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Theory of mind, social cognition, and neural functioning in schizophrenia spectrum disorders Burns, Amy Minh Nhat 2016

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 THEORY OF MIND, SOCIAL COGNITION, AND NEURAL FUNCTIONING IN SCHIZOPHRENIA SPECTRUM DISORDERS  by  AMY MINH NHAT BURNS  B.A., University of Alberta, 2006 M.Ed., University of Alberta, 2009  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY  in  THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Psychology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  October, 2016  © Amy Burns, 2016    ii Abstract Social cognitive functioning has been shown to be impaired in patients with schizophrenia (SZ), and these impairments are associated with functional outcomes. To better understand these deficits this dissertation investigated the neurocognitive processes associated with several social cognitive tasks. A novel irony comprehension paradigm was developed for use with electroencephalogram (EEG). The N400, a negative event related potential (ERP) that occurs 300-500 ms after the onset of a semantically incongruent word, and the P600, a positive ERP that occurs around 500-800 ms, were used to index irony comprehension. Study 1 revealed that SZ performed worse than healthy controls (HC) across three measures of social cognition – emotion perception, Theory of Mind (ToM), and irony comprehension. Furthermore, negative symptoms of SZ were associated with poor ToM performance. ERP findings showed that HC exhibited hemispheric differences in N400 amplitude in response to ironic sentences, with the left hemisphere showing smaller amplitudes to ironic compared to literal statements, whereas SZ did not show this differentiation. Although HC processed ironic statements differently compared to SZ, the direction of the effect was opposite of what was hypothesized. Study 2 examined the durability of this unanticipated finding in a larger group of HC. The N400 effect from Study 1was not replicated – there were no differences in N400 amplitude for ironic and literal statements. A difference in P600 was found whereby the P600 amplitude for literal was greater than for ironic. Self-reported schizotypal traits were associated with poor ToM performance. Study 3 examined whether computerized cognitive remediation (CCR), which has been shown to improve neurocognition, would generalize to social cognition, and whether these changes could be detected at a neural level using EEG. The CCR program implemented in this study produced no improvement in  iii neurocognition or social cognition. Taken together, these results suggest that several aspects of social cognition are impaired in patients with schizophrenia, on a behavioural and possibly a neural level. Future studies are necessary to determine the most effective framework for CCR to minimize the deficits in interpersonal skills that are linked to both general cognitive abilities and social cognition in those with schizophrenia.   iv Preface  I prepared the content of this dissertation with edits from Drs. Lynn Alden, Colleen Brenner, and Lawrence Ward.   The cloze probability test was approved by the University of British Columbia’s Research Ethics Board, H15-01588, Fill in the blank for Irony Comprehension Task.   I was responsible for study conception, design, data analysis, and interpretation in chapter 2. This study was approved by the University of British Columbia’s Research Ethics Board, H11-01626, Neural Correlates of Theory of Mind Reasoning.   Chapter 3 is based on work conducted in UBC’s Clinical and Cognitive Neuroscience Laboratory with Dr. Colleen Brenner. I was responsible for study conception, design, data collection, data analysis and interpretation. Dr. Brenner was responsible for study conception, and design. The study was approved by the University of Columbia’s Research Ethics Board, H11-00118, The Social and Biological Correlates of Cognition.   v Table of Contents Abstract .................................................................................................................................... ii Preface ..................................................................................................................................... iv Table of Contents .................................................................................................................... v List of Tables ........................................................................................................................... x List of Figures ......................................................................................................................... xi List of Abbreviations ............................................................................................................ xii Acknowledgements .............................................................................................................. xvi Dedication ............................................................................................................................ xvii Chapter 1: Introduction ......................................................................................................... 1 1.1 Social Cognition in Schizophrenia ........................................................................... 3 1.1.1 Social Cognition and Functional Outcomes .......................................................... 5 1.1.2 Social Cognition and Symptoms in Schizophrenia ............................................... 6 1.1.3 Theory of Mind ..................................................................................................... 6 1.1.4 Theory of Mind in Schizophrenia ......................................................................... 7 1.1.5 Theory of Mind and Phase of Illness .................................................................... 9 1.2 Models of Irony Comprehension ............................................................................ 14 1.2.1 Standard Pragmatic Model .................................................................................. 16 1.2.2 Direct Access Model ........................................................................................... 16 1.2.3 Graded Salience Hypothesis ................................................................................ 17 1.3 Irony and Schizophrenia ......................................................................................... 18 1.4 ERPs in Schizophrenia ............................................................................................ 19  vi 1.4.1 N400 .................................................................................................................... 22 1.4.2 N400 and Schizophrenia ..................................................................................... 23 1.4.3 P600 ..................................................................................................................... 24 1.4.4 P600 and Schizophrenia ...................................................................................... 25 1.5 Mechanics of Reading in the Brain ........................................................................ 26 1.6 Treatment Implications and Cognitive Remediation in Schizophrenia ............. 31 1.7 General Methodology .............................................................................................. 34 1.7.1 Social Cognitive Assessments ............................................................................. 34 1.7.1.1 Hinting Task .................................................................................................. 35 1.7.1.2 Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) .................. 36 1.7.1.3 Irony Comprehension Task (ICT) ................................................................. 37 1.7.2 Assessment of Psychopathology ......................................................................... 37 1.7.2.1 Structured Clinical Interview for the DSM-IV (SCID) ................................. 37 1.7.2.2 Positive and Negative Syndrome Scale (PANSS) ......................................... 38 1.7.2.3 Schizotypal Personality Questionnaire (SPQ) ............................................... 38 1.7.3 Neuropsychological Assessments ....................................................................... 39 1.7.3.1 Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) ........................................................................................ 39 1.7.4 Electroencephalogram (EEG) ............................................................................. 41 1.7.4.1 Irony Comprehension Task (ICT) ................................................................. 41 1.7.5 Computerized Cognitive Remediation Training ................................................. 43 1.7.5.1 Brain Fitness .................................................................................................. 44 1.8 Overview of Dissertation ......................................................................................... 47  vii Chapter 2: Irony Comprehension in Schizophrenia ......................................................... 50 2.1 Study 1 ...................................................................................................................... 53 2.2 Methods .................................................................................................................... 53 2.2.1 Participants .......................................................................................................... 53 2.2.2 Social Cognitive Measures .................................................................................. 54 2.2.3 Measures of Psychopathology ............................................................................. 55 2.2.4 Measurement of Irony ......................................................................................... 56 2.2.5 Pretests of the Irony Comprehension Task ......................................................... 58 2.2.6 Power Analysis .................................................................................................... 60 2.2.7 EEG Procedure .................................................................................................... 60 2.2.8 EEG Data Acquisition & Analysis ...................................................................... 63 2.2.9 Statistical Analysis .............................................................................................. 63 2.3 Results ....................................................................................................................... 64 2.3.1 Behavioural Results ............................................................................................. 64 2.3.2 Electrophysiological Results ............................................................................... 73 2.4 Discussion ................................................................................................................. 79 2.5 Study 2 ...................................................................................................................... 83 2.6 Methods .................................................................................................................... 84 2.6.1 Participants .......................................................................................................... 84 2.6.2 Power Analysis .................................................................................................... 84 2.6.3 Stimulus Materials ............................................................................................... 84 2.6.4 EEG Procedure .................................................................................................... 85 2.6.5 EEG Data Acquisition & Analysis ...................................................................... 85  viii 2.6.6 Statistical Analysis .............................................................................................. 85 2.7 Results ....................................................................................................................... 86 2.7.1 Behavioural Results ............................................................................................. 86 2.7.2 Electrophysiological Results ............................................................................... 90 2.8 Discussion ................................................................................................................. 93 2.9 General Conclusions ................................................................................................ 95 Chapter 3: Computerized Cognitive Remediation in Schizophrenia............................. 101 3.1 Objectives ............................................................................................................... 107 3.2 Outcomes ................................................................................................................ 107 3.3 Methods .................................................................................................................. 108 3.3.1 Participants ........................................................................................................ 108 3.3.2 Materials ............................................................................................................ 108 3.3.3 Interventions ...................................................................................................... 110 3.3.4 Data Analysis .................................................................................................... 111 3.4 Results ..................................................................................................................... 112 3.5 Discussion ............................................................................................................... 120 Chapter 4: General Discussion .......................................................................................... 123 4.1 Limitations.............................................................................................................. 129 4.2 Future Directions ................................................................................................... 132 4.3 Overall Summary and Conclusions ..................................................................... 133 References ............................................................................................................................ 135 Appendices ........................................................................................................................... 185 Appendix A : Item samples from the Hinting Task ..................................................... 185  ix Appendix B : Item samples from the MSCEIT ............................................................ 186 Appendix C : Item samples from the Schizotypal Personality Questionnaire (SPQ) ........................................................................................................................................... 187 Appendix D : Positive and Negative Syndrome Scale (PANSS) ................................. 188 Appendix E : EEG cap set up ........................................................................................ 189 Appendix F : 32 channel standard EEG recording cap  ............................................. 190 Appendix G : Items from the Irony Comprehension Task (ICT) .............................. 191 Appendix H : Sex differences analysis .......................................................................... 202   x List of Tables  Table 2.1 Examples of Irony Comprehension Task ............................................................... 57 Table 2.2 Descriptive Statistics for Study 1  ........................................................................... 66 Table 2.3 ANCOVA Table for Reaction Time with Education as a Covariate for Study 1 ... 69 Table 2.4 Correlations Between Social Cognition and Original PANSS scores in SZ for Study 1 .................................................................................................................................... 71 Table 2.5 Correlations Between Social Cognition and Five-Factor PANSS scores in SZ for Study 1 .................................................................................................................................... 72 Table 2.6 Descriptive Statistics of the SPQ and Social Cognitive Measures for Study 2 ...... 87 Table 2.7 Correlations Between Social Cognitive Measures and the SPQ for Study 2 ......... 89 Table 3.1 Descriptive Statistics at Baseline for Study 3 ....................................................... 113 Table 3.2 Cognitive and Clinical Measures at Baseline and Post Treatment for Study 3 .... 116 Table 4.1 One-Way ANOVA with Sex as the Dependent Variable in HC for Study 1  ...... 202 Table 4.2 One-Way ANOVA with Sex as the Dependent Variable in SZ for Study 1 ........ 203 Table 4.3 One-Way ANOVA with Sex as the Dependent Variable for Study 2 .................. 204     xi List of Figures  Figure 1.1 An example of the N400 and P600 waveforms. .................................................... 21 Figure 1.2 Schematic of the Retrieval-Integration Cycle in the left hemisphere. ................... 30 Figure 1.3 The MATRICS cognitive domains and subtests. .................................................. 40 Figure 2.1 Example of the Irony Comprehension Task for electroencephalogram (EEG). ... 62 Figure 2.2 The Irony Comprehension Task percent correct by quartile for Study 1. ............. 67 Figure 2.3 ERPs for the ironic and literal conditions in the left hemisphere in study 1. ........ 75 Figure 2.4 ERPs for the ironic and literal conditions in the right hemisphere in study 1. ...... 76 Figure 2.5 ERPs for the HC and SZ groups in study 1 ........................................................... 78 Figure 2.6 Average ERPs at frontal, central, parietal and occipital sites in study 2. .............. 92 Figure 3.1 Model of intermediate variables linking cognition and functional outcomes. .... 102 Figure 3.2 Consolidated Standards of Reporting Trials (CONSORT) chart ........................ 114 Figure 3.3 P300 for the auditory oddball task in study 3. ..................................................... 117 Figure 3.4 ERPs of the ICT for participants in the treatment group in study 3. ................... 118 Figure 3.5 ERPs of the ICT for participants in the wait list control group in study 3. ......... 119   xii List of Abbreviations AC: Auditory cortex ADHD: Attention Deficit Hyperactivity Disorder AG: Angular Gyrus aIFG: Anterior Inferior Frontal Gyrus  ANOVA: Analysis of variance ATC: Anterior Temporal Cortex BACS: Brief Assessment of Cognition in Schizophrenia BDNF: Brain-derived Neurotrophic Factor BREB: Behavioural Research Ethics Board  BVMT-R: Brief Visuospatial Memory Test Revised  CCR: computerized cognitive remediation  CONSORT: CONsolidated Standards of Reporting Trials  CPT-IP: Continuous Performance Test – Identical Pair CPZ: Chlorpromazine equivalents  CRT: Cathode ray tube CZ: Central site, midline C3: Central site, left hemisphere C4: Central site, right hemisphere DAM: Direct Access Model DSM-IV-TR:  Diagnostic and Statistical Manual of Mental Disorders (4th ed., text revised) DP: Dorsal pathway EEG: Electroencephalogram  xiii EOG: Electrooculogram ERP: Event related potentials  FMRI: functional magnetic resonance imaging FZ: Frontal site, midline F3: Frontal site, left hemisphere F4: Frontal site, right hemisphere HC: Healthy controls  HVLTR: Hopkins Verbal Learning Test Revised  ICT: Irony Comprehension Task IIT: Irony Interpretation Task IFG: Inferior Frontal Gyrus KR-20: Kuder Richardson 20 LTPJ: Left Temporo-Parietal Junctions MATRICS: Measurement and Treatment Research to Improve Cognition in Schizophrenia MCCB: MATRICS Consensus Cognitive Battery MCI: Mild cognitive impairment MMN: Mismatch negativity MSCEIT: Mayer-Salovey-Caruso Emotional Intelligence Test NAB: Neuropsychological Assessment Battery NIMH: National Institute of Mental Health OZ: Occipital site, midline O1: Occipital site, left hemisphere O2: Occipital site, right hemisphere   xiv PANSS: Positive and Negative Symptom Scale PET: Positron emission tomography  pMTG: Posterior Middle Temporal Gyrus PZ: Parietal site, midline P3: Parietal site, left hemisphere P4: Parietal site, right hemisphere RAND: Research and Development  ROI: Region of interest RTPJ: Right Temporo-Parietal Junctions SCID-I: Structured Clinical Interview for the DSM-IV SCOPE: Social Cognition Psychometric Evaluation SPQ: Schizotypal Personality Questionnaire SPM: Standard Pragmatic Model SZ: Schizophrenia group  TBI: Traumatic brain injury ToM: Theory of mind TMT: Trail Making Test VC: Visual cortex VCHRI: Vancouver Coastal Health Research Institute VOT: Ventral Occipital-Temporal cortex  VP: Ventral pathway VWF: Visual Word Form area WMS-III SS: Wechsler Memory Scale Spatial Span   xv WMS-III LNS: Wechsler Memory Scale Letter Number Span    xvi Acknowledgements    I am deeply grateful to my supervisor, Dr. Colleen Brenner, for her guidance and support throughout my academic training. I would also like to thank the members of my supervisory committee: Dr. Lynn Alden and Dr. Lawrence Ward, for their thoughtful questions and suggestions, which have greatly improved the dissertation.   I would like to extend my thanks to the staff at Gastown Vocational Services and the Vancouver Early Psychosis Intervention Program for their referrals and collaboration. I am also grateful to all the patients and control participants who volunteered their time for this study.  I would like to thank the Social Sciences and Humanities Research Council of Canada (SSHRC) for supporting me with their trainee award.   Finally, I would like to thank my husband, Dr. David Burns, for proof reading the numerous drafts of this dissertation.  xvii Dedication  I dedicate this dissertation to my mom (Hoa), my husband (David), and my daughter (Lorelai) who have provided me with the unwavering support to allow me to achieve this dream.  1 Chapter 1: Introduction Schizophrenia is a serious mental illness with a lifetime prevalence rate of 0.7%, and onset in late adolescence or early adulthood (Häfner & An Der Heiden, 1997; McGrath, Saha, Chant, & Welham, 2008). The disorder is characterized by psychotic symptoms, which involve a loss of touch with reality that occurs mainly in the form of delusion, hallucination, and disorganization (e.g., frequent derailment or incoherent speech). In addition to psychotic symptoms, schizophrenia may also include grossly disorganized or catatonic behaviour and negative symptoms marked by affective flattening, or a lack of emotional expressiveness; alogia, or poverty of speech; and avolition, or lack of drive or motivation to pursue meaningful goals (American Psychiatric Association, 2000). Deficits in a wide array of social and cognitive skills are well established in schizophrenia and can influence functional outcomes (Green, 1996; Martínez-Domínguez, Penadés, Segura, González-Rodríguez, & Catalán, 2015). The course of schizophrenia is heterogeneous, but longitudinal outcome studies suggest that approximately 40% of persons with schizophrenia achieve social or functional recovery (Crumlish et al., 2009; Lambert et al., 2008) while approximately 25% have poor outcomes, and the remaining individuals exhibit intermediate but not complete social or functional recovery (Menezes, Arenovich, & Zipursky, 2006).  