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  • The neural correlates of cognitive impairment in schizophrenia

    Els correlats neurals del dficit cognitiu en lesquizofrnia

    Jordi Ortiz Gil

    Aquesta tesi doctoral est subjecta a la llicncia Reconeixement- NoComercial CompartirIgual 3.0. Espanya de Creative Commons.

    Esta tesis doctoral est sujeta a la licencia Reconocimiento - NoComercial CompartirIgual3.0. Espaa de Creative Commons.

    This doctoral thesis is licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0. Spain License.

  • The neural correlates of cognitive

    impairment in schizophrenia

    Els correlats neurals del dficit cognitiu en

    lesquizofrnia

    Tesi doctoral

    Jordi Ortiz Gil

    Departament de Psiquiatria i Psicobiologia Clnica

    FIDMAG Germanes Hospitalries / CIBERSAM

    Programa de Doctorat Medicina

    Lnia de recerca: Neurocincies clniques i experimentals

    Directores de la tesi

    Dra. Carme Junqu i Plaja

    Catedrtica de Neuropsicologia

    Departament de Psiquiatria i Psicobiologia Clnica

    Institut de Recerca Biomdica August Pi i Sunyer

    Dra. Edith Pomarol-Clotet

    Directora

    FIDMAG Germanes Hospitalries

  • The neural correlates of cognitive impairment in schizophrenia

    Somebodys reading your mind

    Damned if you know how it is

    Theyre digging through all of your files

    Stealing back your best ideas

    You cover your window with lead

    Even keeping the pets outside

    Then you hear a moment too late

    this sound coming over the phone

    This is the spawning of the cage and aquarium

    Cage & Aquarium (They Might Be Giants, 1988)

    En ocasiones oigo ecos, ecos de voces elctricas, ultrasnicas (). Parecen

    reverberaciones sobrenaturales, pero son cdigos cifrados, seales de otra

    dimensin.

    Testimoni recollit per Ruiz Garzn (2005)

    Dedicat a les persones a qui roben les millors idees de la seva ment, a les

    persones que senten ecos sobrenaturals xifrats... ; amb lesperana que algun

    dia els podem permetre plenament el seu dret a la felicitat i lautonomia.

  • The neural correlates of cognitive impairment in schizophrenia

  • The neural correlates of cognitive impairment in schizophrenia

    En recuerdo de mi padre, que no pudo ver acabada esta tesis,

    su ltima gran ilusin respecto a m.

    Agraments personal(itzat)s

    A Benito Menni CASM, la gent que hi treballa, les seves persones usuries,

    perqu elles sn la causa, el fi i els principals mitjans daquesta feina.

    A Lucha, mi compaera de vida, por los nimos que me has dado, por las

    comidas que me has preparado y por el mal genio que me has aguantado.

    A mi padre y mi madre, porque el esfuerzo y el amor van de la mano. Porque

    soy como soy gracias a vosotros.

    A Edith, per donar-mhi loportunitat, per tot el coneixement i per totes les

    facilitats.

    A Carme, per la supervisi precisa i svia i per tot el que has fet per la

    neuropsicologia.

    To Peter, for your time, wisdom and dedication.

    A Teresa, pel que mhas ensenyat i per la confiana que demostres en mi.

    A Miguel y Helena, a Cristina y a Carlos, a la ta Aurelia, por la generosidad y

    por estar ah, cada cual a su manera.

    A Luca, Pablo y Gloria, por la inmediatez que enseis.

  • The neural correlates of cognitive impairment in schizophrenia

    A Marina, Lus Diego, Luzga, Ana, Pablo, Felipe y el resto de familia paisa, por

    incluirme como uno ms.

    A Erick, por tu disposicin tan buena pa lo que haga falta.

    A Salva, pel teu ajut efica i pels nims. Segur que aviat tamb ho

    aconsegueixes.

    A Rai, per les anlisis marxistes (des de les vessants de Karl i de Groucho) i

    pels mltiples ajuts tcnics. Som Energia!

