez-Galve, L, Flugel, D, Thompson, PJ, Koepp, MJ, Symms, MR, Ron, MA, Foong, J (2012). Cortical abnormalities and their cognitive correlates in patients with temporal lobe epilepsy and interictal psychosis. Epilepsia 53, 10771087.
Gutiérrez-Galve, L, Wheeler-Kingshott, CA, Altmann, DR, Price, G, Chu, EM, Leeson, VC, Lobo, A, Barker, GJ, Barnes, TR, Joyce, EM, Ron, MA (2010). Changes in the frontotemporal cortex and cognitive correlates in first-episode psychosis. Biological Psychiatry 68, 5160.
Hamilton, M (1960). A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 5662.
Ho, BC, Andreasen, NC, Ziebell, S, Pierson, R, Magnotta, V (2011). Long-term antipsychotic treatment and brain volumes: a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry 68, 128137.
Huddy, VC, Hodgson, TL, Kapasi, M, Mutsatsa, SH, Harrison, I, Barnes, TR, Joyce, EM (2007). Gaze strategies during planning in first-episode psychosis. Journal of Abnormal Psychology 116, 589598.
Hulshoff Pol, HE, Kahn, RS (2008). What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophrenia Bulletin 34, 354366.
Ivleva, EI, Bidesi, AS, Keshavan, MS, Pearlson, GD, Meda, SA, Dodig, D, Moates, AF, Lu, H, Francis, AN, Tandon, N, Schretlen, DJ, Sweeney, JA, Clementz, BA, Tamminga, CA (2013). Gray matter volume as an intermediate phenotype for psychosis: Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). American Journal of Psychiatry 170, 12851296.
Jablensky, A, McGrath, J, Herrman, H, Castle, D, Gureje, O, Evans, M, Carr, V, Morgan, V, Korten, A, Harvey, C (2000). Psychotic disorders in urban areas: an overview of the Study on Low Prevalence Disorders. Australian and New Zealand Journal of Psychiatry 34, 221236.
Joyce, EM, Hutton, SB, Mutsatsa, SH, Barnes, TR (2005). Cognitive heterogeneity in first-episode schizophrenia. British Journal of Psychiatry 187, 516522.
Khandaker, GM, Barnett, JH, White, IR, Jones, PB (2011). A quantitative meta-analysis of population-based studies of premorbid intelligence and schizophrenia. Schizophrenia Research 132, 220227.
Konopaske, GT, Dorph-Petersen, KA, Pierri, JN, Wu, Q, Sampson, AR, Lewis, DA (2007). Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology 32, 12161223.
Kuperberg, GR, Broome, MR, McGuire, PK, David, AS, Eddy, M, Ozawa, F, Goff, D, West, WC, Williams, SC, van der Kouwe, AJ, Salat, DH, Dale, AM, Fischl, B (2003). Regionally localized thinning of the cerebral cortex in schizophrenia. Archives General of Psychiatry 60, 878888.
Leeson, VC, Sharma, P, Harrison, M, Ron, MA, Barnes, TR, Joyce, EM (2011). IQ trajectory, cognitive reserve, and clinical outcome following a first episode of psychosis: a 3-year longitudinal study. Schizophrenia Bulletin 37, 768777.
Lezak, MD (1995). Neuropsychological Assessment. Oxford University Press: New York, NY.
Martin-Santos, R, Fagundo, AB, Crippa, JA, Atakan, Z, Bhattacharyya, S, Allen, P, Fusar-Poli, P, Borgwardt, S, Seal, M, Busatto, GF, McGuire, P (2010). Neuroimaging in cannabis use: a systematic review of the literature. Psychological Medicine 40, 383398.
Minatogawa-Chang, TM, Schaufelberger, MS, Ayres, AM, Duran, FL, Gutt, EK, Murray, RM, Rushe, TM, McGuire, PK, Menezes, PR, Scazufca, M, Busatto, GF (2009). Cognitive performance is related to cortical grey matter volumes in early stages of schizophrenia: a population-based study of first-episode psychosis. Schizophrenia Research 113, 200209.
Moncrieff, J, Leo, J (2010). A systematic review of the effects of antipsychotic drugs on brain volume. Psychological Medicine 40, 14091422.
Murray, GK, Corlett, PR, Fletcher, PC (2010). The neural underpinnings of associative learning in health and psychosis: how can performance be preserved when brain responses are abnormal? Schizophrenia Bulletin 36, 465471.
Murray, RM, Lewis, SW (1987). Is schizophrenia a neurodevelopmental disorder? British Medical Journal (Clinical Research Edition) 295, 681682.
Narr, KL, Bilder, RM, Toga, AW, Woods, RP, Rex, DE, Szeszko, PR, Robinson, D, Sevy, S, Gunduz-Bruce, H, Wang, YP, DeLuca, H, Thompson, PM (2005). Mapping cortical thickness and gray matter concentration in first episode schizophrenia. Cerebral Cortex 15, 708719.
Nelson, H, Willson, J (1991). The Revised National Adult Reading Test (NART): Test Manual. NFER-Nelson: Windsor.
Owens, SF, Picchioni, MM, Ettinger, U, McDonald, C, Walshe, M, Schmechtig, A, Murray, RM, Rijsdijk, F, Toulopoulou, T (2012). Prefrontal deviations in function but not volume are putative endophenotypes for schizophrenia. Brain 135, 22312244.
Panizzon, MS, Fennema-Notestine, C, Eyler, LT, Jernigan, TL, Prom-Wormley, E, Neale, M, Jacobson, K, Lyons, MJ, Grant, MD, Franz, CE, Xian, H, Tsuang, M, Fischl, B, Seidman, L, Dale, A, Kremen, WS (2009). Distinct genetic influences on cortical surface area and cortical thickness. Cerebral Cortex 19, 27282735.