Schizophrenia and related disorders occur along a continuum, or spectrum. The schizophrenia spectrum includes schizophrenia, schizoaffective disorder, delusional disorder, schizophreniform disorder, brief psychotic disorder, and schizotypal personality disorder. The differences between these disorders are generally marked by length and severity of symptoms. Along the time continuum, if psychotic symptoms are present for less than one month the illness is considered a brief psychotic disorder. If symptoms are present for less than 6 months, the  2 illness is considered schizophreniform disorder. Beyond six months, the illness is considered schizophrenia. Along the severity continuum, delusional disorder is associated with the presence of firmly held, false beliefs called delusions, with no accompanying hallucinations or disorganization. Schizoaffective disorder is the presence of psychotic symptoms with accompanying mood symptoms such as depression or mania. Schizotypal personality disorder is characterized by an enduring pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships. Individuals with schizotypal personality disorder usually have cognitive or perceptual distortions, and eccentricities in their everyday behaviour (American Psychiatric Association, 2000).  My dissertation examined the neural correlates of social cognition in schizophrenia and subclinical symptoms along the schizophrenia spectrum, with a specific focus on theory of mind (ToM), as it is reflected in irony comprehension. Irony can be defined as expressing one’s meaning using words that normally signify the opposite of their literal meaning (Sperber & Wilson, 2002). More specifically, violation of expectations, predictions, desires, preferences, and social norms are necessary condition for irony comprehensions (Colston, 2001). To understand irony the listener must distinguish what the speaker actually says from what they intend to convey (Champagne-Lavau & Stip, 2010).  In this way, individuals must disregard the literal meaning of the words to infer another person’s thoughts or intentions. To address this issue, I developed a novel measure of irony comprehension and provided some preliminary psychometric information for this measure. I then conducted three studies to evaluate 1) whether individuals with schizophrenia and 2) those with subclinical but related symptoms, display deficits in irony comprehension, and 3) whether these deficits could be remediated with a cognitive intervention.   3 In chapter 1 I will introduce the reader to the concept of social cognition and its importance to functional outcomes in schizophrenia. Specifically, I begin with a concise review of the literature, introducing the domains of social cognition with a particular focus on theory of mind (ToM). Next I introduce irony comprehension and psycholinguistics, which provide a framework for understanding ToM in schizophrenia. Following this, I present a brief summary of electrophysiological studies that examined event-related potential (ERP) components, specifically the N400 and P600, which are affected in schizophrenia. I introduce cognitive remediation as an adjunctive treatment to target cognitive impairments in schizophrenia. Finally, I provide a brief description of my methodological approach to the investigation of social cognition in schizophrenia and an overview of the studies that compose the dissertation.  1.1 Social Cognition in Schizophrenia   Cognitive impairments in schizophrenia are classified into two distinct domains: neurocognition and social cognition. Although social cognition is also associated with the functioning of several areas of the brain, experts in the field, and at the U.S. National Institute of Mental Health (NIMH), have made this distinction because neuroimaging studies suggest that certain measures of social cognition, such as perception of facial affect, may have a distinctive neural substrate from some of the more general cognitive domains (Green et al., 2004; Pinkham, Penn, Perkins, & Lieberman, 2003; Pizzagalli et al., 2002). To be consistent with NIMH’s distinction, the same nomenclature has been used throughout this dissertation. Within neurocognition, seven subdomains have been identified as relevant to schizophrenia according to the NIMH-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus battery: processing speed, attention/vigilance, working memory, verbal  4 learning and memory, visual learning and memory, reasoning and problem solving, and verbal comprehension (Green et al., 2004).  Social cognition refers to how people make sense of their social environment, how people draw inferences about other people’s beliefs and intentions, and how people weigh social situational factors in making these inferences (Green et al., 2008; Penn, Sanna, & Roberts, 2008). A recent survey of expert researchers in the field of schizophrenia, social psychology and autism, as part of the Social Cognition Psychometric Evaluation (SCOPE) study, was conducted to come to a consensus on the social cognitive subdomains relevant to schizophrenia (Pinkham et al., 2014). Experts in the field nominated 6 domains of social cognition: emotion processing, social perception, ToM/mental state attribution, social metacognition, social reciprocity, and attributional style/bias. Using Research and Development (RAND) panel consensus ratings, 4 subdomains that are prominent in schizophrenia research were supported – emotion processing, social perception, attributional style/bias, and ToM/mental state attribution. While the domains of social metacognition and social reciprocity, suggest areas for expansion of social cognitive research, factor analytic studies are still needed to examine the independence of these domains in schizophrenia research.   Emotion processing broadly refers to perceiving and recognizing emotions (Green et al., 2008). Tests of emotion processing include ratings of emotions that are displayed in faces, voices or ratings from brief vignettes of how individuals manage, regulate or facilitate emotion (Edwards, Jackson, & Pattison, 2002; Kohler, Bilker, Hagendoorn, Gur, & Gur, 2000; Kohler, Walker, Martin, Healey, & Moberg, 2010; Sachs, Steger-Wuchse, Kryspin-Exner, Gur, & Katschnig, 2004; Silver & Bilker, 2014). Social perception is the ability to make inferences about nonverbal, paraverbal, or verbal cues in complex or ambiguous social situations (Green et  5 al., 2008). Investigations of social perception include identifying social roles, societal rules, and social context (Penn, Ritchie, Francis, Combs, & Martin, 2002; Sergi, Rassovsky, Nuechterlein, & Green, 2006; Toomey, Schuldberg, Corrigan, & Green, 2002). Attributional style/bias refers to how people typically interpret, make sense of, or explain, positive and negative social events. Assessments of attributional style include vignette style questionnaires (Combs, Penn, Wicher, & Waldheter, 2007; Mannarini & Boffo, 2013). Theory of mind refers to the capacity to infer intentions, beliefs and mental states of others (Brune, 2005b). ToM assesses skills such as understanding false beliefs, interpreting hints and intentions, discerning faux pas, metaphor, and irony (Brune, 2005a; Corcoran, Mercer, & Frith, 1995; Drury, Robinson, & Birchwood, 1998; Frith & Corcoran, 1996; Gregory et al., 2002).  1.1.1 Social Cognition and Functional Outcomes   Social cognitive impairment in schizophrenia is a rapidly emerging area of study, with a considerable increase in the number of publications since 2000 (Green & Leitman, 2008). The interest in social cognition reflects findings that there is a robust association between social cognition and functional outcomes, particularly between social problem solving and community functioning (Brekke, Hoe, Long, & Green, 2007; Couture, Penn, & Roberts, 2006). Social cognition was more strongly related to functional outcomes and community functioning than was neurocognition, with the strongest association being between ToM and functional outcomes (Fett et al., 2011). Furthermore, social cognition predicts interpersonal skills above and beyond what can be attained by using neurocognition alone (Pinkham & Penn, 2006). Although processing of social cognition may rely on some neurocognitive processes (e.g., attention or memory), research indicates that they are distinct domains (Allen, Strauss, Donohue, & van Kammen, 2007; Sergi et al., 2007; van Hooren et al., 2008). One study, however, does indicate that disorganized  6 symptoms may moderate the relationship between neurocognition and social cognition (Minor & Lysaker, 2014).  1.1.2 Social Cognition and Symptoms in Schizophrenia  The relationship between social cognition and the symptoms of schizophrenia has been examined in relation to positive (e.g., delusion and hallucination), negative (e.g., affective flattening, alogia, and avolition) and disorganized symptoms (e.g., frequent derailment or incoherent speech). Social cognitive performance is correlated with positive psychotic symptoms (Mancuso, Horan, Kern, & Green, 2011). Guastella et al., (2013) concluded that it might be the strongest concurrent predictor of positive psychotic symptoms; however other researchers found a smaller but still significant association between social cognition and positive symptoms (Fett & Maat, 2013; Ventura, Wood, & Hellemann, 2013). In addition, disorganized symptoms, have consistently and significantly been associated with social cognitive performance (Fett & Maat, 2013; Ventura et al., 2013), although some researchers found only a moderate relationship between social cognition and negative symptoms (Sergi et al., 2007). The findings regarding social cognition and symptoms may be a reflection of the multiple, separable dimensions of social cognition, and the ways in which these various factors show distinct patterns of correlation with clinical features. For this reason it is important to examine specific social cognitive processes. Here, I will focus on ToM since the association between ToM and functional outcomes is greater than that between cognition and functional outcomes.  1.1.3 Theory of Mind  The term theory of mind (ToM) was first used to describe the ability of chimpanzees to attribute mental states to themselves and others (Premack & Woodruff, 1978). ToM refers to an individual’s understanding that another individual has thoughts and insights that may be different  7 from their own and that the other person’s interpretation of the world depends upon these different observations. In other words, ToM involves recognizing that other people may have a perspective different than one’s own. The ability to infer other persons’ mental states - such as beliefs, desires, intentions and emotions - is an important skill to possess in order to successfully navigate our rich social world. Wimmer & Perner (1983) were the first to examine ToM. These researchers used a false belief measure, now known as the Sally-Anne task, and found that children can represent a person’s beliefs and desires around the age of four, but not before this age. Since then, ToM has been extensively studied in both healthy and disordered populations including children with autism (Baron-Cohen, Leslie, & Frith, 1985; Leekam & Perner, 1991; Moran et al., 2011; Perner, Frith, Leslie, & Leekam, 1989) and adults with schizophrenia (Brune, 2005a; Corcoran & Frith, 2003; Doody, Götz, Johnstone, Frith, & Owens, 1998; Greig, Bryson, & Bell, 2004; Pickup & Frith, 2001).  1.1.4 Theory of Mind in Schizophrenia  Frith (1992) proposed that the core symptoms of schizophrenia might result from an impaired ability to infer the mental states of others. For example, an inability to attribute mental states - such as thoughts, beliefs and intentions - to others may contribute to persecutory delusions in patients. Likewise, impairments in patients’ ability to consider others’ perspectives during conversations may underlie some kinds of incoherent speech. In other words, some incoherent speech may result from a failure to infer the knowledge and intentions of others. In such circumstances patients fail to provide information that would be critical for others to understand what they are talking about. In the same way, failing to recognize social cues and intentions may lead to communication breakdown and eventually formal thought disorder. According to Frith (1992), patients with different symptoms of schizophrenia will differ in their  8 ToM abilities. Frith theorized that patients with paranoid symptoms would perform poorly on ToM tasks, not because they lack ToM, but because they have difficulty using contextual information and make incorrect inferences about mental states. On the other end of the continuum, patients with negative symptoms would have the most difficulty with ToM tasks because of their incapacity to represent mental states at all. One of the advantages of Frith’s model is that it makes specific predictions about ToM performance related to the symptoms of schizophrenia. Given that schizophrenia is a heterogeneous disorder, and that two people diagnosed with schizophrenia may not share symptoms, Frith’s model provides a framework within which hypotheses about ToM in relation to specific symptoms associated with schizophrenia can be made.   There appears to be some empirical support for Frith’s model. Patients with paranoid ideation have been found to experience impaired ToM abilities (Corcoran et al., 1995; Corcoran, Cahill, & Frith, 1997; Marjoram et al., 2005). In addition, patients with negative symptoms have shown poorer performance on ToM tasks (Corcoran et al., 1995). Not all studies, however, found a link between poor mentalizing abilities and positive symptoms (Langdon, Coltheart, Ward, & Catts, 2001; Mazza, De Risio, Surian, Roncone, & Casacchia, 2001). The lack of consensus surrounding ToM impairments in schizophrenia led to the “hyper-theory of mind” (Abu-Akel, 1999; Abu-Akel & Bailey, 2000). According to the authors, ToM performance can be viewed along a continuum: (1) genuine impairment in ToM abilities with no abilities to understand or represent mental states, (2) having representational understanding of mental states but difficulty in applying this understanding, (3) hyper-representational understanding of mental states or over-generation of hypotheses about mental states (i.e., paranoid ideations). The “hyper-theory of mind” accounts for some findings that individuals with positive symptoms do not exhibit ToM  9 deficits (Langdon et al., 2001; Mazza et al., 2001), that first episode patients show mixed evidence of impaired ToM reasoning (Achim, Ouellet, Roy, & Jackson, 2012; Kettle, O’Brien-Simpson, & Allen, 2008), and that some patients with schizophrenia demonstrate intact ToM skills in clinical interactions (McCabe, Leudar, & Antaki, 2004).  Since Frith first proposed that psychotic symptoms of schizophrenia may be explained by faulty ToM reasoning, a substantial body of research has accumulated examining this relationship (for reviews see Bora, Yucel, & Pantelis, (2009a); Brune, (2005b); Harrington, Siegert, & McClure, (2005); Sprong, Schothorst, Vos, Hox, & Engeland, (2007)). After almost two decades of research, critical reviews and meta-analyses support a large and statistically significant ToM impairment in schizophrenia that cannot be accounted for by either executive functioning or more general cognitive impairments. A meta-analysis conducted by Bora et al., (2009) found that the effect sizes (Cohen’s d) between people with schizophrenia and healthy controls were large and vary from 0.9 – 1.08, depending on the types of measures used. Despite the robust finding of an overall deficit, the consistency of moderator variables on the relationship is less established. Moderator variables that have been postulated to affect ToM performance are: (1) phase of illness, (2) symptom subtypes, and (3) paranoid symptoms. The following section will specifically review the relationship between ToM and phase of illness because much of the research has focused on this moderator.  1.1.5 Theory of Mind and Phase of Illness Theory of Mind provides a fruitful and promising model with which to understand the heterogeneous symptoms of schizophrenia. Much of the focus of research on ToM in schizophrenia has centered on ascertaining whether ToM is related to the course of the illness. The controversy about ToM in schizophrenia is not over whether it exists but whether these  10 deficits are state- or trait-specific. A state-specific hypothesis assumes that people with schizophrenia develop normal ToM abilities and that these abilities become impaired as the illness develops. In other words, ToM abilities may represent vulnerability-linked impairments, which are augmented during symptom exacerbation. In contrast, a trait-specific hypothesis assumes that ToM abilities are inherently impaired and are independent of active symptoms. To determine whether ToM deficits reflect a fluctuating state, or underlying trait, researchers have relied on cross-sectional studies. There are no longitudinal studies to clarify whether ToM deficits are a by-product of or a risk factor for chronic schizophrenia. Cross-sectional studies have examined ToM abilities in patients at ultra high risk, those in the early stage of the illness, those in the remitted stages, and in healthy controls that score high in schizotypal personality disorders.   The criteria for ultra high risk for schizophrenia include having a family history of psychotic disorder combined with some functional decline and the presence of subthreshold or attenuated forms of psychotic symptoms (Yung et al., 2003; Yung, Phillips, Yuen, & McGorry, 2004). Not all individuals classified as ultra high risk go on to develop a diagnosable psychotic disorder. Estimates of transition to schizophrenia spectrum disorders vary from 33% to 41% within a 6 to 12 month period (Nelson, Yuen, & Yung, 2011; Yung et al., 2003). Benefits of looking at deficits in high-risk populations include minimizing confounds associated with chronicity (i.e., exposure to antipsychotic medication, by-products of adaptation due to the illness), and therefore can provide insight into factors associated with vulnerability to developing schizophrenia. Most studies found impaired ToM abilities in at-risk individuals compared to controls and these deficits appear to predate the conversion to psychosis (Addington, Penn, Woods, Addington, & Perkins, 2008; Chung, Kang, Shin, Yoo, & Kwon, 2008; Green et al.,  11 2012; Healey, Penn, Perkins, Woods, & Addington, 2013; Kim et al., 2011; Phillips & Seidman, 2008; Thompson et al., 2012). The effect size of ToM impairment in the clinical high risk population is estimated to be moderate (d=.45), suggesting ToM impairment is attenuated in prodromal subjects (Bora & Pantelis, 2013).  Researchers have also examined ToM in individuals experiencing their first episode of psychosis. Interest in early psychosis comes from the clinical staging model, which is widely used in clinical medicine, but has not received a lot of attention in psychiatric disorders. Clinical staging differentiates initial and milder clinical presentation from more chronic forms. It focuses on the continuum of the illness progression and places emphasis on where a person lies on the progression of the disease. McGorry, Hickie, Yung, Pantelis, and Jackson, (2006) applied the clinical staging model as a solution to improve the timing of interventions or even to prevent or delay progression from earlier to later stages of psychosis. One of the advantages of studying early psychosis is that it helps to distinguish vulnerability markers from sequelae of the disease. ToM has been found to be substantially impaired in first-episode psychosis and this deficit was comparable to findings in chronic patients (Bertrand, Sutton, Achim, Malla, & Lepage, 2007; Emre Bora & Pantelis, 2013; Kettle et al., 2008). Similarly Green et al (2012) directly compared recent onset and chronic patients and found comparable ToM deficits across phase of illness. Effect size estimates of ToM impairments in early onset schizophrenia (d=1.0; Bora & Pantelis, 2013) and chronic schizophrenia (d=1.10; Bora et al., 2009) suggest similar ToM impairments in chronic and recent onset populations.  Several investigators found that patients with remitted symptoms performed more poorly than control subjects (Bora, Gokcen, Kayahan, & Veznedaroglu, 2008; Herold, Tenyi, Lenard, & Trixler, 2002; Inoue et al., 2006; Mo, Su, Chan, & Liu, 2008). Extending this work, Janssen,  12 Krabbendam, Jolles, and van Os, (2003) included a group of first-degree relatives along with remitted schizophrenia or schizoaffective patients and healthy controls in their study design. They found that patients with remitted symptoms performed more poorly than their relatives. Moreover, these relatives performed more poorly than healthy controls. However, the evidence of ToM impairment in first-degree relatives of schizophrenia patients is mixed, with Kelemen, Kéri, Must, Benedek, & Janka, (2004) finding that unaffected relatives show intact performance.  Schizotypal personality disorders share features (e.g., paranoid ideation, magical thinking, social avoidance, and vague and digressive speech) with schizophrenia, although these features are often clinically subthreshold. In addition, schizotypal personality disorder can sometimes precede the onset of schizophrenia (DSM-IV-TR, 2000). Schizotypal personality disorder is thus often viewed as subclinical on the schizophrenia continuum. Interestingly, those individuals exhibiting schizotypal traits may exhibit ToM deficits similar to those with schizophrenia. For example, Langdon and Coltheart (1999) examined the ToM performance of those with high versus low schizotypy and found that high-schizotypal adults were significantly impaired in their ToM ability. In addition, they found that those who had more difficulty with the task tended to have higher amounts of magical thinking and unusual perceptual experiences. Similarly, endorsing more schizotypal traits is associated with worse ToM performance in nonclinical individuals (Pickup, 2006).  Another approach to examining the state-trait hypothesis is to investigate the relationship between ToM deficits and chronicity of illness. Several studies report a negative relationship between duration of illness and ToM abilities (Brune, 2003; Harrington et al., 2005; Langdon, Coltheart, Ward, & Catts, 2002; Langdon et al., 1997; Sarfati, Passerieux, & Hardy-Baylé, 2000; Uhlhaas, Phillips, Schenkel, & Silverstein, 2006), which may suggest that the deficit is a  13 function of chronicity of illness. Similarly, there is some evidence to suggest that patients with a longer history of illness tend to perform more poorly on ToM tasks (Drury et al., 1998; Pickup & Frith, 2001; Sarfati et al., 2000). In summary, ToM abilities were found to be impaired across phase of illness (Green et al., 2012), suggesting ToM impairment appears to be present before the onset of the illness and remains stable over a 12-month period (Addington, Saeedi, & Addington, 2006; Horan et al., 2012). In addition, ToM deficits have been found in schizotypal personality disorder and unaffected relatives. Taken together, these studies suggest that poor ToM abilities reflect an underlying trait and show promise as a possible “biomarker” or “endophenotype” for schizophrenia, according to Gottesman & Gould (2003).   