    A Marisa, Mnica, Jaime, Paco, M ngels, Roser, Ral, Miguel, Pedro, por

    haber despertado en m la pasin por el cerebro.

    A Ramn, Brbara y Bene, por las mltiples sesiones de tapaterapia de grupo...

    A Antnia, Roco, Natlia, Montse, Bea, Chema i resta de gent de la Guttmann,

    pel que hi vaig poder aprendre i compartir.

    A Bibiana, pel temps que vam ser companys de lluita.

    A Bea, per la teva confiana i complicitat.

    A Eullia, per les converses socials i artstiques i pels mltiples ajuts

    administratius.

    A Jess, por lo que me has enseado y lo que me has compartido. Mucha

    suerte en NY!

    A Gemma, per tot el que dones amb un somriure.

    A Silvia, a Pilar, a lia, a Teresa, a Maria, a Quim, a Laura, Amalia, Merc,

    Laura, Paloma, Eva,... perqu, en la vostra companyia, la feina s ms fcil.

  • The neural correlates of cognitive impairment in schizophrenia

    A Silvia, Naroa, Davinia, Joana i Guisi, pel vostre ajut i acollida en el temps

    amb vosaltres.

    A Yolanda, Capri, Pablo, Bibiana, Roger, Laura, Sergi, Isa,... per humanitzar

    Barcelona i rodalies.

    A Isaac, Montse, Pep, Mireia, Theo, Julie, Laia, Sergio, Sergi, Txell, Julie... per

    fer de Sants un barri de deb.

    A Raquel, per fer ms fcil i humana la feina quotidiana.

    A Ldia, per la confiana i facilitats donades.

    A scar, Anuncia, Pilar, Lola, Carlos, Marta, Nria... i la resta de gent de

    Granollers, per la rebuda i per crear, tantes vegades, un bon ambient a la

    feina.

    A Germn, por las alegras y penas compartidas, incluido el doctorado.

    A la Jose, por la complicidad.

    A Marien, Paco, Malini, Empar, Sergi, ngel, les Lauretes, Floreta i les vostres

    circumstncies, que mheu acompanyat des que comenc amb la psicologia i

    abans. Per tot el que continuarem compartint!

    Al tren, la meva musa en molts moments durant el darrer any.

  • The neural correlates of cognitive impairment in schizophrenia

  • The neural correlates of cognitive impairment in schizophrenia

    Index

    1. Introduction ..........................................................................................1

    1.1. The clinical features of schizophrenia ..............................................4

    1.2. Course and outcome of schizophrenia.............................................7

    1.3. Treatment of schizophrenia..............................................................8

    1.4. The aetiology of schizophrenia ...................................................... 10

    1.5. Neural bases of schizophrenia....................................................... 15

    1.6. Cognitive impairment in schizophrenia........................................... 28

    1.7. The neural basis of cognitive impairment in schizophrenia ............ 36

    2. Hypothesis and objectives of the thesis.............................................. 47

    3. Methods ............................................................................................. 51

    3.1. Participants.................................................................................... 53

    3.2. Psychopathological assessment .................................................... 58

    3.3. Cognitive assessment.................................................................... 58

    3.4. Statistical analysis of the demographic, psychopathological

    and the cognitive data.................................................................... 59

    3.5. Neuroimaging procedure ............................................................... 59

    4. Results............................................................................................... 67

    4.1. Structural neuroimaging findings.................................................... 69

    4.2. Functional imaging findings............................................................ 76

  • The neural correlates of cognitive impairment in schizophrenia

    5. Discussion.......................................................................................... 91

    5.1. Summary of findings ...................................................................... 93

    5.2. Structural neuroimaging findings in relation to previous

    studies ........................................................................................... 94

    5.3. Functional imaging findings in relation to previous studies............. 98

    5.4. Implications of the findings for understanding cognitive impairment in

    schizophrenia .............................................................................. 104

    5.5. Implications of the findings for treatment...................................... 106

    5.6. Limitations ................................................................................... 107

    6. Conclusions ..................................................................................... 111

    7. Resum ............................................................................................. 115

    Annex 1 .................................................................................................... 151