Perkins, DO, Leserman, J, Jarskog, LF, Graham, K, Kazmer, J, Lieberman, JA (2000). Characterizing and dating the onset of symptoms in psychotic illness: the Symptom Onset in Schizophrenia (SOS) inventory. Schizophrenia Research 44, 110.
Rais, M, Cahn, W, Van Haren, N, Schnack, H, Caspers, E, Hulshoff Pol, H, Kahn, R (2008). Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients. American Journal of Psychiatry 165, 490496.
Reilly, JL, Sweeney, JA (2014). Generalized and specific neurocognitive deficits in psychotic disorders: utility for evaluating pharmacological treatment effects and as intermediate phenotypes for gene discovery. Schizophrenia Bulletin 40, 516522.
Reuter, M, Fischl, B (2011). Avoiding asymmetry-induced bias in longitudinal image processing. NeuroImage 57, 1921.
Reuter, M, Schmansky, NJ, Rosas, HD, Fischl, B (2012). Within-subject template estimation for unbiased longitudinal image analysis. NeuroImage 61, 14021418.
Roiz-Santianez, R, Tordesillas-Gutierrez, D, Ortiz-Garcia de la Foz, V, Ayesa-Arriola, R, Gutierrez, A, Tabares-Seisdedos, R, Vazquez-Barquero, JL, Crespo-Facorro, B (2012). Effect of antipsychotic drugs on cortical thickness. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine. Schizophrenia Research 141, 2228.
Sahakian, BJ, Owen, AM (1992). Computerized assessment in neuropsychiatry using CANTAB: discussion paper. Journal of the Royal Society of Medicine 85, 399402.
Schultz, CC, Koch, K, Wagner, G, Roebel, M, Schachtzabel, C, Gaser, C, Nenadic, I, Reichenbach, JR, Sauer, H, Schlosser, RG (2010). Reduced cortical thickness in first episode schizophrenia. Schizophrenia Research 116, 204209.
Selemon, LD (2001). Regionally diverse cortical pathology in schizophrenia: clues to the etiology of the disease. Schizophrenia Bulletin 27, 349377.
Sun, D, Stuart, GW, Jenkinson, M, Wood, SJ, McGorry, PD, Velakoulis, D, van Erp, TG, Thompson, PM, Toga, AW, Smith, DJ, Cannon, TD, Pantelis, C (2009). Brain surface contraction mapped in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Molecular Psychiatry 14, 976986.
Thompson, PM, Vidal, C, Giedd, JN, Gochman, P, Blumenthal, J, Nicolson, R, Toga, AW, Rapoport, JL (2001). Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proceedings of the National Academy of Sciences USA 98, 1165011655.
Uranova, NA, Vostrikov, VM, Orlovskaya, DD, Rachmanova, VI (2004). Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophrenia Research 67, 269275.
van Haren, NE, Cahn, W, Hulshoff Pol, HE, Kahn, RS (2012). The course of brain abnormalities in schizophrenia: can we slow the progression? Journal of Psychopharmacology 26, 814.
van Haren, NE, Hulshoff Pol, HE, Schnack, HG, Cahn, W, Brans, R, Carati, I, Rais, M, Kahn, RS (2008). Progressive brain volume loss in schizophrenia over the course of the illness: evidence of maturational abnormalities in early adulthood. Biological Psychiatry 63, 106113.
van Haren, NE, Schnack, HG, Cahn, W, van den Heuvel, MP, Lepage, C, Collins, L, Evans, AC, Hulshoff Pol, HE, Kahn, RS (2011). Changes in cortical thickness during the course of illness in schizophrenia. Archives of General Psychiatry 68, 871880.
Vernon, AC, Natesan, S, Modo, M, Kapur, S (2011). Effect of chronic antipsychotic treatment on brain structure: a serial magnetic resonance imaging study with ex vivo and postmortem confirmation. Biological Psychiatry 69, 936944.
Vidal, CN, Rapoport, JL, Hayashi, KM, Geaga, JA, Sui, Y, McLemore, LE, Alaghband, Y, Giedd, JN, Gochman, P, Blumenthal, J, Gogtay, N, Nicolson, R, Toga, AW, Thompson, PM (2006). Dynamically spreading frontal and cingulate deficits mapped in adolescents with schizophrenia. Archives of General Psychiatry 63, 2534.
Voets, NL, Hough, MG, Douaud, G, Matthews, PM, James, A, Winmill, L, Webster, P, Smith, S (2008). Evidence for abnormalities of cortical development in adolescent-onset schizophrenia. NeuroImage 43, 665675.
Wechsler, D (1997). Wechsler Adult Intelligence Scale – 3rd Edition (WAIS-III). The Psychological Corporation: San Antonio, TX.
Wisco, JJ, Kuperberg, G, Manoach, D, Quinn, BT, Busa, E, Fischl, B, Heckers, S, Sorensen, AG (2007). Abnormal cortical folding patterns within Broca's area in schizophrenia: evidence from structural MRI. Schizophrenia Research 94, 317327.
Young, RC, Biggs, JT, Ziegler, VE, Meyer, DA (1978). A rating scale for mania: reliability, validity and sensitivity. British Journal of Psychiatry 133, 429435.


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A longitudinal study of cortical changes and their cognitive correlates in patients followed up after first-episode psychosis

  • L. Gutiérrez-Galve (a1) (a2) (a3), E. M. Chu (a1), V. C. Leeson (a4), G. Price (a1), T. R. E. Barnes (a4), E. M. Joyce (a1) and M. A. Ron (a1)...


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