Thus, while many studies reported above indicate that ToM abilities function as a trait, some data suggest it reflects a more state-like deficit. Pousa et al., (2008) reported ToM deficits in patients with residual positive symptoms but not in patients without such symptoms, which suggests a more state-like deficit. Other evidence that refutes the notion that ToM deficits persist beyond the acute phase of psychosis come from patients in remission showing normal performance on ToM tasks (Corcoran et al., 1995; Drury et al., 1998). Furthermore, relatives of individuals with schizophrenia who had experienced psychotic symptoms showed more ToM deficits than those relatives who had not experienced psychotic symptoms (Marjoram et al., 2006). The mixed and opposing findings may be due to a number of factors. One factor may be how the studies define remission and whether it is defined by the absence of positive symptoms, negative symptoms or both. Another may be the difference in the nature of the tasks used to measure ToM, which has been shown to influence outcomes. Studies that used more advanced tasks, including irony and faux pas, reported greater magnitude of impairment than did studies  14 that employed simpler measures, such as false belief stories (Bora, Yucel, & Pantelis, 2009b). Therefore, while many studies suggest that ToM deficits in patients with schizophrenia reflect a possible trait-related deficit, studies that focus on phase of illness suggest at least part of these deficits are related to acute symptom manifestation. It is unlikely that the state/trait debate will be settled unless an agreement can be made regarding how remission is defined and a ‘gold standard’ for measuring ToM can be established. 1.2 Models of Irony Comprehension “As philosophers claim that no true philosophy is possible without doubt, by the same token, one may claim that no authentic human life is possible without irony” (Kierkegaard, 1965, p.378)   Human communication is complex and not always linear; many aspects of what we want to say are not explicitly communicated. An important example is figurative language like irony and metaphor. Ironic utterances can serve multiple communicative purposes and are typically used as an attention-getting devices or as politeness strategies in socially difficult situations (Gibbs, 2000). In order to accurately understand irony, contextual and pragmatic information is required to go beyond the literal meaning to comprehend the implied meaning of the speaker. Although there are various ways that irony can be communicated, most often it is defined as a figure of speech that is the opposite in meaning to what has been stated.  While language processing may or may not be required to initially form a representation of someone’s thoughts, it is required to elicit a response to measure mental state reasoning. With the exception of a few non-verbal tasks (i.e., Brunet, Sarfati, Hardy-Baylé, & Decety, 2003; Gallagher et al., 2000), most ToM tasks depend heavily on language skills. Grice (1975) proposed that language involves a set of conversational rules, referred to as “pragmatics,” to  15 communicate our ideas and wishes to others in a useful way. Furthermore, he emphasized that communication is essentially cooperative and proposed five maxims for its success: be brief, be orderly, be informative, speak the truth and be relevant. Many of the maxims proposed require some understanding of the current state of the knowledge of the person with whom one is speaking. For example, the maxim be informative stipulates that the speaker should provide as much information as necessary for the purpose of communication but should not provide more information than is required. Many of the speech disturbances found in schizophrenia can be explained as violations of some of the maxims proposed by Grice. For example, tangential speech, or the loose associative process whereby patients say things that are apparently irrelevant, may be a result of failing to be orderly or failing to be relevant. Another example, alogia, or poverty of speech, violates the maxim of quantity whereby the speaker fails to provide enough information to be informative.   The use of figurative language, such as metaphor and irony, is a special case of communication because it violates Grice’s maxim of speak the truth. Sperber and Wilson (1995), building on the work of Grice, proposed the Relevance Theory, which characterized instances of communication as essentially cooperative exchanges used to maximize relevance and meaning.  The Relevance Theory is better able to account for figurative language such as metaphors and irony because it proposes that effective use of language requires the ability to use contextual cues to understand underlying meaning, that is, to go beyond the literal meaning of words and utterances to infer the speaker’s communicative intent (Sperber & Wilson, 1995). According to the relevance theory, understanding irony requires the listener to understand that the speaker is dissociating from the opinion expressed and, in fact, actually holds the opposite view. More  16 recently, Sperber and Wilson (2002) proposed the existence of a submodule of ToM that allows humans to extract relevant information from speech or utterances in a cognitively efficient way.  Various models of figurative language comprehension have been proposed that focus on the time course of irony comprehension. I will review three models that have received support in the psycholinguistic literature.  1.2.1 Standard Pragmatic Model  The Standard Pragmatic Model (SPM) arose from the work of Grice (1975). In this model, irony comprehension consists of a three-step process that involves 1) the computation of semantic/literal meaning; 2) the recognition of a violation of a maxim; and 3) the computation of an implicature. This suggests that the literal meaning of an ironic sentence must initially be accessed and rejected, resulting in longer processing time when integrating the literal meaning with prior contextual information. Support for the SPM comes from Dews and Winner, (1999) and Schwoebel, Dews, Winner, and Srinivas (2000), who found longer reaction times for sentences that had ironic meaning compared to their equivalent nonironic meaning.  1.2.2 Direct Access Model  The Direct Access Model (DAM; (Gibbs, 1994, 2002) is based on the assumption that understanding literal and non-literal meaning is dependent on pragmatic knowledge and understanding the speaker’s figurative mode of thought. By combining pragmatic knowledge with contextual information very early on, a direct understanding of non-literal speech is achieved without relying on an incompatibility during semantic processing. Thus the comprehension of non-literal speech is hypothesized to be no more difficult than that of literal speech. Support for the DAM comes from studies that show no differences in reading times for sarcastic and non-sarcastic utterances (Gibbs, 1986; Gibbs, O’Brien, & Doolittle, 1995).   17 1.2.3 Graded Salience Hypothesis   A parallel model combining the SPM and the DAM, called the Graded Salience Hypothesis, has been proposed by Giora (1997, 2002). In this model the most salient meaning of words or expressions will be accessed first from the mental lexicon, whereas non-salient meanings are assumed to require further processing. During the initial processing, contextual information is processed in parallel but does not interact with lexical processes, nor does it inhibit salient meanings when contextually incompatible (Peleg, Giora, & Fein, 2001). In situations where the activated salient meanings are incompatible with contextual information, additional processes will be recruited for processing appropriate non-salient meanings. Salience is a function of familiarity, prototypicality, frequency, and the lexical meaning of a word. In situations in which words or expressions have multiple meanings varying in salience, Giora (2003) suggests that this process is graded, i.e., more salient meanings are accessed earlier than less salient meanings. The graded salience hypothesis thus predicts that processing of figurative sentences only diverges from that of literal sentences during later stages of processing when salient meanings cannot be integrated with contextual information. In that situation, salient meanings are discarded for less salient but contextually appropriate meanings.   These three models of figurative language comprehension are important because they speak to the time course of irony comprehension, an issue that is relevant to the current research. To investigate the timing of the potential mechanisms outlined by these theories, I developed an irony comprehension test and then used EEG to measure processing time. EEG has high temporal resolution and therefore can detect electrical activity in the brain on the millisecond time scale.   18 1.3 Irony and Schizophrenia  Researchers have postulated three potential theoretical explanations for the deficit of irony comprehension in schizophrenia. First, irony comprehension could be understood as an impairment in theory of mind (ToM) processes (Happé, 1993; Langdon, Davies, & Coltheart, 2002) and in the ability to take on the perspective of the speaker (Blasko & Kazmerski, 2006). Second, there could be impairment in higher order language function mediated by the right hemisphere, which may be essential to accurate understanding of communicative intent (Mitchell & Crow, 2005). In essence, irony comprehension relates to hemispheric interaction and involves both the cerebral hemispheres (Giora, Zaidel, Soroker, Batori, & Kasher, 2000; Rapp et al., 2010; Rapp, Mutschler, & Erb, 2012) and their interplay so that irony comprehension may provide insight into hemispheric interaction in schizophrenia. Thus, dysfunction of the right cerebral hemisphere and/or defective interaction between the cerebral hemispheres may underlie difficulties interpreting irony in schizophrenia (Crow, 2010). Third, left hemisphere language regions that are associated with schizophrenia (left middle/superior temporal gyrus or the left dorsolateral-prefrontal cortex) have been found to play a role in irony comprehension (Uchiyama et al., 2006). The medial prefrontal cortex, a key region for the comprehension of irony in healthy subjects (Rapp et al., 2010; Shamay-Tsoory, Aharon-Peretz, & Levkovitz, 2007; Shamay, Tomer, & Aharon-Peretz, 2002) have been previously demonstrated to underlie affective metalizing in schizophrenia (Brunet-Gouet & Decety, 2006; Sugranyes, Kyriakopoulos, Corrigall, Taylor, & Frangou, 2011). These three theories are not mutually exclusive with the first focusing on psychological factors, while the latter two focus on the biological mechanisms that may underlie the first theory. The dissertation will explore irony processing under the framework of ToM, consistent with the first theory. The poor spatial resolution of EEG does not  19 lend itself to investigate the relative contribution of certain brain regions and their interactions that make up the core of the second theory. However, hemispheric differences in ERPs may have the ability to blend the first and third theories, thus providing an important link between more psychological and biologically based theories of irony comprehension.  In an extensive study to parse out language difficulties as a mediating factor in the relationship between ToM and irony, Langdon et al., (2002) examined the understanding of metaphor and irony in relation to schizophrenia patients’ performance on ToM tasks. They found that ToM deficits were related to an impaired understanding of irony but not metaphor comprehension. Moreover, both ToM and irony comprehension were associated with severity of formal thought disorder. Converging evidence from functional neuroanatomy using fMRI indicates that the medial prefrontal cortex, a key region for ToM processing, is also involved in the processing of irony (Shamay-Tsoory et al., 2007; Wakusawa et al., 2007).   1.4 ERPs in Schizophrenia   Since Kraepelin first defined dementia praecox as a progressive brain disease at the end of the 19th century investigators have been searching for the underlying neurobiological factors that may contribute to schizophrenia. It was not until the emergence of noninvasive techniques to assess brain function, such as event-related potentials (ERPs), positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and structural MRI, that definitive evidence of neurobiological abnormalities in schizophrenia were identified (Ross, Margolis, Reading, Pletnikov, & Coyle, 2006). ERPs have been used to investigate schizophrenia since the 1950s, and the neural mechanisms associated with sensory, attention, working memory, linguistic, and decision-making deficits have been well characterized (Turetsky et al., 2007).   20  Event-related potentials (ERPs) are generated from the signal-averaged epochs of the electroencephalogram (EEG) that are time-locked to the onset of a stimulus. The ERP waveform consists of a series of positive and negative voltage deflections (measured in microvolts), which are related to a set of underlying components plotted over time (measured in milliseconds). The components of ERPs are thought to reflect functionally relevant electrical activity within the brain. There are several advantages to using ERPs in the study of the pathophysiology of schizophrenia. Event-related potentials, measured on the surface of the scalp, are a direct electrophysiological index of fast, online neural activity and have high temporal resolution (Handy, 2005). Thus ERPs are useful in the investigation of neurotransmission, connectivity and synchronization (Lewis & Lieberman, 2000; Ross et al., 2006). In addition, ERPs are inexpensive and have fewer exclusion requirements and thus the technique is more accessible to a larger number of participants.   The following section will review two ERP components, the N400 and P600, both of which are associated with semantic processing and have been shown to be affected in schizophrenia. These components are good candidates for biomarkers for deficits in social cognition. Examples of the N400 and P600 waveforms are shown in Figure 1.1.     21  Figure 1.1 An example of the N400 and P600 waveforms.  The N refers to a negative-going deflection, while the P refers to a positive-going deflection relative to the just-previous voltage level. Thus, even though the P600 has a negative amplitude relative to baseline, its positive-going deflection characterizes the waveform as a P600.    22 1.4.1 N400  The N400 is a negative-going deflection that peaks around 400 ms after stimulus onset. It has a broad scalp distribution with maximal amplitudes at midline central or parietal sites.  The component was first characterized as related to semantic processing by Kutas and Hillyard (1980) in a sentence-reading paradigm. The N400 response is often associated with semantic anomaly. The N400 amplitude reflects the likelihood that a word is congruent or consistent with the prior semantic context and the N400 latency reflects speed of processing related to the semantic network (Van Petten & Kutas, 1990). The sentence-reading paradigm is well suited to measure contextual effects on lexical processing, such as irony processing. For example, a word that is incongruent with the preceding context is expected to generate a larger N400 than a word that is congruent with the context of the sentence.   The amplitude of the N400 is modulated by the degree of anomaly as well as by predictability. Less expected sentence endings generate a larger N400 than highly expected ones, even when both endings are semantically congruent (for example, “He liked lemon and sugar in his coffee” would generate a larger N400 amplitude than “He liked lemon and sugar in his tea”) (Kutas & Hillyard, 1984). The response to an anomalous word, however, is also modulated by the relationship of the target word to the ‘expected’ ending. For example an anomalous ending that shares semantic features with the contextually predicted ending (for example, “He liked coffee with cream and salt”) would produce a smaller N400 amplitude than (“He liked coffee with cream and socks”). Irony comprehension, which typically contains an unexpected ending, may reflect integration difficulties and therefore generate a larger N400 than would comprehension of a contextually-predicted ending (Lau, Phillips, & Poeppel, 2008).   23 1.4.2 N400 and Schizophrenia  Most studies that investigate the N400 component have examined the amplitude and latency elicited from a key word in either a sentence reading or a word priming paradigm. I will focus on the sentence reading paradigm as it is the most analogous to the Irony Comprehension Task (ICT). The differences in N400 amplitude between patients with schizophrenia and healthy controls is conventionally measured as a difference waveform, computed by subtracting the N400 amplitude for congruent sentences from that for incongruent sentences. The use of difference waveforms assumes that healthy controls and patients with schizophrenia show similar amplitudes for congruent sentences. However, some authors report reduced N400 in schizophrenia for both congruent and incongruent conditions, which may contribute to the differences in the N400 congruency effect reported in the literature (Adams et al., 1993; M A Niznikiewicz et al., 1997). A recent review by Mohammad & DeLisi (2013) found that of the 10 studies that examined N400 in schizophrenia, one showed no difference in N400 between schizophrenia patients and controls (Andrews et al., 1993), eight showed N400 deficits, suggesting poor use of context, and one showed a larger difference in N400 amplitude between congruent and incongruent conditions in schizophrenia compared to healthy controls (Sitnikova, Goff, & Kuperberg, 2009). Converging evidence suggests that the latency of the N400 is often delayed for patients with schizophrenia, suggesting slowing in semantic processes (Nestor et al., 1997; M A Niznikiewicz et al., 1997). Furthermore, the N400 amplitude deficits are robust to modalities and have been found in visual as well as auditory contexts (Nestor et al., 1997; M A Niznikiewicz et al., 1997; Salisbury, Shenton, Nestor, & McCarley, 2002). Findings that the N400 amplitude is generally more negative (i.e., larger) in patients with schizophrenia suggests a deficit in contextual integration even when the discourse is fully coherent. Therefore, it appears  24 that schizophrenia has differential effects on the N400 depending on task demands, and that the congruency effect measured in sentence-reading paradigms may be affected by more basic deficits in the generation of N400 amplitude with respect to context processing.   1.4.3 P600  The P600 is a positive-going waveform with a mainly posterior scalp distribution that peaks approximately 600 ms after stimulus onset. It was originally associated with syntactic violations (Gunter, Stowe, & Mulder, 1997) but there is an ongoing debate about the precise neurocognitive processes that the P600 reflects. Some investigators found the P600 to be associated with the process of reanalysis or general context updating (Coulson, King, & Kutas, 1998; Kuperberg, Sitnikova, Caplan, & Holcomb, 2003). Others have suggested that the P600 may reflect the interaction of semantic and syntactic processes (Gunter, Friederici, & Schriefers, 2000). For example, it is thought that the processing of syntactic and semantic information is autonomous during early processing, but that these processes must interact during a later processing phase. Yet other investigators postulate that the P600 reflects syntactic integration after the activation of parallel semantic and syntactic structures (Kaan et al., 2000). Although the exact contribution of syntactic or semantic information to the P600 is still under investigation, it is clear that the P600 is distinct from the cognitive process of semantic integration reflected by the N400 in terms of time course and morphology of the waveform.   The P600 has often been employed in the study of figurative speech. An increase in the amplitude of the P600 component has been found for metaphors (Yang, Bradley, Huq, Wu, & Krawczyk, 2013), irony (Regel, Gunter, & Friederici, 2011; Spotorno, Cheylus, Van Der Henst, & Noveck, 2013) and indirect requests (Coulson & Lovett, 2010). Figurative speech is distinctive and often requires an additional level of analysis to resolve a conflict between the  25 literal interpretation and the metaphorical or ironic meaning, based on the context and information within semantic memory. If encountering unexpected stimuli in the course of an interaction requires reanalysis of verbal information, the P600 could represent activity associated with rechecking or reanalyzing information to aid in metaphor and irony comprehension.  1.4.4 P600 and Schizophrenia  Considerably fewer studies have examined the P600 effect in schizophrenia than the N400. Unlike the N400, studies that examined the P600 differed dramatically in their paradigm based on whether they were investigating syntactic or semantic phenomena. Below, I focus the review on sentence reading paradigms and have excluded studies that utilized auditory stimuli or the affective picture viewing task (for example, Horan, Wynn, Kring, Simons, & Green, 2010; Papageorgiou et al., 2001). Using a different psycholinguistic paradigm, Kuperberg, Sitnikova, Goff, and Holcomb (2006) manipulated not only semantic but syntactic parameters to get a better understanding of their interaction. For example, the sentence “At breakfast the boys would bury every day” would elicit a large N400 to the word “bury” because the word is incongruent with the sentence and would be an example of a semantic violation. In contrast, the sentence “At breakfast the boys would eats everyday” would elicit a P600 but not an N400 to the word “eats” because it is an example of syntactic violation. The sentence, “At breakfast the eggs would eat everyday” would be an example of semantic-syntactic violation because the words in the sentence are plausible in meaning. However eggs, being inanimate, cannot eat. Thus the word “eat” evokes both an N400 and a P600 effect. Kuperberger et al., (2006) found a reduction in the P600 effect (the difference in amplitude of the P600 to violating relative to nonviolating words) related to syntactic violations and an absence of the P600 effect to semantic-syntactic violations in patients with schizophrenia (SZ) compared to healthy controls. Similarly, Ruchsow, Trippel,  26 Groen, Spitzer, and Kiefer (2003) also found an abnormally reduced P600 effect to syntactic violations in patients with schizophrenia. In conclusion, the limited number of studies thus far suggest that the P600 is sensitive to both syntactic and semantic-syntactic integration in language processing in patients with schizophrenia.  