    Annex 2 .................................................................................................... 163

    Annex 3 .................................................................................................... 181

  • The neural correlates of cognitive impairment in schizophrenia

    Index of figures

    Figure 1. Volumetric reductions in WM in schizophrenia according to a recent meta-

    analysis of 24 studies (adapted from Bora et al., 2011a)...........................................20

    Figure 2. FA reduction using DTI in schizophrenia according to a recent meta-analysis of

    23 studies (adapted from Bora et al., 2011a).............................................................22

    Figure 3. Two different ways in which an apparent activation can be found in a task of

    interest, as described by Gusnard and Raichle (2001)..............................................27

    Figure 4. Median effect size of cognitive impairment among cognitive domains, with data

    from several meta-analyses. Taken from Reichenberg (2010)..................................31

    Figure 5. Model proposed by the group of Weinberger.............................................................40

    Figure 6. Example of 1-back and 2-back sequences. ...............................................................63

    Figure 7. Scatterplot of the cognitively preserved and cognitively impaired participants

    scores on the RMBT and the BADS. Data form the subsamples of the structural

    MRI study. ..................................................................................................................72

    Figure 8. Brain regions showing significant GM volume reduction in cognitively preserved

    individuals with schizophrenia compared to healthy controls. ...................................75

    Figure 9. Brain regions where the cognitively preserved individuals with schizophrenia

    showed significant failure to de-activate compared the controls in the 2-back vs 1-

    back contrast. .............................................................................................................81

    Figure 10. Boxplot of the averaged level of activation from the cognitively preserved patients

    and the healthy control groups in the medial frontal cluster of significant

    difference in the 2-back vs baseline contrast. ............................................................83

  • The neural correlates of cognitive impairment in schizophrenia

    Figure 11. Boxplot of the averaged level of activation from the cognitively preserved patients

    and the healthy control groups in the medial frontal cluster of significant

    difference in the 2-back vs 1-back contrast. ..............................................................83

    Figure 12. Brain regions where the cognitively impaired schizophrenia group activated

    significantly less than the cognitively preserved group in the 2-back vs 1-back

    contrast.......................................................................................................................85

    Figure 13. Brain regions where the cognitively preserved individuals with schizophrenia

    showed significant failure to de-activate compared the controls in the working

    memory load contrast.................................................................................................88

    Figure 14. Brain regions where the cognitively impaired schizophrenia group activated

    significantly less than the cognitively preserved group in the working memory load

    contrast.......................................................................................................................89

  • The neural correlates of cognitive impairment in schizophrenia

    Index of tables

    Table 1. Comparison of regional brain volume of participants with schizophrenia and

    healthy controls in 58 studies.....................................................................................17

    Table 2. Summary of the positive findings of a review of 27 studies relating cognition and

    psychopathology. .......................................................................................................34

    Table 3. Subtests included in the RBMT and description, including the cognitive domains

    assessed by each test................................................................................................56

    Table 4. Subtests included in the BADS and description, including the cognitive domains

    assessed by each test................................................................................................57

    Table 5. Demographic, cognitive and psychopathological characteristics of the participants

    with schizophrenia and controls in the structural neuroimaging study.......................70

    Table 6. Whole brain and lateral ventricular volume measures in the controls and in the

    combined schizophrenia group. .................................................................................73

    Table 7. Whole brain and lateral ventricular volume measures in the controls, and in the

    cognitively preserved and cognitively impaired schizophrenia groups. .....................74

    Table 8. Significant cluster and the corresponding peak values in each anatomical region

    where cognitively preserved individuals with schizophrenia show a significant

    decrease in GM volume, when compared to controls, using VBM. ...........................75

    Table 9. Mean values, standard deviations and statistical results of demographic, cognitive

    and psychopathological characteristics of the fMRI sample. .....................................78

    Table 10. Significant clusters and corresponding peak values in each anatomical region in

    the 2-back versus baseline contrast...........................................................................80