1.5 Mechanics of Reading in the Brain  Although we do not fully understand how reading circuitry operates, research on how the illiterate brain changes through the acquisition of literacy has revealed changes in anatomical connectivity (Dehaene, Cohen, Morais, & Kolinsky, 2015). First, literacy modifies the posterior temporoparietal portion of the left arcuate fasciculus – a bundle of axons that link the ventral temporal lobe with the inferior parietal and posterior superior temporal regions (De Schotten, Cohen, Amemiya, Braga, & Dehaene, 2012). Second, literacy reliably induces thickening of the splenium and/or the isthmus of the corpus callosum, suggesting rapid integration of written information that appears in the left and right hemifields (Carreiras et al., 2009; Molko et al., 2002). Third, literacy acquisition may also increase grey-matter density in several regions of the angular, supramarginal and temporal gyri, which are activated during reading (Carreiras et al., 2009; Petersson, Silva, Castro-Caldas, Ingvar, & Reis, 2007). In addition to literacy studies, child developmental reading studies found a consistent response in a specific region of the left ventral occipital-temporal cortex (left VOT), when children or adults are presented with a readable word (Dehaene et al., 2015). This region has also been called the visual word form area (VWF) (Dehaene & Cohen, 2011). Additional support for the role of the VOT being a critical area for visual analysis of letter and word reading comes from autopsies on, and MRI of, patients with alexia (Dehaene, 2009). Likewise, regions of the dorsal occipito-parietal cortex are strongly activated during word naming compared with object naming (Taylor, Rastle, & Davis, 2014).  27 Altogether it can be reasonably concluded that the temporal, parietal, and occipital cortical regions are recruited during reading tasks.   A model of reading put forth by McClelland and Rumelhart (1981) proposes three hierarchical layers of neuron-like units: 1) feature level; 2) letter level; and 3) word level. Letter and word identification result from an active top-down decoding process whereby the brain adds information to the visual signal (Dehaene, 2009). The neural basis of reading has been investigated using electroencephalography (EEG), with markers of orthographic processing starting as early as 90 ms post word onset and continuing through 600 ms (Holcomb & Grainger, 2006). The ERP components that are associated with orthographic processing include the P150, N250, P325, and N400 (Grainger & Holcomb, 2009) and reflect early sensory processing. For example, the P150 was found to be significantly larger when responding to mismatches between prime and target letter cases, but more so when the features of the lower- and uppercase versions of the letters were physically different compared to when they were physically similar (for example, A-A compared to a-A vs. C-C compared to c-C) (Petit, Midgley, Holcomb, & Grainger, 2012). Within the later ERPs, the N400 has been found to be larger in response to words that were unrelated to their primes but not for pseudoword targets (Kiyonaga, Grainger, Midgley, & Holcomb, 2007). This finding was interpreted as the N400 reflecting interactions between levels of representation for whole words and concepts or the “form-meaning interface” (Holcomb, Anderson, & Grainger, 2005). Thus, the N400 reflects the amount of effort involved in forming links between these levels, with a larger N400 effect indicating that more effort is involved (Grainger & Holcomb, 2010)  A recent trend in cognitive neuroscience is the integration of the time-course of cognitive processing from ERPs with data on cortical functional organization from fMRI. This integrated  28 approach has been applied to language comprehension to understand how the brain creates meaning from linguistic input. The processing of language requires two major components: accessing long-term memory representations (such as words or morphemes) and integrating these representations into the current semantic, syntactic, and discourse structures (Lau et al., 2008). An understanding of the link between time and place of language comprehension is crucial in order to understand the neurocognitive network. Brouwer and Hoeks (2013) have put forth a new functional-anatomical mapping of a cortical network for language comprehension that includes the N400 and the P600 component entitled the Retrieval-Integration Cycle (see Figure 1.2). They proposed that words reach the posterior Middle Temporal Gyrus (pMTG) via the auditory cortex or the visual cortex. The pMTG then retrieves the lexical information associated with a word from the association cortices (generating the N400). This information is then connected to the Inferior Frontal Gyrus (IFG) via one of the white matter tracts in either the dorsal or ventral pathways. The IFG integrates this information with a representation of the prior context into an updated representation of what is being communicated (generating the P600). The information constructed in the IFG feeds back to the pMTG via white matter tracts, causing pre-activation of lexical features of possible upcoming words (Brouwer & Hoeks, 2013). Brouwer and Hoeks (2013)’s model includes minimal cortical networks from the pMTG and IFG; two areas presumed to be the generators for the N400 and P600 respectively. Another functional neuroanatomical model for language processing proposed by Lau et al. (2008) involves several other cortical areas in addition to the pMtG and IFG, including the Anterior Temporal Cortex (ATC), Angular Gyrus (AG), and the Anterior Inferior Frontal Gyrus (aIFG). The ATC and AG are presumed to be involved in integrating incoming information into current contextual and syntactic representations. The aIFG mediates retrieval of lexical representations  29 based on top-down information. Although Lau’s model includes more cortical areas that have been associated with language areas, and areas where semantic information from reading is processed (e.g., Angular Gyrus), Brouwer & Hoek’s model makes more specific predictions about where the N400 and P600 are generated.      30  Figure 1.2 Schematic of the Retrieval-Integration Cycle in the left hemisphere.  Information enters the pMTG via either the visual or auditory cortex. The pMTG then retrieves the lexical information associated with a word, thus generating the N400. This information is relayed to the IFG via either the dorsal or ventral pathways. The IFG integrates the information with a representation of the prior context into an updated representation of what is being communicated, thus generating the P600.     31 1.6 Treatment Implications and Cognitive Remediation in Schizophrenia   The strong relationship between social cognition and functional outcomes has led researchers to examine whether social cognition can be improved. While medication can be effective in treating many of the symptoms of schizophrenia, the cognitive and social deficits experienced by those with schizophrenia are often not alleviated by pharmacological treatment (Kucharska-Pietura & Mortimer, 2013). This has led to a growing interest in psychosocial treatments as means of improving social cognition.   Cognitive deficits in schizophrenia are persistent and widespread, encompassing memory, auditory and visual attention, spatial abilities, executive function, language processing and general intelligence (Aleman, Hijman, de Haan, & Kahn, 1999; Heinrichs & Zakzanis, 1998). These cognitive deficits may comprise a core feature of the disorder since they are present in the prodromal and early stages of the illness and persist despite improvement of other symptoms. For example, when positive (i.e., hallucinations, delusions) and negative (i.e., avolition, anhedonia) symptoms improve, patients with schizophrenia may have the motivation to return to work or school, but are often unable to do so because of persistent cognitive problems. Therefore, it is critical that drug treatment is paired with effective rehabilitation in cognitive and social domains.  Cognitive remediation refers to a range of behavioural treatments that employ a variety of methods such as drill and practice exercises and compensatory and adaptive strategies to improve cognitive functioning and reduce the effects of cognitive impairments. The Cognitive Remediation Experts Workshop for Schizophrenia, which included leading developers and evaluators of cognitive remediation, defined it as “a behavioural-training based intervention that aims to improve cognitive processes (attention, memory, executive function, social cognition, or  32 metacognition) with the goal of durability and generalization” (Wykes & Spaulding, 2011, p. 84). There are several theoretical models of cognitive remediation that were derived from work on patients with traumatic brain injury. The restorative model is based on neural plasticity and focuses on the correction and strengthening of neuroanatomical connections associated with cognitive abilities (Krabbendam & Aleman, 2003; Medalia & Choi, 2009). This approach uses repeated rehearsal and extensive practice to resuscitate unused circuitry associated with inefficient connections or task avoidance (Wexler & Bell, 2005). In contrast, the compensatory model focuses on the use of alternative strategies and so-called “cognitive prosthetics”. The goal of which is to utilize residual cognitive abilities to adapt to the environment in ways that lead to functional gains, but not necessarily improved neural functioning (Medalia & Choi, 2009). Unfortunately, the literature regarding cognitive remediation in schizophrenia rarely differentiates between these models (Twamley, Jeste, & Bellack, 2003). The use of EEG in the proposed study will allow for an examination of these models by comparing patterns of brainwave activity pre- and post-treatment within subjects as well as between those with schizophrenia and a healthy control group. Patterns of EEG activity after treatment that begin to resemble the healthy control group may represent restorative change, while improved behavioural performance with no change in EEG activity may be more indicative of compensatory processes.   Research investigating the biological mechanisms of cognitive remediation in schizophrenia indicates that it is associated with changes in brain activation. It is therefore reasonable to assume that EEG may be sensitive to cognitive remediation protocols. For example, Wexler et al., (2000) and Wykes et al., (2002) found that increased activation in the frontal cortex was associated with cognitive training. Eack et al., (2010) found that maintenance  33 or increases in parahippocampal, fusiform gyrus and amygdala volume were associated with improved cognitive performance at 2-year follow-up after cognitive enhancement therapy. Similarly, Adcock and colleagues reported normalized serum brain-derived neurotrophic factor (BDNF) levels and a trend towards normalized magnetoencephalography measured asymmetry in patients who received computerized cognitive remediation (Adcock et al., 2009). These studies provide excellent, albeit preliminary, examples that cognitive remediation can produce measurable biological change in those with schizophrenia. However, the different cognitive remediation programs employed (rote rehearsal, dynamic computerized exercises, cognitive enhancement therapy), and the lack of theoretical models, make it difficult to interpret the meaning of these biological changes.   Thus far, the data on whether various cognitive remediation programs are effective for use on those with schizophrenia are generally positive, depending on the outcome of interest. When used as an adjunct to work therapy or computer skills training, cognitive remediation is associated with greater number of hours worked and larger working memory gains, respectively (M. D. Bell, Zito, Greig, & Wexler, 2008; Kurtz & Nichols, 2007). Not surprisingly, several studies found increased generalizability of cognitive gains when the cognitive remediation program was paired with other treatments such as vocational rehabilitation or psychosocial rehabilitation (McGurk & Wykes, 2008). Similarly, a meta-analysis by McGurk, Twamley, Sitzer, McHugo, and Mueser, (2007) found that programs based on rehearsal-based learning strategies were associated with greater cognitive gains whereas programs that utilized a compensatory model (i.e., adjunct psychosocial rehabilitation) were associated with greater functional gains. Several studies also agree that cognitive remediation is not particularly useful for treatment of the positive and negative symptoms of schizophrenia (Harvey, Koren,  34 Reichenberg, & Bowie, 2006; McGurk et al., 2007; however see Bellucci, Glaberman, & Haslam, 2003), and at least one study reported a link between improved cognitive functioning and subjective increased quality of life (Fiszdon, Choi, Goulet, & Bell, 2008). In addition to these supportive findings, it is important to note that more methodologically rigorous studies have failed to find conclusive evidence for the efficacy of cognitive remediation in schizophrenia (Dickinson et al., 2010; Lecardeur et al., 2009; Medalia, Revheim, & Case, 2000; Wykes et al., 2007).  Based on recent meta-analyses by McGurk, Twamley, Sitzer, McHugo, and Mueser (2007) and Wykes, Huddy, Cellard, McGurk, and Czobor, (2011) that found cognitive remediation improved psychosocial functioning, I was interested in the generalizability of cognitive remediation to other social cognitive domains such as irony comprehension. 1.7 General Methodology  The following section provides a summary of how the constructs investigated in the dissertation were measured.  1.7.1 Social Cognitive Assessments   Measures of ToM in schizophrenia research have thus far been adopted from developmental psychology, where tasks were developed to assess young children’s ability to infer the mental states of others (e.g., Baron-Cohen et al., 1985; Wimmer & Perner, 1983). Two popular categories of tests that have been commonly used are false-belief tasks (Brune & Bodenstein, 2005; Frith & Corcoran, 1996) and the Hinting Task (Corcoran et al., 1995). This dissertation used the Hinting Task, a separate measure of emotional intelligence, and a newly created Irony Comprehension Task (ICT), to index three aspects of social cognition. Further information on the Hinting Task and the Mayer-Salovey-Caruso Emotional Intelligence Test  35 (MSCEIT), a measure of emotional intelligence is provided in the proceeding sections. Information on the ICT task is provided in section 1.7.4.1.  1.7.1.1 Hinting Task The Hinting Task measures the capacity to infer intentions behind indirect speech by presenting statements to participants who are then required to understand the real intended meaning (Corcoran et al., 1995). The task consists of ten short vignettes about the interactions of two characters. The vignettes end with one of the characters dropping a hint to the other character. The participant is asked what the character really means by their utterance. A correct response on the first trial receives two points, a correct response after an additional hint is given receives one point, and an incorrect response after the hint receives zero points. The task has good face validity and has been sensitive to ToM difficulties in a number of studies (Corcoran et al., 1995; Marjoram et al., 2005). The task also has good test-retest reliability (Pearson r = .64) and good internal consistency (Cronbach’s alpha = .73) among patients with schizophrenia (Pinkham, Penn, Green, & Harvey, 2016). Please see Appendix A  for sample items. Performance on the Hinting Task has been shown to be impaired in patients with negative symptoms (Corcoran et al., 1995), positive symptoms (Marjoram et al., 2005), first episode psychosis (Bertrand et al., 2007), and paranoid delusions (Craig, Hatton, Craig, & Bentall, 2004). In terms of acute vs. chronic cases the results are more ambiguous, with Corcoran et al., (1995) showing no Hinting Task deficit in remitted patients whereas Bora, Gokcen, Kayahan, and Veznedaroglu, (2008) and Pinkham and Penn, (2006) show Hinting Task deficits in remitted patients. One noted disadvantage of the Hinting Task is that it is prone to ceiling effects and thus may lack the power necessary to detect group differences.    36 The original Hinting Task (Corcoran et al., 1995) was selected over other modified versions because it has robust psychometric properties as demonstrated by the Social Cognition Psychometric Evaluation (SCOPE) study. The Hinting Task has good test-retest reliability, internal consistency and distinguished schizophrenia patients’ performance from healthy controls (Pinkham et al., 2016). In addition, the SCOPE study classified the Hinting Task as “Acceptable As Is” (Pinkham et al., 2016, p. 8). The Hinting Task represents an established measure of social cognition, which was used to compare the new Irony Comprehension Task thus strong psychometric properties was an important consideration.  1.7.1.2 Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT)  The MSCEIT (Mayer, Salovey, & Caruso, 2002a) is an emotional intelligence (EI) test designed to measure the four-branch model of EI: (1) perceive emotion, (2) use emotion to facilitate thought, (3) understand emotions, and (4) manage emotion. The managing emotions branch of the MSCEIT, a paper-and-pencil multiple-choice test that assesses how people manage their emotions, is included in the social cognition domain of the MATRICS Consensus Cognitive Battery (MCCB). Please see Appendix B  for sample items. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) is an initiative by the National Institute of Mental Health (NIMH) to stimulate research to improve cognition in schizophrenia and provide a relatively brief evaluation of key cognitive domains relevant to schizophrenia that can be used in repeated testing. The MSCEIT full-test split-half reliability is r = 0.93, 0.91 for general and expert consensus scoring, respectively. In terms of the managing emotions branch, the reliability is high for both general and expert scoring (r = 0.83, 0.81) respectively (Mayer, Salovey, Caruso, & Sitarenios, 2003).  Only the managing emotions branch of the MSCEIT was  37 administered, as it has been found to be associated with functional status in schizophrenia samples (Nuechterlein et al., 2008).   1.7.1.3 Irony Comprehension Task (ICT)  The Irony Comprehension Task consists of 100 vignettes involving two characters. Each story contained 3-5 sentences that describe the interaction between the two characters followed by a target sentence. The stories were written in such a way that the meaning of the story could only be identified when the last word of the target sentence was read. The ICT was presented on a computer screen. Participants read the context of the interaction at their own pace. The target sentence was displayed one word at a time for 250 ms/word. Following the last word of the target sentence, a comprehension question was displayed until the subject’s response. Please see sections 1.7.4.1, 2.2.4, and 2.2.5 for more detail on the task.  1.7.2 Assessment of Psychopathology  The following section describes measures that were used to determine diagnostic information and assess symptoms of schizophrenia as well as schizotypal personality traits. 1.7.2.1 Structured Clinical Interview for the DSM-IV (SCID)  This semi-structured clinical interview was used to assess DSM-IV Axis I diagnoses (SCID-I; First, Spitzer, Gibbon, & Williams, 1997). The reliability of the psychosis module has been determined to be in the fair (Kappa of 0.65; Williams et al., 1992) to good (Kappa of 0.94; Skre, Onstad, Torgersen, & Kringlen, 1991) range on the previous version of the SCID. Determining the validity of the SCID-I has been more difficult, as the “gold standard” for psychiatric diagnoses remains elusive. However, a number of studies have used the SCID as the “gold standard” in determining the accuracy of clinical diagnoses (e.g., Shear et al., 2000; Steiner, Tebes, William, & Walker, 1995). Modules A through E were administered.   38 1.7.2.2 Positive and Negative Syndrome Scale (PANSS)  The PANSS (Kay, Fiszbein, & Opler, 1987) is a 30-item rating instrument consisting of seven positive syndrome items, seven negative syndrome items, and sixteen comprehensive pathological items used to quantify the severity of symptoms of schizophrenia. Please see Appendix D  for more details. The PANSS is one of the most widely used instruments for schizophrenia. It has been found to be a valid and psychometrically sound assessment of schizophrenia symptoms, possessing good internal reliability with α coefficients for the positive, negative, and general psychopathology scales of 0.80, 0.82, and 0.82, respectively (Peralta & Cuesta, 1994).  1.7.2.3 Schizotypal Personality Questionnaire (SPQ) Schizotypal personality disorder is often viewed as subclinical on the schizophrenia continuum. Schizotypal traits were measured using the SPQ (Raine, 1991), a 74-item true-false questionnaire designed to measure schizotypal personality traits in the normal population. The SPQ has nine subscales: ideas of reference, social anxiety, odd beliefs/magical thinking, unusual perceptual experiences, eccentric/odd behaviour and appearance, no close friends, odd speech, constricted affect, and suspiciousness/paranoid ideation. Please see Appendix C  for sample items. Overall, the test has high internal reliability (0.90 to 0.91), sampling validity (using all nine schizotypal subscales), test-retest reliability (0.82), convergent validity (r=0.59 to 0.81), discriminant validity (r=0.63) and criterion validity (r=0.68) (Raine, 1991).  39 1.7.3 Neuropsychological Assessments 1.7.3.1 Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS)  The MATRICS Consensus Cognitive Battery (MCCB) is a standardized battery designed for use with adults with schizophrenia-related disorders. It was developed to help researchers and clinicians measure cognition in individuals diagnosed with schizophrenia-related disorders. The MCCB consists of ten tests, which take approximately 1 to 1.5 hours to administer. The MCCB measures 8 cognitive domains: speed of processing, attention/vigilance, working memory (nonverbal), working memory (verbal), verbal learning, visual learning, reasoning and problem solving, and social cognition. The ten tests of the MCCB are: Brief Assessment of Cognition in Schizophrenia (BACS): Symbol Coding, Category Fluency: Animal Naming (Fluency), Trail Making Test (TMT): Part A, Continuous Performance Test, Wechsler Memory Scale – 3rd Edition (WMS-III): Spatial Span, Letter-Number Span (LNS), Hopkins Verbal Learning Test – Revised (HVLT-R), Brief Visuospatial Memory Test – Revised (BVMT-R), Neuropsychological Assessment Battery (NAB): Mazes, Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT): Managing Emotions. Figure 1.3 shows the cognitive domains and tests of the MCCB.       40 Cognitive Domain Test Speed of Processing Brief Assessment of Cognition in Schizophrenia (BACS): Symbol Coding Category Fluency: Animal Naming (Fluency) Trail Making Test (TMT): Part A Attention/Vigilance Continuous Performance Test Working Memory (nonverbal) Wechsler Memory Scale – 3rd Edition (WMS-III): Spatial Span Working Memory (verbal) Letter-Number Span (LNS) Verbal Learning Hopkins Verbal Learning Test – Revised (HVLT-R) Visual Learning Brief Visuospatial Memory Test – Revised (BVMT-R) Reasoning and Problem Solving Neuropsychological Assessment Battery (NAB): Mazes Social Cognition Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT): Managing Emotions Figure 1.3 The MATRICS cognitive domains and subtests.     41 1.7.4 Electroencephalogram (EEG)   Electroencephalogram (EEG) detects electrical activity in the brain via small electrodes attached to the scalp. Please see Appendix E  for an example of an EEG cap set up.  Appendix F  shows the electrode placement of a 32 channel standard EEG recording cap. Event-related brain potentials (ERPs), which are signal-averaged epochs of electroencephalogram time-locked to the onset of sensory or cognitive events, were used to index irony comprehension. ERPs are thought to reflect the summed activity of postsynaptic potentials produced when a large number of neurons fire in synchrony while processing information. ERPs offer a high degree of temporal resolution with regard to the on-going neurocognitive functions on the order of milliseconds, thus allowing us to infer the time course of the processing of irony.  1.7.4.1 Irony Comprehension Task (ICT) Forty-five stories adapted from the Irony Interpretation Task (Trew, 2007), along with an additional fifty-five stories created in-lab, comprise the Irony Comprehension Task (ICT). In the original Irony Interpretation Task (IIT), two versions of each vignette described a positive and negative outcome for the same scenario. The vignettes were neither imaginative nor highly fictional. They involved interactions between two characters in everyday life situations. The vignettes were written to be largely unambiguous so that only one interpretation of the situation would be made. All vignettes were written in such a way that the participant was cast as an actor in the scenario (e.g., “You and a friend ...”; “Your friend says to you...”).  The original task was developed by asking undergraduate students to rate the vignettes for plausibility, positivity/negativity, and likelihood of the event being described. The effectiveness of the irony manipulation was rated on a 7-point scale (1 = not at all, 7 = very). Items that did not score in the anticipated direction (for ironic conditions, scores at or above 4.25  42 and the literal conditions scores at or below 3.75 on this scale) were discarded. The task was pilot tested to remove items that were implausible and otherwise problematic before constructing the final IIT. The final version of the IIT had mean irony ratings of 1.54 for literal statements and 5.85 for ironic statements.  The original Irony Interpretation Task was a paper-pencil task that consisted of 45 items. To modify the Irony Interpretation Task to conform to EEG testing, an additional 55 items were created and the presentation was computerized. In addition, the word that distinguished the ironic and literal versions of each vignette was placed as the last word in the response. The original task also had a positive and negative outcome vignette with positive and negative responses. The two versions were replaced with one version counterbalanced for positive and negative outcomes with positive and negative responses. The measure was pilot tested in 2 phases. First, the paper-pencil measure was pilot tested on six individuals who provided feedback on the tolerability and ease of comprehension of the task. Items on the task that were flagged as confusing or difficult to understand were rewritten or removed from the final task. Second, the EEG based ICT was pilot tested on an additional 3 individuals who provided feedback on the computer-based presentation of the task under EEG testing condition. The purpose of the EEG pilot testing was to examine whether the ICT induced the N400 & P600 waveforms. In addition, participants provided feedback on the clarity of the instructions, and tolerability of the length of the paradigm. The average completion time of the task was 30 minutes and participants did not express any concerns regarding the clarity of the instructions.  The Irony Comprehension Task consists of 100 vignettes ranging from three to five sentences in length. The context of the story was presented on a monitor screen one sentence at a time and participants advanced the story with a button press via a response box on their lap. At  43 the end of each story, the character’s response was presented one word at a time and did not require input from the participants. Following the response, participants were asked to indicate whether the response was congruent with the preceding story. Following Kutas and Hillyard’s (1980) paradigm, half of the responses ended with a word that is semantically congruent with the context of the story, and half of the responses ended with a word that is semantically incongruent with the story. ERP analysis was time locked to the last word of the response, which was either “congruent” or “incongruent” with the story.  No feedback was given to signal performance accuracy. Each word of the response was presented for 250 milliseconds. The width of the words subtended about 2º. Following the last word of the target sentence, the probe remained on the screen until a response was made and the next trial started 1000 milliseconds later. Please see Appendix G  for a complete list of items on the ICT. 1.7.5 Computerized Cognitive Remediation Training  Approaches to computerized cognitive remediation (CCR) are based on drill-and-practice, strategy training, or a combination of both and have been shown to produce moderate improvements in neurocognition (McGurk et al., 2007; Wykes et al., 2011). Despite the variability in training programs and emphasis, the increasing number of randomized, controlled studies has supported the efficacy of a range of cognitive remediation interventions for cognitive deficits in schizophrenia. Some CCR programs train sensory processing (e.g., tone frequency discrimination) (Fisher, Holland, Merzenich, & Vinogradov, 2009), others train discrete neuropsychological areas (e.g., attention, memory and problem-solving) (Bell, Bryson, Greig, Corcoran, & Wexler, 2001), while some others focus on strategies to facilitate learning of information (Wykes et al., 2007). In addition to variability in training programs, CCR programs also vary in terms of duration, intensity, and training stimuli (McGurk et al., 2013).  44 Notwithstanding these differences all CCR programs share a common intent of improving cognitive processes (attention, memory, executive function, social cognition or metacognition) with the goal of durability and generalization (Kurtz, Mueser, Thime, Corbera, & Wexler, 2015).   One drill-and-practice program that has been investigated in a number of randomized controlled trials is Brain Fitness by PositScience. Previous studies have found that patients with schizophrenia who completed the PositScience auditory training module (Brain Fitness) improved cognitive function compared to a control treatment consisting of computer games (Fisher et al., 2009; Keefe et al., 2012; Vinogradov, Fisher, Holland, et al., 2009). Interestingly, when the visual training module (Insight) was added to the auditory training module the results are less robust (Rass et al., 2012; Surti, Corbera, Bell, & Wexler, 2011). Surti and colleagues (2011) found that visual training only improved visual memory impairment while Rass and colleagues (2015) found that CCR training alone did not result in generalized effects on cognitive or electrophysiological measures. It is unclear why the addition of visual training module may lessen the robustness of cognitive training, but some factors that have may play a role in null findings, include anticholinergic burden from medications, lack of intensity in training regimen, and illness severity and chronicity (Vinogradov, Fisher, Warm, et al., 2009).  1.7.5.1 Brain Fitness  Participants in the cognitive remediation training condition used the Brain Fitness Program created by Posit Science (www.positscience.com), which has foundations in cognitive neuroscience research and employs a restorative rehabilitation model. The PositScience system is the software most often used in academic research settings, and is the only system that has been used to investigate the biological bases of cognitive improvement in schizophrenia (Adcock et al., 2009; Vinogradov, Fisher, Holland, et al., 2009). Furthermore, since the PositScience system  45 is entirely computerized, administration is not labour intensive and can be done by a technician without a graduate degree.  The Brain Fitness program has been investigated in a number of conditions including Attention Deficit Hyperactivity Disorder (ADHD) (Mishra, Merzenich, & Sagar, 2013), chemotherapy related cognitive decline (Von Ah et al., 2012), geriatric depression (Morimoto et al., 2014), mild cognitive impairment (MCI) (Barnes et al., 2009), and traumatic brain injury (TBI) (Lebowitz, Dams-O’Connor, & Cantor, 2012). In schizophrenia, the Brain Fitness Program has been found to improve vocational outcomes (M. D. Bell, Kee-Hong Choi, Dyer, & Bruce Wexler, 2014; M. D. Bell et al., 2008), verbal memory (Fisher et al., 2009), working memory (Subramaniam et al., 2014), visual memory (Surti et al., 2011), and social cognition (Hooker et al., 2012, 2013).  The Brain Fitness program has both auditory and visual modules that begin with training in basic sensory processing. It consists of six cognitive tasks (within each modality) that are approximately fifteen-minutes in duration that uniquely adapt to the participant’s ability level to maximize training. The cognitive training program selectively chooses tasks for each training session based on client performance. The program takes a hierarchical approach, beginning the session with exercises that engage early perceptual processes and proceed to engagement of “higher order” skills (e.g., Fisher et al., 2009). As clients continually maintained an approximate 85% correct response rate on early perceptual processing tasks, they were gradually introduced to tasks that required more “higher order” skills. In this way, not all tasks were presented in every 60-minute training session. All tasks provided immediate, trial-by-trial feedback, and correct responses were rewarded with points and animations. Due to time constraints, the current study employed only the auditory module of the Brain Fitness program. The auditory training  46 module appears to be more robust and several authors found positive effects (Fisher et al., 2009; Richard Keefe et al., 2012; Vinogradov, Fisher, Holland, et al., 2009). Interestingly, when visual and auditory training were combined the results were less robust (Rass et al., 2012) There are two approaches to cognitive training: compensatory and restorative. Compensatory approaches teach individual skills and strategies to compensate for cognitive impairment so that the impact of these deficits on daily function is minimized. Some examples of compensatory strategies include chunking or acronyms to compensate for memory difficulties, using structured problem-solving and planning methods to compensate for executive dysfunction, using day planners, and modifying work space to reduce distracting stimuli (Huckbans et al., 2013). Restorative approaches seek to strengthen specific cognitive domains in order to improve functional performance more generally. The Brain Fitness training program corresponds to the restorative model of cognitive remediation in that it aims to first strengthen neural networks at the sensory level, and to gradually build upon these foundations in successively more complex cognitive tasks. A common restorative approach is to use structured and repeated practice of specific cognitive tasks and mental exercises to improve cognitive abilities. The rationale behind restorative training is that training on one task might enhance the cognitive abilities that are needed to perform similar tasks (near transfer) or very different tasks (far transfer). Whereas compensatory approaches tend to only produce near transfer effects by benefiting the specific training task that is targeted, restorative training aims to produce far transfer effects on the assumption that cognitive functions can be enhanced beyond the specific domain of training.  Each session is made up of four exercises. These exercises are:  47 High or Low – Participants differentiate between two types of sweeping sounds – one which begins at a low frequency and sweeps upward, and another that begins at a high frequency and sweeps downward.   Tell us Apart – Participants choose between two syllables that sound alike, such as boe and doe.  The speech is synthesized and lengthened and is designed to challenge auditory discrimination.  Match It – Participants start out with a grid of “tiles.” They click on the tiles, trying to find two matching sounds.  The sounds are single syllables and short words, which have been specially processed.  The goal is to clear the grid of tiles with as few clicks of the mouse as possible.  Sound Replay – Participants will hear a series of syllables (from two to nine) and then repeat the syllables in order by clicking on the matching boxes that appear on the screen.  The goal is to improve the brain’s ability to discriminate between sounds, store them in memory, and recall them.  Listen and Do – Participants will listen to a series of instructions and respond by following them in the correct order. The instructions are to either click on or move specific objects, such as people or pets.   Story Teller – Participants will listen to story segments and then answer multiple-choice questions about the story’s content.  1.8 Overview of Dissertation  The dissertation investigated the connection between social cognition and neural circuits that are known to be dysfunctional in schizophrenia, using a novel Irony Comprehension Task. In addition, it examined the extent to which social cognitive impairments observed in  48 schizophrenia occur along a continuum (i.e., examining the contribution of schizotypy to social cognitive deficits, in particular, irony comprehension). Finally, it examined whether computerized cognitive remediation can improve social cognition.    The second chapter examined whether patients with schizophrenia and those with subclinical symptoms along the schizophrenia spectrum have difficulty understanding irony and whether neural activity reflects this deficit. In study 1, it was hypothesized that performance on social cognition would be impaired in patients with schizophrenia. Furthermore, it was hypothesized that schizophrenia patients would have longer reaction times to ironic statements of the ICT. Based on Frith’s model, it was hypothesized that negative symptoms of schizophrenia would be associated with worse performance on the Hinting Task and ICT, two measures presumed to require ToM. Regarding the ERPs, it was hypothesized that N400 and P600 would be most attenuated in patients with schizophrenia. Specifically, it was predicted that the N400 and P600 would be larger for ironic compared with literal statements in healthy controls and that this difference would be attenuated in schizophrenia patients.   Unexpected findings in study 1 whereby the N400 ERPs were in the opposite direction of the hypothesis prompted me to undertake an additional study. Study 2 allowed me to examine the reliability of the N400 finding from study 1 in a larger sample of healthy individuals, and also provided the opportunity to investigate the effect of subclinical schizophrenia spectrum traits on social cognition. It was hypothesized that performance on social cognitive tasks in those with subclinical symptoms would exhibit mild impairment.   The third chapter examined whether cognitive remediation can improve social cognition in schizophrenia. It was hypothesized that computerized cognitive remediation would improve neurocognition and that this gain would generalize to social cognition. Recognizing the need for  49 effective treatment that targets cognitive functioning to improve the quality of life for individuals with schizophrenia, a neuroplasticity-based, restorative approach to training, which has the potential to maximize improvements in functional outcome, was employed. The study used a commercially available, computerized remediation program that is readily adaptable by direct care providers.   The fourth chapter summarized the findings from all three studies and concluded with an integrative discussion of the relationship between neural correlates of social cognition and symptoms of schizophrenia. In addition, clinical implications of the study and issues for future investigation are discussed.     50 Chapter 2: Irony Comprehension in Schizophrenia  Comprehension of irony is an important skill for navigating our rich social world, and one that is impaired in schizophrenia (Kantrowitz, Hoptman, Leitman, Silipo, & Javitt, 2014; Mo et al., 2008; Sparks, McDonald, Lino, O’Donnell, & Green, 2010; Ziv, Leiser, & Levine, 2011). Irony is a special category of speech because ironic words express the opposite of the intended meaning. In order to understand ironic utterances, the listener must go beyond what the speaker says to infer meaning (Sperber & Wilson, 1995, 2002). It has been postulated that irony comprehension is related to Theory of Mind (ToM), the ability to understand another’s intentions, which is one aspect of social cognition (Happé, 1993; Langdon et al., 2002). Social cognitive deficits are hallmark features in schizophrenia (Green, Kern, & Heaton, 2004; Green et al., 2012; Penn et al., 2008; Savla, Vella, Armstrong, Penn, & Twamley, 2013) and play an important role in functional outcomes (Couture et al., 2006; Fett et al., 2011).   Many studies report deficits in irony comprehension in those with schizophrenia. Specifically, patients with schizophrenia misinterpret sarcastic comments as more literal than psychiatric controls, a difference not explained by current or pre-morbid intellect (Langdon et al., 2002; Mitchley, Barber, Gray, Brooks, & Livingston, 1998). In addition, irony comprehension deficits persist beyond the acute phase and have been found in remitted patients (Herold et al., 2002; Mo et al., 2008).   Schizotypal personality traits refer to a pattern of personality disturbances that are closely related to schizophrenia (Kendler & Gardner, 1997; Kendler et al., 1993; Meehl, 1962). Schizotypy exists on a continuum and is viewed as a subclinical expression of traits related to schizophrenia. Patients with schizophrenia (Rossi & Daneluzzo, 2002), their healthy relatives (Fanous & Gardner, 2001; Kendler & Gardner, 1997), those in the premorbid phase of the illness  51 (Raine, 2006), and those at high-risk (Johnstone, Ebmeier, & Miller, 2005) exhibit higher degrees of schizotypal personality traits. Beyond schizotypal personality disorders, healthy individuals with high level of self reported schizotypy have intact metaphor understanding but impaired irony comprehension, suggesting continuity between schizophrenia and self reported schizotypy in terms of irony appreciation (Langdon & Coltheart, 2004). Furthermore, different aspects of schizotypy in college students may be differentially associated with ToM performance (Gooding & Pflum, 2011). Since schizotypy exists on a spectrum, understanding the relationship between schizotypy and irony comprehension may shed light on the deficit in patients with schizophrenia.  There is evidence to suggest that key brain regions implicated for ToM processing, for example, the medial prefrontal cortex and temporal parietal regions (Overwalle & Baetens, 2009; Saxe & Kanwisher, 2003; Shamay-Tsoory et al., 2007) are also involved in the process of irony detection. Neural correlates of irony comprehension from fMRI studies have implied a role for posterior medial prefrontal and right temporal regions in aberrant irony comprehension in schizophrenia (Overwalle, 2009; Rapp, Langohr, & Mutschler, 2014). When and how the comprehension of irony occurs compared to literal language, however, cannot be precisely defined using fMRI techniques. In order to investigate the timing of irony comprehension as it occurs in social interactions, researchers have conducted event-related potential (ERP) studies. The two ERP components that received the most attention in this field are the N400 and the P600.   The N400, a negative deflection peaking around 400 ms after stimulus presentation, is associated with semantic violations (Kutas & Hillyard, 1980). It is modulated by semantic expectancy and contextual constraint (Kutas & Federmeier, 2011). The N400 amplitude is larger  52 for unexpected endings with low cloze probability, smaller for expected endings with high cloze probability, and intermediate in amplitude for words with intermediate cloze probabilities (Kutas & Hillyard, 1984). Cloze probability refers to the degree to which the target word completes the particular sentence frame. The cloze method was developed to examine context-based word prediction – specifically, the predictability of the sentence-final word on the basis of the prior context of the sentence (Taylor, 1953). Further detail on cloze probability can be found in section 2.2.5. The N400 appears to be sensitive to lexical-semantic and pragmatic information processing as evidenced by modulation of N400 in pragmatic anomalies (Otten & Berkum, 2007), and violations of world knowledge (Hagoort, Hald, Bastiaansen, & Petersson, 2004; Hald, Steenbeek-Planting, & Hagoort, 2007). The N400 effects have high test-retest reliability in healthy adults (Kiang, Patriciu, Roy, Christensen, & Zipursky, 2013) and in schizophrenia (Boyd, Patriciu, McKinnon, & Kiang, 2014). The N400 is expected to be sensitive to irony comprehension since ironic utterances are unexpected and often in the opposite direction of the speaker’s intention.   The P600, or late positivity, emerges around 500 ms post-stimulus and is elicited when there are either syntactic or semantic violations. Early studies of the P600 found larger P600 amplitudes in syntactic violation or ambiguous sentence structures (Friederici, 2002; Kaan et al., 2000). Others, however, have challenged the finding that the P600 reflects purely syntactic violations, instead suggesting that the P600 may represent a monitoring process that represents semantically-based reanalysis processes (Ericsson & Olofsson, 2008; Herten, Kolk, & Chwilla, 2005). More recently, irony comprehension has been associated with increased P600 amplitude, and might be a reflection of pragmatic interpretation processes (Regel et al., 2011; Spotorno et al., 2013).   53 2.1  Study 1  The first study sought to determine the impact of schizophrenia on brain-related indicators of irony comprehension in an EEG task. It was hypothesized that: 1) schizophrenia patients’ ability to comprehend irony would be impaired relative to that of healthy controls.  2) the N400 and P600 amplitude would be significantly different in the ironic and literal conditions in the healthy control sample but not in the schizophrenia sample. Specifically in the HC group we expected to find a larger N400 amplitude for the ironic condition compared to the literal condition, reflecting effective semantic context processing. Moreover, a greater P600 amplitude was predicted for the ironic compared to the literal condition, indexing the pragmatic context integration necessary to infer the speaker’s ironic intention. 