    Table 11. Significant clusters and the corresponding peak values of increased activation in

    each anatomical region in the cognitively preserved schizophrenia group

    compared to the control group in the 2-back versus 1-back contrast. .......................82

    Table 12. Significant clusters and corresponding peak values of significantly decreased

    activation in each anatomical region in the cognitively impaired schizophrenia

    group when compared to the cognitively preserved group in the 2-back versus 1-

    back contrast. .............................................................................................................86

  • The neural correlates of cognitive impairment in schizophrenia

  • The neural correlates of cognitive impairment in schizophrenia

    Abbreviations

    ANOVA: Analysis of Variance

    BA: Brodmanns area

    BADS: Behavioural Assessment of the Dysexecutive Syndrome

    BOLD: Blood-Oxygenation-Level-Dependent

    C: Healthy Control Participants

    CGI: Clinical Global Impression

    CNVs: Copy number variants

    CPZ: Chlorpromazine

    CSF: Cerebrospinal Fluid

    CT: Computed Tomography

    DLPFC: Dorsolateral prefrontal cortex

    DMN: Default Mode Network

    DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th Ed.

    DTI: Diffusion tensor imaging

    ES: Effect Size (using Cohens d)

    ESs: Effect Sizes (using Cohens d)

    F: Female

    FA: Fractional Anisotropy

    FE: First Psychotic Episode

    FEAT: FMRI Expert Analysis Tool software

    FIRST: FMRIB's Integrated Registration and Segmentation Tool software

    fMRI: Functional Magnetic Resonance Imaging

    FSL: FMRIB Software Library software

    GE: General Electrics

    GLM: General Linear Model

    GM: Gray Matter

    I: Cognitively Impaired Participants with Schizophrenia

    IQ: Intelligence Quotient

    K-W: Kruskal-Wallis (2-test)

    M: Male

    MMSE: Mini-Mental State Examination

    MNI: Montreal Neurological Institute

    MRI: Magnetic Resonance Imaging

    M-W: Mann-Whitneys (U-test)

  • The neural correlates of cognitive impairment in schizophrenia

    NART: National Adult Reading Test

    P: Cognitively Preserved Participants with Schizophrenia

    PANSS: Positive and Negative Syndrome Scale

    PET: Positron Emission Tomography

    RBMT: Rivermead Behavioural Memory Test

    ROI: Region of Interest

    SD: Standard deviation

    SIENAX: Structural Image Evaluation, using Normalisation, of Atrophy software

    SPECT: Single Photon Emission Computed Tomography

    SPM: Statistical Parametric Mapping software

    TAP: Test de acentuacin de palabras [Word Accentuation Test]

    TE: Echo Time

    TI: Inversion Time

    TR: Repetition Time

    VBM: Voxel-based Morphometry

    WAIS-III: Wechsler Adult Intelligence Scale, 3rd Ed.

    WASI: Wechsler Abbreviated Scale of Intelligence

    WCST: Wisconsin Card Sorting Test

    WM: White Matter

    WMS-III: Wechsler Memory Scale, 3rd Ed.

  • The neural correlates of cognitive impairment in schizophrenia 1

    1. Introduction

  • The neural correlates of cognitive impairment in schizophrenia 2

  • The neural correlates of cognitive impairment in schizophrenia 3

    Schizophrenia is a severe and debilitating psychiatric disorder. It is

    considered to be one of the ten medical disorders that cause the most severe

    long-term disability (Mueser and McGurk, 2004). According to the World Health

    Organisation, it is also the third leading contributor to the global burden of

    mental, neurological and substance use disorders, and the fifth among high-

    income countries (Collins et al., 2011). The economic burden of schizophrenia

    can be divided into direct costs and indirect costs. Direct costs refer to medical

    care, including pharmacological and non-pharmacological treatment and

    hospital admissions, and criminal justice costs. Indirect costs relate to the

    decrease in economic productivity of individuals with the disorder and the

    people taking care of them, mainly relatives (McEvoy, 2007), plus costs derived

    of increa