3) the behavioural Irony Comprehension Task would be correlated with other established behavioural measures of social cognition; specifically, the Mayer-Salovey-Caruso Emotional Intelligence Test (Mayer et al., 2002a) and the Hinting Task (Corcoran et al., 1995).  2.2 Methods  The study measures and procedures were approved by the Behavioural Research Ethics Board (BREB) of the University of British Columbia and the Vancouver Coastal Health Research Institute (VCHRI) ethics review board. 2.2.1 Participants  A total of 63 participants provided written informed consent. Five participants were excluded (4 with EEG data that were greater than 3x the interquartile range, 1 with no EEG data available). Electrophysiological data analysis included 33 participants with schizophrenia spectrum disorder (n = 25 with schizophrenia; n = 8 with schizoaffective disorder) as determined by the Structured Clinical Interview for the DSM-IV (SCID) and 25 healthy control participants.   54  Controls were recruited using flyers and online advertisements and were screened by telephone for a history of psychiatric illnesses, neurological disorders, history of stroke, and excessive drug use. Excessive drug use was defined as meeting DSM-IV criteria for substance abuse. Participants who met inclusion criteria were invited to the laboratory, where the SCID was administered, to confirm the absence of current or past psychiatric illnesses.  Patients were stable outpatients recruited from community mental health centers at Vancouver Coastal Health, and online at British Columbia Schizophrenia Society’s website. Exclusion criteria for both groups included head injury resulting in loss of consciousness >10 minutes, self-reported neurological impairment, excessive history of substance use, learning disability, and self-reported hearing impairment. Medication information was obtained for all but one patient; mean chlorpromazine (CPZ) equivalent was 336.28 (SD = 273.49). Four patients were taking typical antipsychotics only, and twenty-eight were taking atypical antipsychotics. Of those taking atypical antipsychotics, twenty-one were taking a combination of more than one atypical antipsychotic or an antipsychotic combined with an anxiolytic or an antidepressant. 2.2.2 Social Cognitive Measures  The Hinting Task (Corcoran et al., 1995) consists of ten short vignettes about the interactions of two characters, with one character dropping a hint to the other character. The participant must identify the meaning of the hint on the first try for two points, or after an additional hint for one point. The Hinting Task is scored out of 20 total points. Cronbach’s alpha for the Hinting Task in the current sample was acceptable (α = 0.75).  The Managing Emotions subscale of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT; Mayer, Salovey, & Caruso, 2002b) is a multiple choice measure that assesses how individuals would manage their emotions within different interpersonal scenarios and yields  55 scaled scores that are interpreted as follows: < 70 improve, 70-90 consider developing, 90-110 competent, 110-130 skilled, and > 130 expert. Two scoring methods are available for the MSCEIT: consensus scoring method and expert scoring method. Consensus scoring is based upon the agreement of 5,000 individuals from the normative data. Expert scoring employs 21 members of the International Society for Research on Emotions. The two scoring methods yield very similar results. The consensus scoring method was used in the current study.   2.2.3 Measures of Psychopathology  Schizotypal personality traits were assessed via the Schizotypal Personality Questionnaire (SPQ), a 74-item true-false questionnaire (Raine, 1991). The SPQ has high internal reliability (0.90 to 0.91), test-retest reliability (0.82), convergent validity (r=0.59 to 0.81), discriminant validity (r=0.63) and criterion validity (r=0.68) (Raine, 1991). Cronbach’s alpha for the total SPQ score in the current sample was high for both patients with schizophrenia (0.96) and healthy control (0.86).   The Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987) was administered by Master’s level graduate students in clinical psychology to assess the severity of psychopathology symptoms of schizophrenia. Interrater reliability was acceptable; for the PANSS, the intraclass correlation coefficient was 0.76. The PANSS is a 30-item rating instrument consisting of seven positive syndrome items, seven negative syndrome items, and sixteen comprehensive pathological items used to quantify the symptoms of schizophrenia. The PANSS is one of the most widely used instruments for schizophrenia, possessing good internal reliability with α coefficients for the positive, negative, and general psychopathology scales of 0.80, 0.82, and 0.82, respectively (Peralta & Cuesta, 1994). The PANSS was administered to schizophrenia patients within 2 weeks of assessment. The PANSS was scored using the original  56 scoring criteria (Kay et al., 1987) and the five-factor model (van der Gaag et al., 2006), which reflects a more face valid approach and is consistent with clinical presentations. The five-factors extracted from the PANSS are: positive, negative, disorganization, excitement, and emotional distress.  2.2.4 Measurement of Irony   The Irony Comprehension Task consists of 100 vignettes ranging from three to five sentences long followed by a target sentence. The vignettes were neither imaginative nor highly fictional. They involved interactions between two characters in everyday life situations. The vignettes were written to be largely unambiguous so that only one interpretation of the situation would be made. In the ironic discourse, the target sentence contained a response that is opposite in meaning than would be expected in the context. In the literal discourse, the target sentence corresponded with the preceding context. The final word in the target sentence determined whether the meaning of the discourse was ironic or literal (see Table 2.1 and Appendix G). Participants read the vignettes at their own pace. The stem of the vignettes was presented one sentence at a time and participants pressed a button to advance to the next screen. In the target sentence, the words were presented one word at a time; each word of the response was presented for 250 milliseconds. Following the final word in the target sentence, participants had to decide whether the response statement was “congruent (match)” or “incongruent (does not match) ” with the story. Half of the statements were consistent and half were inconsistent. Responses were given via a button press. Participants were not provided with feedback on their performance on the task.       57 Table 2.1 Examples of Irony Comprehension Task   Ironic Condition Examples Literal Condition Examples  1) Your brother James is coming for a visit and you agree to pick him up from the bus station.  On the way, there is a ton of traffic and you hit all the red lights.  You make it there an hour after he does.  James says to you:   “You are always early.”  1) It is your first day at a new job and you are nervous.  However, you work very hard and impress your boss and coworkers.  At the end of the day your boss says to you:    “You did excellent.”  2) You are studying for a math exam that is scheduled for tomorrow.   You say to your sister Jill, “I’ll be glad when this midterm is over!”  You receive 96% on your math exam, and Jill says to you:   “Your math skills are terrible.” 2) You are really nervous before the final game of the basketball tournament.  You play very well, making lots of baskets and practically winning the game for your team. After, your teammate Cameron says to you:   “You played well.”  3) You take your father out to dinner at a fancy restaurant for Father's Day.   After you ordered, you had to wait an hour before your meal was served.  Your father tells you:   “The service here is fantastic.” 3) You decide to try cooking a new recipe for your roommate Carl. You don’t have one of the ingredients, so you decide to improvise. The recipe turns out great and you both have seconds. Carl says to you:   “That meal was good.”      58  The internal consistency reliability of the Irony Comprehension Task was calculated using Kuder-Richardson 20 (KR-20). KR-20 is analogous to Cronbach’s alpha, where Cronbach’s alpha is used on continuous data and KR-20 is used on dichotomous data. The ICT was found to be highly reliable (98 items; Kuder-Richardson-20 = 0.95). Two items were excluded from the analysis because they had zero variance (all participants answered the items correctly). KR-20 for the 48 literal items and 50 ironic items were 0.85 and 0.96, respectively. 2.2.5 Pretests of the Irony Comprehension Task  The cloze probability is the percentage of participants who completed a particular sentence fragment with the targeted word. The cloze probability for the ICT was calculated to ensure that target sentences for ironic and literal conditions differed in their semantic expectancy. By means of a cloze probability test (Taylor, 1953) the final word of the response for each vignette was replaced with a blank space. Participants were instructed to write in the word they think was deleted. Instructions were provided to participants as follow:  Below are 105 passages, each with the final word left blank. Your task is simply to read  each sentence at your normal rate, and type the word that first occurs to you as a likely  end of that sentence. Don't try to be either unique or average; just be natural. Please only  include one response word per sentence. The word should 'make sense' in the sentence,  and be from an appropriate class of words (nouns, verbs, adjectives, etc.). Please use  English words only and do not include proper names, hyphenated or contracted words.  For some of the sentences, the response will seem obvious; for others, any number of  words will seem possible. This is intentional, since we are interested in a range of  possible sentence endings.  59 The cut-offs to determine whether a sentence has high or low cloze probability vary considerably by study. High cloze probability is defined by Coulson, Urbach, and Kutas (2006), as 40% or higher. However, Bloom and Fischler (1980) utilized a more stringent criterion of 90% or above. Other researchers have defined low cloze probability as 0%-33%, medium cloze probability as 34%-66% and high cloze probability as 67%-100% (Block & Baldwin, 2010). For the purposes of the present study, significant separation between the cloze probability of the ironic and literal conditions was a key variable rather than a particular criterion.  One hundred and sixty two participants were recruited from MTurk.com to complete the cloze test for payment. The study was approved by the Behavioural Research Ethics Board (BREB) of the University of British Columbia. In addition to the 100 vignettes from the ICT, five attention questions were interspersed throughout the test to ensure participants were following instructions and paying attention. For example, “You and Joe are playing basketball. Please type the word ‘dunk’ to indicate you are paying attention.” Only participants who received a perfect score on all five attention questions were included in the analysis. Overall, seven participants were excluded (5 – whose first language was not English; 2 – who did not get all five attention questions correct). One hundred and fifty-five participants (100 women, mean age = 36.17 years, SD = 12.39) whose first language was English and who lived in the USA were included in the analysis.  The cloze test was scored using exact wording and by using semantically acceptable procedures (Alderson, 1979). Literal sentences had an expectancy of 16.93% (SD = 19.01) and ironic sentences had an expectancy of 0.57% (SD = 1.41) in the exact match condition. In the semantically acceptable replacement condition, synonyms or semantically similar words with more than five agreements were scored as correct. For example, words such as “good”,  60 “wonderful”, and “fantastic” may be counted as a match for “great” if more than five participants arrived at the same response. Literal sentences had an expectancy of 48.03% (SD = 22.70) and ironic sentences had an expectancy of 1.09% (SD = 2.53) in the semantically acceptable condition. A significant difference between expectancy of ironic and literal conditions was observed in the exact word match [t(98) = -6.13, p < .001] and in the semantically acceptable procedures [t(98) = -14.68, p < .001]. Both the exact word and semantically acceptable scoring procedures resulted in higher cloze probability for the literal condition as compared to the ironic condition. These analyses indicate that the manipulation for the ICT was as intended – the expectancy of the word in the ironic condition is significantly lower compared to the word in the literal condition.  2.2.6 Power Analysis  The power analysis and calculation of sample size were estimated based on differences between groups. The effect size of the Hinting Task in differentiating patients with schizophrenia from controls was estimated to be d = 1.06 (Bora et al., 2009). It was thus determined that the minimal significant difference that the study would be powered to detect would have that effect size. The sample size required to obtain an effect size of d = 1.06 at power of 0.95 and alpha of 0.05 for a t-test of mean differences between two independent groups was calculated using G*Power 3 (Faul, Erdfelder, Lang, & Buchner, 2007). A sample size of 20 in each group, for a total of 40 participants, was determined. 2.2.7 EEG Procedure  Participants were seated in a quiet, darkened room and stimuli were presented on a cathode ray tube (CRT) monitor approximately 110 cm in front of the participants. The vignettes were presented one sentence at a time and participants controlled the pace of the story via a  61 response box. At the end of each vignette, a character’s response was presented one word at a time; each word of the response was presented for 250 milliseconds. Following the last word of the response, participants were asked to determine whether the response was congruent or incongruent with the story. After the response was given there was an intertrial interval of 1000 msec before the next trial started. No feedback was given to signal performance accuracy (see Figure 2.1). The visual angle of the stimuli subtended 6.64°. The task consisted of 100 trials; 50 ironic and 50 literal expressions.   62  Figure 2.1 Example of the Irony Comprehension Task for electroencephalogram (EEG).  Participants read the vignette at their own pace and advanced the slides via a button press. At the end of the vignette, the target sentence was presented one word at a time. ERPs were measured from the onset of the last word.      63 2.2.8 EEG Data Acquisition & Analysis  The EEG was recorded from 31 electrode sites using Brain Vision QuickAmps. Data were captured at 1000 Hz using a common average reference and all impedances were kept below 10 kΩ. Eye blink activity was recorded using bipolar electrodes placed above and below the left eye and on each temple for offline eye-blink correction (Gratton, Coles, & Donchin, 1983). Only trials in which participants provided a correct response were analyzed further. Accuracy rates were recorded to measure behavioural performance.   Data for ERP analysis were filtered using a .01-30 Hz (12 dB/octave) Butterworth zero phase filters except for the vertical and horizontal EOG channels, which were filtered using a .5-1 Hz (12 dB/octave) filter. Data were segmented with a 200 msec baseline and a 1000 msec epoch from the onset of the critical word. Artefacts greater than  ±100 μV were excluded.  The N400 component was quantified as the mean activity (μV) within the 300-500 msec window and the P600 component as the mean activity within the 500-800 msec window (Herten et al., 2005; Osterhout & Holcomb, 1992). The N400 and P600 were analyzed using analyses of variance to assess the effects of conditions (ironic and literal), regions of interest (frontal, central, parietal and occipital) and laterality (left, central, and right).   2.2.9 Statistical Analysis   N400 and P600 were analyzed using a four-way mixed design ANOVA with group (healthy controls or schizophrenia patients) as a between-subjects variable, and condition (ironic or literal), ROI (frontal, central, parietal, or occipital), and laterality (left, central, or right) as within-subjects variables. Mauchly’s Test of Sphericity was used to test the assumption of sphericity. A Greenhouse-Geisser correction was applied when sphericity was violated. Differences in demographic variables (age and education level) between groups were examined  64 using a t-test. Potential significant differences in education level between groups were corrected using an ANCOVA.   Reaction times were analyzed using a three-way mixed design ANOVA with group (healthy controls or schizophrenia patients) as a between-subjects variable, and condition (ironic or literal) and phase (early or late) as within-subjects variables. The “early” phase variable refers to the first 50 trials and the “late” phase variable refers to the second 50 trials of reaction time on the ICT.  To examine whether symptoms of schizophrenia were related to EEG and social cognitive measures, the N400 amplitudes, P600 amplitudes, and social cognitive measures were correlated with the PANSS positive, negative, and general scores using Spearman’s rank correlations.  2.3 Results 2.3.1 Behavioural Results  Demographic and behavioural data are presented in Table 2.2. Overall, the sample consisted of 25 participants in the healthy control (HC) group and 33 in the schizophrenia (SZ) group. A chi-square test of independence was performed to examine the relationship between gender and group. The relationship between these two variables was non-significant [X2 (2, N = 58) = 2.42, p > .051]. Both groups were similar in age [t(55) = -.05, p > .05] but there were statistically significant differences in education level [t(46) = 5.24, p < .01] with the HC group                                                   1 Sex differences were examined separately for HC and SZ to determine whether sex influenced social cognitive measures or symptom severity for patients. For both groups, there were no sex differences on social cognitive measures or symptom severity. There were no sex differences on the ERP variables. Please see Table 4.1 and Table 4.2 of Appendix H  for more detail.   65 reporting a mean education level of 15.54 (SD = 1.72) and the SZ group reporting a mean education level of 12.67 (SD = 2.07). As expected, patients with schizophrenia endorsed significantly higher levels of schizotypal traits than healthy controls [F(1,51) = 23.70, p < .01] as measured by the SPQ. An independent samples t-test revealed a significant effect of group for accuracy on the Irony Comprehension Task (ICT) [t(56) = 1.97, p = .05], the Hinting Task [t(56) = 4.34, p < .01], and the MSCEIT Managing Emotions branch [t(56) = 3.21, p < .01], with participants in the schizophrenia group performing more poorly than healthy controls. A breakdown of the accuracy rate of the ICT task by quarters was undertaken to examine fatigue effect. A two-way ANOVA with group as a between-subjects factor and quartiles as a within-subject factor revealed a main effect of group F(1,55) = 4.30, p < .05, indicating that the HC group had higher accuracy rate. There were no significant main effect of quartile and no group x quartile interaction, indicating both the HC and SZ groups performed consistently throughout the task, showing no fatigue effect (see Figure 2.2). Mean accuracy rates for the HC group by quarters are: [Q1 = 91.84% (SD = 9.13); Q2 = 93.44% (SD = 7.47); Q3 = 92.16% (SD = 11.22); Q4 = 92.32% (SD = 10.89)]. Mean accuracy rates for the SZ group by quarters are: [Q1 = 85.58% (SD = 14.35); Q2 = 86.55% (SD = 14.52); Q3 = 86.55% (SD = 14.28); Q4 = 86.55% (SD = 14.96)].  66 Table 2.2 Descriptive Statistics for Study 1  * p < .05 ** p < .01 Note. SPQ = Schizotypal Personality Questionnaire; PANSS = Positive and Negative Syndrome Scale; MSCEIT = Mayer-Salovey-Caruso Emotional Intelligence.    HC SZ N  25 33 Sex (m:f) 10:15 20:13 Age Education (yrs) Ethnicity    Asian   Caucasian     Hispanic   Black   Other SPQ Total 30.04 (8.51) 15.54 (1.72)  10 9 1 0 5 10.71 (7.85) 30.21 (7.68) 12.67 (2.07)**  14 15 2 1 1 29.31 (17.27) ** PANSS ORIGINAL     PANSS Positive   12.41 (4.44)    PANSS Negative  13.06 (4.81)    PANSS General PANSS FIVE FACTOR    PANSS POS    PANSS NEG    PANSS EXEC    PANSS EMO    PANSS DIS  27.48 (8.57)  13.48 (5.71) 13.84 (5.29) 11.69 (3.35) 15.91 (6.13) 15.97 (4.64) Irony Comprehension Task (%) 92 (8.87) 86 (13.16) * Hinting Task (%) MSCEIT Managing Emotion 91 (7.60) 95.36 (6.65) 74 (18.28) ** 87.21 (11.27) **     67     Figure 2.2 The Irony Comprehension Task percent correct by quartile for Study 1.  There were no statistically significant differences between quartiles in the HC or SZ groups, indicating that both groups performed consistently throughout the task.   808284868890929496Q 1 Q 2 Q 3 Q 4% CORRECT ON ICTQUARTILEIRONY COMPREHENSION TASK BY QUARTILEHC SZ 68  A three-way mixed ANCOVA of reaction time with group (HC or SZ) as the between-subjects variable and condition (ironic or literal) and phase (early or late) as the within-subjects variables and education level as a covariate revealed a trend level main effect for condition [F(1,55) = 3.62, p = .06], indicating that all participants had slightly longer reaction times to the ironic (RT = 1228.91 msec, SD = 927.42) as compared to literal (RT = 1193.70 msec, SD = 898.95) trials. A main effect of group was also significant [F(1,55) = 6.11, p <.05], indicating that the HC group had faster reaction times (RT = 960.12 msec, SD = 736.68) compared to the SZ group (RT = 1481.62 msec, SD = 998.64). There were no interactions between group, condition or phase (see Table 2.3). Reaction time was not correlated with CPZ equivalents (all p’s > .05).     69 Table 2.3  ANCOVA Table for Reaction Time with Education as a Covariate for Study 1   F p Main effects      Group 6.11   .01    Condition    Phase Interactions     Condition x Group    Phase x Group    Condition x Phase    Condition x Phase x Group 3.62 .68  2.32 .28 .14 .00 .06 .42  .13 .60 .71 .96    70  To determine whether the social cognitive measures were related, Spearman’s correlations were conducted between the Hinting Task, ICT, and MSCEIT because the ICT violated assumptions of normality. All three measures of social cognition were significantly and positively correlated with one another (see Table 2.4). An examination of the relationships between symptom severity (original PANSS scoring criteria) and social cognitive measures revealed an inverse correlation between PANSS Negative scores and Hinting Task performance [r = -.57, p < .01], indicating greater negative symptoms were associated with worse performance. The five-factor PANSS scoring method resulted in similar findings between PANSS Negative symptoms and Hinting Task performance [r = -.51; p < .01]. In addition the PANSS Disorganization symptoms were negatively correlated with Hinting Task performance [r = -.43; p < .05] (see Table 2.5). As expected, schizotypal personality was associated with the original PANSS Positive scores [r = .54; p < .01] and the five-factor PANSS Positive scores [r = .67, p < .01]. An inverse correlation was found between schizotypal personality and the Hinting Task [r = -.30; p < .05], indicating that higher endorsement of schizotypal traits was associated with worse performance.  71 Table 2.4  Correlations Between Social Cognition and Original PANSS scores in SZ for Study 1 Measure  1 2 3 4 5 6 7 1. Irony Comprehension Task Spearman’s ρ N -    .31*     49   .47** 58 -.21  32 -.15   32 -.03 31 -.23 53 2. Hinting Task Spearman’s ρ N  -   .34** 49 -.21  26   -.57** 26 -.25 25 -.30* 47 3. MSCEIT Managing Emotion  Spearman’s ρ N   - -.26  32 -.35  32 -.12 31 -.23 53 4. PANSS Positive  Spearman’s ρ N    - .15  32 .61** 31 .54** 28 5. PANSS Negative  Spearman’s ρ N     - .43* 31 -.23 28 6. PANSS General Spearman’s ρ N      - .28 28 7. SPQ  Spearman’s ρ N       -  * p < .05 ** p < .01 Note. MSCEIT = Mayer-Salovey-Caruso Emotional Intelligence; PANSS = Positive and Negative Syndrome Scale; SPQ = Schizotypal Personality Questionnaire.       72  Table 2.5  Correlations Between Social Cognition and Five-Factor PANSS scores in SZ for Study 1  Measure  1 2 3 4 5 6 7 8 9 1. Irony Comprehension Task Spearman’s ρ N -    .33*     48   .48** 57 -.18  32 -.11   31 -.12 32 -.18 32 -.09 31 -.23 52 2. Hinting Task Spearman’s ρ N  -   .34* 48 -.10  25   -.51* 24 -.16 25 -.11 25 -.43* 24 -.29 46 3. MSCEIT Managing Emotion  Spearman’s ρ N   - -.13  32 -.27  31 -.37* 32 -.24 32 -.23 31 -.22 52 4. PANSS Positive  Spearman’s ρ N    - .13  31 .56** 32 .77** 32 .29 31 .67** 28 5. PANSS Negative  Spearman’s ρ N     - .64** 31 .45* 31 .70** 31 -.11 28 6. PANSS Excitement Spearman’s ρ N      - .80** 32 .67** 31 .26 28 7. PANSS Emotional Distress Spearman’s ρ N       -  .48** 31 .43* 28 8. PANSS Disorganization Spearman’s ρ N        - -.04 28 9. SPQ   Spearman’s ρ N         -  * p < .05 ** p < .01 Note. MSCEIT = Mayer-Salovey-Caruso Emotional Intelligence; PANSS = Positive and Negative Syndrome Scale; SPQ = Schizotypal Personality Questionnaire.    73  2.3.2 Electrophysiological Results N4002  Data for the 300-500ms window (N400) were analyzed using a four-way mixed-design ANCOVA with group (healthy controls or schizophrenia patients) as a between-subjects variable, and condition (ironic or literal), ROI (frontal, central, parietal, or occipital), and laterality (left, central, or right) as within-subjects variables and education level as a covariate. Mauchly’s Test of Sphericity indicated that the assumption of sphericity had been violated for ROI [χ2(5) = 137.36, p < .001] and condition x laterality [χ2(2) = 15.47, p < .001] therefore degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity (ε = 0.45; 0.78, respectively). There were no significant main effects. Significant interactions were found for condition x laterality [F(1.59, 84.30) = 5.85, p < .01], condition x laterality x education level [F(1.59, 84.30) = 5.03, p < .05], and condition x laterality x group [F(1.59, 84.30) = 6.16, p < .01]. Post-hoc tests of the condition x laterality interaction showed that for both conditions, midline > right (p < .001), midline > left (p < .001), with no significant differences between left and right.   Follow-up analyses of the condition x laterality x education level interaction were performed separately for each condition. Separate ANCOVAs for each condition yielded a main effect of laterality in the ironic [F(3,53) = 3.20, p < .05] and literal [F(3,53) = 3.90, p < .05] conditions. These differences appear to be driven by larger N400 amplitudes recorded from the right hemisphere for both the ironic condition [F(1,55) = 7.93, p < .01] and the literal condition                                                   2 N400 data were re-analyzed excluding the 7 individuals with schizoaffective disorder. Significant main and interaction effects were unchanged.   74 [F(1,55) = 9.46, p < .01]. A bivariate correlation of education level and laterality separately for each condition showed significant negative correlations between education level and right literal [r = -0.35, p < .01]; and education level and right ironic [r = -0.36, p < .01]. These correlations indicated that higher levels of education were associated with larger N400 amplitudes recorded on the right side of the scalp.  Follow-up analyses of the condition x laterality x group interaction were performed separately for each diagnostic group. The healthy control group revealed a condition x laterality interaction [F(8,90) = 2.31, p < .05 ], whereby the N400 amplitude in the ironic condition in the left hemisphere was significantly smaller than that in the literal condition [t(24) = -2.54, p < .05]. There were no significant main effects or interactions within the SZ group. Grand average ERPs for the left and right hemispheres are shown in Figure 2.3 and Figure 2.4 respectively.     75   Figure 2.3 ERPs for the ironic and literal conditions in the left hemisphere in study 1. Significant ERP differences were found in the N400 for the HC group in the left hemisphere. No ERP differences were found for the SZ group. 76    Figure 2.4 ERPs for the ironic and literal conditions in the right hemisphere in study 1.    77 P6003  Within the 500-800ms window of the P600, Mauchly’s Test of Sphericity indicated that the assumption of sphericity had been violated for ROI [χ2(5) = 134.49, p < .001], therefore degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity (ε = 0.44). Main effects of laterality [F(2,49) = 3.85, p < .05] were qualified by an interaction of group x laterality [F(2,49) = 4.26, p < .05]. Follow-up analyses of the group x laterality interaction showed that at midline, HC had larger P600 amplitudes than SZ [F(1,56) = 5.70, p < .05], see Figure 2.5. The main effect of condition was not significant. EEG and Symptom Severity   An examination of the relationships between symptom severity and electrophysiological measures revealed positive correlations between PANSS Negative scores and N400 amplitude at Pz ironic [r = .61, p < .01] and Pz literal [r = .49, p < .01] that were significant after a Bonferroni correction, indicating more severe symptoms were associated with larger N400. There were no significant correlations between symptoms and the P600.                                                      3 P600 data were re-analyzed excluding the 7 individuals with schizoaffective disorder. The results for the P600 showed that the main effect of laterality was no longer significant. All other main effects and interactions were unchanged.  78                Figure 2.5 ERPs for the HC and SZ groups in study 1. Significant group differences were found in the P600 window across conditions.   79 2.4 Discussion  The current study examined the neural correlates of irony comprehension in patients with schizophrenia and age-matched healthy controls. The data supports the hypothesis that social cognitive deficits are present in patients with schizophrenia, across all three measures of social cognition used in the study. Group differences between patients with schizophrenia and healthy controls were identified for irony comprehension as measured by the Irony Comprehension Task (ICT), indirect speech as measured by the Hinting Task, and emotional intelligence as measured by the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Furthermore, patients with SZ had longer reaction time compared to the controls on the ICT. This is consistent with other studies that found reading deficits (Hayes & O’Grady, 2003; Revheim et al., 2014) and delayed cognitive processing in SZ (Green, 2006; Keefe et al., 2006; Nuechterlein et al., 2004). Both HC and SZ had longer reaction times for ironic sentences compared to literal sentences that was trending significance. This trend is consistent with the standard pragmatic model, which assumes that the processing of ironic sentences requires a longer reaction time than literal sentences (Grice, 1975; Searle, 1979). Interestingly, the group x condition interaction was not significant, thus we did not find differentially longer reaction times when patients with schizophrenia responded to ironic statements.  Concerning the ERP data, healthy controls exhibited hemispheric differences in the interpretation of ironic sentences, with the left hemisphere showing smaller N400 amplitudes to ironic as compared to literal statements. Conversely, schizophrenia patients did not show this differentiation, which is consistent with their worse behavioural performance and reaction time. Furthermore, they showed much smaller N400, consistent with the amplitude of N400 being associated with more SZ traits. This indicates that schizophrenia patients processed literal and  80 ironic statements using similar neural mechanisms. It is possible that the processing of irony relied more on left hemisphere involvement, as the left hemisphere contains several areas specialized for language processing (Fedorenko, Duncan, & Kanwisher, 2012; Rachel Giora et al., 2000; Vigneau et al., 2006). The lack of differentiation between ironic and literal waveforms in the left hemisphere in schizophrenia may reflect dysfunction in this area. Support for the involvement of left hemispheric dysfunction in schizophrenia has come from findings of reduced gray matter volume in the left hemisphere (Shenton, Dickey, Fruman, & McCarley, 2001), postmortem studies of brain structure (Falkai, Bogerts, Greve, & Pfeiffer, 1992), and left hemispheric impairment in schizotypal personality (Besche‐ Richard, Iakimova, Hardy-Bayle, & Passerieux, 2014; Gruzelier & Doig, 1996).   The treatment of schizophrenia includes a wide range of medications that raises anticholinergic serum which have been shown to adversely affect cognition (McGurk et al., 2004; Minzenberg, Poole, Benton, & Vinogradov, 2004) and several ERP studies have demonstrated a reduced N400 effect in schizophrenia patients (Mohammad & DeLisi, 2013; Wang, Cheung, Gong, & Chan, 2011). However, as far as I am aware, there are no studies that have examined the effects of typical or atypical antipsychotic medications on N400 or P600. There have been studies that examined the N400 in those with schizotypal personality disorder who are medication naïve (Niznikiewicz et al., 1999) that found abnormality consistent with schizophrenia patients who are on medication (Niznikiewicz et al., 1997). However, there are no studies that directly examined the N400 and P600 effect in schizophrenia patients who are medication naïve and those who are on medications. Given the large variability in chlorpromazine equivalents in our sample, the anticholinergic burden from medications effects on the N400 and P600 cannot be ruled out.   81  Different N400 amplitudes to ironic and literal statements in HC indicate that task manipulation was effective in separating both task conditions and groups. Unexpectedly, this pattern showed larger amplitudes to literal as compared to ironic statements. This contradicted our hypothesis, which predicted that the ironic statements would evoke larger amplitudes compared to literal statements. That the SZ group did not show a difference between literal and ironic processing partially supports the original hypothesis that N400 amplitudes would be affected in those with schizophrenia. However, given the contradictory results in the HC group, the lack of differentiation between literal and ironic statements in the SZ group should be interpreted with caution.   Contrary to our hypothesis, there was no association between P600 and irony comprehension as measured by the ICT. This implies that difficulty with pragmatic or conceptual integration of the final word with the proceeding context was not affected in this sample. This finding is in contrast with observations of Regel and colleagues (2011) and Spotorno and colleagues (2013), who found a large late positive component during the processing of irony. Although the ICT manipulation did not elicit a differential P600 effect in irony comprehension, it was observed that patients with schizophrenia had smaller P600 amplitudes at midlines sites across both conditions compared to controls. These results are in line with observations by Niznikiewicz and colleagues (1997), and Kuperberg and colleagues (2006), who also described attenuated P600 in language processing tasks in patients with schizophrenia.   In the current sample, there was a positive correlation between all measures of social cognition, providing further support that ToM, emotional intelligence and irony comprehension are related constructs. The hypothesis that symptoms of schizophrenia would be correlated with social cognition was partially supported by an inverse correlation between negative symptoms  82 and the ability to understand social hints. These findings are similar to those of Corcoran and colleagues (1995), who also found that negative symptoms were significantly associated with ToM (as measured by the Hinting Task). The correlation of the Hinting Task with PANSS negative score fits with the literature suggesting a correspondence between ToM and negative symptoms (Bell & Mishara, 2006; Brune, 2005b; Harrington et al., 2005; Mizrahi, Korostil, Starkstein, Zipursky, & Kapur, 2007; Woodward, Mizrahi, Menon, & Christensen, 2009). Furthermore, both ToM and negative symptoms have been found to be significant predictors of social competence in patients with schizophrenia (Bora, Eryavuz, Kayahan, Sungu, & Veznedaroglu, 2006; Couture, Granholm, & Fish, 2011; Couture et al., 2006).  As expected, SZ patients endorsed more schizotypal traits compared to HC. Similar to the finding that nonclinical individuals who endorse more schizotypal traits exhibit worse ToM performance (Pickup, 2006), more endorsement of schizotypal traits by both the HC and SZ groups was inversely correlated with ToM performance as well as emotional intelligence.   Regarding the relationship between ERP measures and symptom severity, there was a correlation between negative symptoms and parietal N400 amplitudes. These results are in contrast to previous studies that found decreased N400 amplitude to be associated with thought disorder (Kostova, Passerieux, Laurent, & Hardy-Bayle, 2005), hallucinations (Mathalon, Faustman, & Ford, 2002), and positive symptoms (Boyd et al., 2014). One explanation for the finding that negative symptoms were associated with smaller N400 may be reflected in how the N400 was generated. The current study used an irony comprehension paradigm whereas the above studies used a priming paradigm. Contextual and pragmatic information in social interactions may be more impaired in those with negative symptoms, and this may be reflected in constrained semantic network function. This explanation is in line with Frith’s theory that  83 patients with prominent negative symptoms would perform more poorly on ToM tasks (Frith, 1992).   In summary, the behavioural and reaction time data support the hypotheses that patients with schizophrenia would exhibit poorer performance on several measures of social cognition and have slower reaction times. The electrophysiological data resulted in some unexpected outcomes.  The finding that healthy controls processed literal and ironic statements differently while patients with schizophrenia did not supports the hypothesis that N400 is sensitive to irony processing. However, this difference was in an unexpected direction, with literal statements producing larger N400 amplitudes compared to ironic ones. The null P600 findings were also unexpected. One possible explanation for this is that the current study did not have enough power to detect a P600 amplitude difference between literal and ironic processing. The number of participants for the current study was determined using a power analysis designed to detect differences on the Hinting Task, for which published effect sizes were available. It is perhaps the case that the ICT manipulation is weaker than the Hinting Task and that more participants are thus required to detect a difference for the P600 ERP. Based on the contradictory finding of the N400 and the null finding of the P600, a second study with a larger sample of healthy undergraduate students was undertaken to examine potential effects of statistical power. In addition, study 2 aimed to investigate subclinical traits along the schizophrenia spectrum and their relation to irony comprehension and other measures of social cognition.  2.5 Study 2  The results of study 1 imply that the comprehension of irony does not involve syntactic/contextual-processing as reflected in the P600, but rather semantic processing  84 associated with the N400 component. Whether this ERP pattern is reliably evoked is investigated in study 2. Study 2 also included the SPQ to measure schizotypal personality traits in the general population and to investigate their relationship with irony comprehension and related measures of social cognition.  2.6 Methods 2.6.1 Participants  Seventy healthy, right-handed students from the University of British Columbia participated in the study for course credit. The analysis excluded five participants (2 with EEG data that were greater than 3x the interquartile range, and 3 with no EEG data available). The mean age was 20.75 (SD = 2.80) and the ratio of male to female was 22:43. The study was approved by the Behavioural Research Ethics Board (BREB) of the University of British Columbia. All participants had normal or corrected-to-normal vision, no self-reported psychological or neurological disorders.  2.6.2 Power Analysis  The power analysis and calculation of sample size was based on a study by Regel, Coulson, & Gunter, (2010) that compared the ERPs between ironic and literal statements made by an ironic and a non-ironic speaker. A large effect size, d = .80 was reported between accuracy rates of ironic and literal statements made by an ironic speaker. Based on d = 0.80 at power of 0.95 and alpha of 0.05, a sample size of 70 would be required (G*Power 3; Faul, Erdfelder, Lang, & Buchner, 2007). 2.6.3 Stimulus Materials  The Irony Comprehension Task, MSCEIT Managing Emotions subtest, and Hinting Task were administered, as described in section 2.2.2 and 2.2.4. In addition, the Schizotypal  85 Personality Questionnaire (SPQ) (Raine, 1991), a 74-item true-false questionnaire designed to measure personality traits associated with unusual perceptual experiences was administered. The SPQ has nine subscales, which have high internal reliability (Cronbach’s alpha = 0.91). Cronbach’s alpha for the total SPQ score in the current study was high (0.92).  The internal consistency reliability of the Irony Comprehension Task was calculated using Kuder-Richardson 20 (KR-20). The ICT was found to be highly reliable (88 items; KR-20 = 0.88). Twelve items with zero variance (all participants answered the items correctly) were excluded from the analysis. KR-20 for the 39 literal items and 49 ironic items and were 0.71 and 0.86, respectively. 2.6.4 EEG Procedure  The EEG procedure was the same as described in section 2.2.3. 2.6.5 EEG Data Acquisition & Analysis   EEG data acquisition was described in section.  2.6.6 Statistical Analysis  N400 and P600 were analyzed using a three-way ANOVA to assess the effect of condition (ironic or literal), ROI (frontal, central, parietal, or occipital), and laterality (left, central, or right). Mauchly’s Test of Sphericity was used to test the assumption of sphericity. A Greenhouse-Geisser correction was applied when sphericity was violated.   Reaction times were analyzed using a two-way ANOVA with condition (ironic or literal), and phase (early or late) as the independent variables. The “early” phase variable refers to the reaction time on the first half of the ICT and the “late” phase variable refers to the reaction time on the second half of the ICT.  86  To examine whether schizotypal traits were related to EEG and social cognitive measures, the N400 amplitudes, P600 amplitudes, and social cognitive measures were correlated with the SPQ total score using Spearman’s correlations.   2.7 Results  2.7.1 Behavioural Results  Participants showed excellent comprehension on the Irony Comprehension Task (ICT), the mean accuracy rate was 93.11% (SD = 4.99)4. A breakdown of accuracy rate by quartiles showed no statistical significance between the quartiles, indicating participants performed consistently throughout the ICT task [Q1 = 92.36% (SD = 8.41); Q2 = 93.09% (SD = 6.14); Q3 = 93.64% (SD = 5.83); Q4 = 93.33 (SD = 7.24)]. Mean accuracy for the Hinting task was 89.48% (17.9/20; SD = 9.93). On the emotional intelligence test, participants performed in the average range with mean standard score of 99.10 (SD = 13.05). The mean SPQ total was 17.85 (SD = 11.55). SPQ subscales and behavioural measures are reported in Table 2.6                                                     4 There were no sex differences on the ICT task with males and females performing equally well [F(1,64) = .11, p > .05]. There were also no sex differences on the Hinting Task, MSCEIT, levels of schizotypy, or ERP variables. Please see Table 4.3 of Appendix H    87 Table 2.6  Descriptive Statistics of the SPQ and Social Cognitive Measures for Study 2            Note. SPQ = Schizotypal Personality Questionnaire; MSCEIT = Mayer-Salovey-Caruso Emotional Intelligence.   Scale Mean  SD Min Max SPQ Total    Ideas of Reference    Social Anxiety    Odd Beliefs    Unusual Perceptual Experiences    Odd Beliefs    No Friends    Odd Speech    Constricted Affect    Paranoid Ideation Irony Comprehension Task (%) Hinting Task (%) MSCEIT Managing Emotion (SS) 17.85 2.89 2.80 .77 1.49 1.66 1.75 3.28 1.52 1.68 93.11 89.48 99.10 11.55 2.21 2.24 1.01 1.46 1.89 2.08 2.15 1.79 1.71 4.99 9.93 13.05 0 0 0 0 0 0 0 0 0 0 74 55 65.40 53 8 8 4 5 7 9 9 7 6 99 100 158.54     88  Spearman’s correlation coefficients were computed to assess the relationship between social cognitive measures and schizotypal traits as all variables violated assumptions of normality. Self-reported schizotypal traits displayed a significant negative correlation with the Hinting Task, [r = -.34, p < .01]; which indicated that individuals with higher schizotypy traits had poorer understanding of speakers’ intended meaning. There were no correlations between SPQ, MSCEIT, and ICT. The correlations among social cognitive measures; the Hinting Task, MSCEIT and ICT did not reach statistical significance, which is inconsistent with study 1. Results pertaining to the correlations can be seen in Table 2.7    89 Table 2.7  Correlations Between Social Cognitive Measures and the SPQ for Study 2 Measure  1 2 3 4 1. Irony Comprehension Task Spearman’s ρ N - .23 66 .18 66 -.10    64 2. Hinting Task Spearman’s ρ N  - -.09 66   -.34** 64 3. MSCEIT Managing Emotion  Spearman’s ρ N   - -.02   64 4. SPQ Spearman’s ρ N    - ** p < .01 Note. MSCEIT = Mayer-Salovey-Caruso Emotional Intelligence; SPQ = Schizotypal Personality Questionnaire              90  A two-way ANOVA of reaction time with condition (ironic or literal) and phase (early or late) as the independent variables was statistically significant for phase [F(1,56) = 43.20, p < .01], indicating that participants had faster reaction times in the second half of the test. Participants responded more slowly in the first half of the task (RT = 1116.77 msec, SD = 663.06) as compared to the second half of the task (RT = 809.99 msec, SD = 523.20). Reaction time was not correlated with the SPQ (all p’s > .05).  2.7.2 Electrophysiological Results N400  Data for the 300-500ms window (N400) were analyzed using a three-way ANOVA with condition (ironic or literal), ROI (frontal, central, parietal, or occipital), and laterality (left, central, or right) as within-subjects factors. Mauchly’s Test of Sphericity indicated that the assumption of sphericity had been violated for ROI [χ2(5) = 131.56, p < .001] and laterality [χ2(2) = 6.79, p < .05], therefore degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity (ε = 0.53; 0.90, respectively). Main effects of ROI [F(1.59, 96.95) = 49.29, p < .001] and laterality [F(1.81, 110.20) = 31.70, p < .001], were qualified by an interaction of ROI x laterality [F(4.09, 249.67) = 11.24, p < .001]. Follow-up analysis of the ROI x laterality interaction showed that N400 amplitudes were largest at midline, followed by left and right for frontal, central, and parietal sites. There were no laterality differences at occipital sites.  P600  The analysis within the 500-800ms window indicated that the assumption of sphericity had been violated for ROI [χ2(5) = 94.51, p < .001], laterality [χ2(2) = 16.70, p < .001], ROI x condition [χ2(5) = 111.50, p < .001], and ROI x laterality [χ2(20) = 68.60, p < .001], therefore degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity (ε = 0.57;  91 0.81, 0.53, 0.72, respectively). Main effects of ROI [F(1.69, 110.09) = 81.85, p < .001] and laterality [F(1.63, 105.72) = 32.92, p < .001] were qualified by an interaction of ROI x laterality [F(4.30, 279.75) = 4.84, p < .001] and ROI x condition [F(1.60, 104.16) = 3.42, p < .05]. Follow-up analysis of the ROI x laterality interaction showed that midline sites had the highest amplitude with no differentiation between left and right at frontal, parietal and occipital sites. At central sites the right hemisphere showed greater P600 than then left hemisphere. Follow-up analysis of the ROI x condition interaction showed a statistically significant effect of condition at frontal [t(65) = -2.00, p < .05] and central sites [t(65) = 1.97, p < .05] indicating larger (more positive) P600 values in the literal condition. Grand average ERPs are shown in Figure 2.6.   The SPQ total score was not significantly correlated with N400 or P600 amplitudes. 92 Figure 2.6 Average ERPs at frontal, central, parietal and occipital sites in study 2.  In the P600 window, ERPs for the literal condition were larger than ironic condition at frontal and central sites.          93 2.8 Discussion  In study 2, the neural correlates of irony comprehension as well as its relationship to schizotypy, were examined in a large sample of healthy undergraduate students. Behavioural data showed that participants had excellent understanding of social cognition as measured by the Hinting Task, ICT and MSCEIT. Reaction time data suggested that irony detection became faster over time with no improvement in accuracy rate. However participants showed excellent performance on the ICT (accuracy rate > 90%), and this lack of improvement in accuracy rate might be due to a ceiling effect. Schizotypal traits were associated with poorer Hinting Task performance but not with the ICT nor the MSCEIT as was found in study 1. Schizotypy in nonclinical populations has been associated with subtle impairment in Theory of Mind (Pflum, Gooding, & White, 2013; Pickup, 2006), although these findings may not be consistent (Fernyhough, Jones, Whittle, Waterhouse, & Bentall, 2008). The seemingly inconsistent results may be partly due to the multifaceted nature of schizotypy. Rather than quantifying schizotypy as “high” and “low”, Gooding & Pflum, (2011) explored different aspects of schizotypy and found that ToM impairments were associated with poorer performance for those with positive schizotypy compared to those with negative schizotypy. However, even this characterization of schizotypy is not consistent as Fernyhough and colleagues (2008) found ToM performance were unrelated to positive signs of schizotypy and levels of persecutory delusion-like beliefs.   There was no N400 amplitude difference between the literal and ironic conditions, which suggests that the neural activity did not differentiate when participants had to integrate an ironic, as compared to a literal, word. The amplitude of the N400 has been shown to be modulated by the ease of semantic integration and to increase with the difficulty of word integration during the processing of literal language (Friederici, Steinhauer, & Frisch, 1999; Van Petten, Coulson,  94 Rubin, Plante, & Parks, 1999). One explanation may be that the undergraduate student sample found irony easier to understand than older healthy adults in the community. However, their comparable behavioural performance would suggest otherwise. Given that both groups performed very well, their behavioural performance may not be sensitive due to ceiling effects. Taken together, the N400 finding in study 1 should be interpreted with caution.   The P600 effect was evoked in irony comprehension, albeit in an unexpected direction. At this point, the functional interpretation of the current P600 remains speculative. One interpretation may be that the P600 indeed reflects comprehension processes at a pragmatic or conceptual level. Because different types of information need to be integrated, the P600 might be a function of late integration process of semantic and pragmatic information. One speculative explanation for the P600 effect found in the current sample may be related to task demand. Perhaps participants in study 1 processed irony by integrating semantic information and the participants in study 2 processed contextual information, although it is unclear what may have led to this differential processing style. This explanation is necessarily speculative and further studies that directly address irony-processing strategies are warranted.   Self-reported schizotypal traits were not correlated with the N400 nor the P600. Given that the sample in study 2 is from healthy undergraduate students, this finding may be due to a restricted range. Studies that show the N400 is sensitive to schizotypy have been conducted in those who met full criteria for schizotypal personality disorder or those with family members of individuals with schizophrenia (Kimble et al., 2000; Niznikiewicz et al., 1999, 2002). Further research is needed on samples that represent the range of schizotypal symptoms that extend beyond the restricted range within the undergraduate student sample provided here.  95 2.9 General Conclusions  Investigations into the complex construct of irony comprehension are in their early stages. This is the first such task to investigate the electrophysiological pattern of irony comprehension in English. While this provides an exciting area of exploration, the interpretation that follows should be made with caution until further replications can be conducted.   The finding that the N400 was sensitive to irony comprehension in study 1 is consistent with the known characteristics of the component; however, the direction of the amplitude was unexpected with the healthy control group displaying larger amplitude in the literal condition. More importantly, this differentiation was not seen in the schizophrenia sample. The lack of neural differentiation in the schizophrenia sample parallels the poorer behavioural performance that the SZ exhibited on all measures of social cognition: the ICT, the Hinting Task, and the MSCEIT. Increased N400 amplitude is typically found when the target word deviates in semantic meaning from the expected word within that sentence context. These findings are robust and have been reported in a variety of languages and sensory modalities (Berkum, Hagoort, & Brown, 1999; Cornejol, Simonetti, & Aldunate, 2007; Mecklinger, Schriefers, Steinhauer, & Friederici, 1995); however, as noted above, this pattern did not emerge here.    One explanation for the differing HC finding is that the choice of EEG reference in this study, the common average reference, was different from previous studies that used the left mastoid (Regel et al., 2011; Spotorno et al., 2013). Electrical potentials at the scalp are defined with respect to a reference, an arbitrarily chosen zero level. References in EEG include mastoid, CZ, ears, or average reference. The choice of reference depends on the recording parameters and personal preference. I chose common average reference because it has been shown to be more psychometrically reliable (Gudmundsson, Runarsson, Sigurdsson, Eiriksdottir, & Johnsen,  96 2007). The mastoids are located behind the ear on the temporal bones and are presumed to be free of electrical activity. However, they are not electrically silent and are located very close to the lateral temporal language areas. With multi-channel recordings (I recorded from 32 channels), it is recommended to compute the average reference and then subtract the average from each electrode for each time point (Dien, 1998). Comparative studies of the effect of reference electrode placement for EEG have demonstrated that linked mastoids show significant shifts to the right, frontal and superficial positions, whereas average reference shifts the spatial amplitude weight centre significantly to a deeper position (Yao et al., 2005). Given these findings, I re-referenced the data to channel TP7, the closest to the left mastoid that was recorded, to ascertain if the choice of reference could have impacted the findings. The results from the re-referenced data did not shift the direction of the amplitudes for conditions or significantly change the pattern of results. However, because I did not record from the mastoids, I cannot rule out the effect of referencing as a possible cause for the different pattern of activity between this and previous studies.   Another explanation is that this is the first study to use the irony comprehension task in English, which may affect the overall pattern of neural activity with respect to differentiating ironic from literal sentences. Previous studies using similar paradigms have been conducted in French (Spotorno et al., 2013), German (Regel et al., 2011), and Spanish (Cornejol et al., 2007). Irony comprehension in these studies followed a similar paradigm used in the current studies. The stimuli consisted of stories that described an everyday situation and an exchange between two characters. The context was composed of 3-5 sentences that introduced the two characters, the situation and described the development of the situation. The last word in the target sentence was critical for interpreting whether the response was ironic or literal. Ironic sentences contained  97 an opposite meaning of what could be literally expected as a reply in the context. In the French and Spanish version, the stories were presented visually. In the German version, the auditory and visual stimuli were investigated separately. Thus, in the three previous studies, both the stimulus presentation and the operationalization of the hypothetical construct of “irony” were the same as that depicted in the current studies. The German study also included an auditory version of the task. Idiosyncrasies in the different languages may account for the differences in findings. For example, in English, adjectives virtually always precede the nouns they modify, however, in French and Spanish, adjectives may be placed before or after the noun. This may affect the word order and account for a differential pattern of expectancies. Although German adjectives are like English, in that they usually precede the nouns, their endings depend on several factors including gender and case. This added level of complexity might provide additional clues to interpretation that are absent in English. Further studies using similar paradigms in English are needed to clarify this possible explanation.  The current study utilized a paradigm similar to previous studies that examined irony comprehension using electrophysiological measures (Regel et al., 2011; Spotorno et al., 2013). Participants were presented with the context of a story in 3-4 sentences followed by the target sentence presented one word at a time. As in this task, the final word in the sentence was critical for sentence interpretation. The ironic condition contained an opposite meaning to what would be expected as an adequate reply in the context. In contrast, the literal condition contained a response that corresponded well with the preceding context. Consistent with other studies, the participants in the current study showed excellent performance on the Irony Comprehension Task with a mean accuracy rate of 93.11%. Regel et al., (2011) and Spotorno et al., (2013) reported mean accuracy rate of 95.3% and 91.5%, respectively. Even though the language and  98 content of the task differed, convergence in mean accuracy rates across studies using very similar paradigms provides reasonable evidence that the current studies are measuring irony comprehension in a way that is consistent with the literature.   Another limitation to this study is that the Irony Comprehension Task was presented visually. Some may argue that the measure used in the current study does not reflect irony as it occurs in daily life because it does not incorporate other nuances associated with irony comprehension, such as prosody, which has been found to be impaired in schizophrenia (Michelas et al., 2014). Development of an irony comprehension task is fraught with challenges because irony is a nuanced social interaction that relies on inflections and voice modulations that are difficult to capture and re-create in the lab – especially in a visual EEG task. Given that the ironic stimuli used in the ICT were relatively novel, an appropriate ironic meaning may or may not have been interpreted as one. The cloze probability findings suggest that ironic endings were unexpected and thus incongruent with the preceding context developed by the sentence. Although the ICT may not capture all aspects of irony comprehension, it is likely that the more linguistic/contextual part of this construct was captured. At the very least one can conclude that the task reflects congruence or incongruence between the stem and final word. Verbal and multi-modal studies of irony comprehension may represent a more comprehensive and face-valid approach. Further investigation of this issue is necessary.   With regards to subclinical symptoms along the SZ spectrum, it was found that endorsement of more schizotypal traits was correlated with worse Hinting Task performance. Although the current study did not find an association between irony comprehension and SPQ scores, other studies (Del Goleto, Kostova, & Blanchet, 2016; Rapp et al., 2010) found a negative correlation between irony comprehension and SPQ scores. Rapp and colleagues (2010)  99 found a negative association between SPQ total score and brain activation during irony comprehension in the middle temporal gyrus. The middle temporal gyrus is a key region of language comprehension on a sentence level (Chow, Kaup, Raabe, & Greenlee, 2008; Rapp, Leube, Erb, Grodd, & Kircher, 2004), and Rapp and colleagues (2010) concluded that schizotypy was associated with dysfunction in key language processing regions of the brain rather than regions typically found in theory of mind processing such as the medial prefrontal or inferior parietal regions. Del Goleto and colleagues (2016) compared a low-SPQ group with a high SPQ-group and found significant N400 (i.e., literal statements elicited N400 amplitudes that were less negative compared to incompatible sentences) and P600 (i.e., ironic sentences elicited P600 amplitudes that were more positive than literal sentences) amplitude differences in the low SPQ group. Together, these studies suggest that schizotypy is associated with poorer understanding of hints and irony comprehension during highly verbal paradigms. These findings further strengthen previous assertions that schizotypal traits and schizophrenia exist on a continuum, and that both may be associated with deficits in social cognition.   The results of the first study helped to answer questions about language processing, particularly irony comprehension in patients with schizophrenia. Patients with schizophrenia were impaired on all measures of social cognition including the newly developed ICT. In addition, schizophrenia patients differed from healthy controls in their pattern of neural activity during irony comprehension. However, the unexpected finding from the electrophysiological data that ironic sentences had smaller N400 amplitudes than literal sentences in the healthy control group prompted us to undertake a second study to ensure that the direction of effect was reliable. The results of the second study failed to replicate the N400 findings from the first study  100 in 65 healthy undergraduate students. However, in study 2 it was found that the P600 effect was linked to irony comprehension.   I am unable to account for why ironic sentences generated smaller N400 amplitudes in these studies. However, the pattern of left lateralized N400 linked to irony comprehension suggests that understanding of irony occurs early in the language processing stream and reflects automaticity of language comprehension. Patients with schizophrenia were perhaps less efficient in this process, as evidenced by their relative lack of differentiation in neural activity and poorer behavioural performance. The late positivity finding in healthy undergraduates suggests that some participants recruited neural resources later in the processing of semantic information and irony comprehension, although this recruitment may not be necessary for accurate comprehension of irony. There were no changes in accuracy rate in irony comprehension as a result of the P600 activation as participants from both studies showed excellent performance in irony comprehension. This, and the N400 effect in study 1, may suggest that the neural processes underlying the generation of either the N400 or the P600 may alone be sufficient for irony comprehension. Further studies using a similar paradigm, administered in English, are warranted to assess the reliability of these results and to provide further information about the role of language processing in irony comprehension.    101 Chapter 3: Computerized Cognitive Remediation in Schizophrenia  Cognitive deficits in schizophrenia impact overall functioning and recovery (Fervaha et al., 2014; Palmer, Dawes, & Heaton, 2009), and appear resistant to pharmacologic interventions that are effective at reducing positive and negative psychotic symptoms (Bellack et al., 2004; Green, 2007; McGurk, Mueser, & Pascaris, 2005). Several studies have proposed intermediate variables that may provide steps linking cognition and functioning (Bowie, Reichenberg, Patterson, Heaton, & Harvey, 2006; Sergi et al., 2006) (see Figure 3.1). Furthermore, it has been suggested that cognitive deficits may underlie the social, occupational and everyday functional difficulties of patients with schizophrenia, leading to increased use of health care services and a limited presence in the workforce (Green et al., 2004; Kurtz, Wexler, Fujimoto, Shagan, & Seltzer, 2008). To address these deficits, a number of cognitive remediation therapies have been developed. Cognitive remediation broadly refers to interventions that target cognitive deficits and that aim to generalize improvements in functional outcomes. These therapies can be conceptualized as having two distinct foci: higher level cognitive training that targets cognitive domains such as memory, attention, and executive functioning, or neuroplasticity-based interventions that use repetitive training in basic perceptual skills to improve higher order cognitive functions (Reddy, Horan, Jahshan, & Green, 2014). Neuroplasticity-based approaches are based on the premise that training in basic perceptual and lower-level cognitive domains facilitates synaptogenesis, which leads to changes in higher-order cognitive functions (Genevsky, Garrett, Alexander, & Vinogradov, 2010). Both training programs can be administered as a stand-alone treatment or with an adjunctive psychosocial component.     102  Figure 3.1 Model of intermediate variables linking cognition and functional outcomes.        103 There is considerable heterogeneity regarding the extent of cognitive improvements that can be expected from cognitive remediation. The first review of cognitive remediation found no benefits to attention, verbal memory, visual memory, planning, cognitive flexibility or mental state and the authors concluded that cognitive remediation does not appear to confer reliable benefits for patients with schizophrenia and could not be recommended for clinical practice (Pilling et al., 2002). Recent reviews have been more favourable towards cognitive remediation. For example, McGurk, Twamley, Sitzer, McHugo, and Mueser (2007) found that cognitive remediation not only improved performance on cognitive functioning but also improved psychosocial functioning and symptoms. The effects of cognitive remediation on psychosocial functioning were significantly stronger in studies that provided adjunctive psychiatric rehabilitation along with cognitive remediation. Similarly, Wykes, Huddy, Cellard, McGurk, and Czobor, (2011) also found cognitive remediation to be more effective when combined with other psychiatric rehabilitation. The Psychiatric Rehabilitation Association defines psychiatric rehabilitation as an intervention that:  promotes recovery, full community integration, and improved quality of life for persons  who have been diagnosed with any mental health condition that seriously impairs their  ability to lead meaningful lives. Psychiatric rehabilitation services are collaborative,  person directed, and individualized. They focus on helping individuals develop skills and  access resources needed to increase their capacity to be successful and satisfied in the  living, working, learning, and social environments of their choice. (Anthony & Fark,  2009, p. 9)  In addition, Wykes and colleagues (2011) found that cognitive remediation showed a moderate improvement in overall cognitive performance, and that this effect was maintained at  104 follow-up. Moreover, there was a significant small-to-medium effect on functional outcomes at post treatment and follow-up. Some of the variability in the literature is related to methodological issues such as sample sizes, rigor, characteristics of the training program utilized, and duration of treatment. Overall, cognitive remediation in schizophrenia yields small-to-medium, durable, effect sizes across multiple neurocognitive and social-cognitive domains (Grynszpan et al., 2011; McGurk, et al., 2007; Wykes et al., 2011). The empirical support for cognitive remediation is encouraging and generally positive, depending on the outcome of interest.  In addition to neuropsychological improvements, neural changes using several neuroimaging methods have been reported in response to computerized cognitive remediation (CCR) (Thorsen, Johansson, & Loberg, 2014). For example, CCR resulted in improvements in biological markers of cognition, such as brain-derived neurotrophic factor (BDNF) (Vinogradov et al., 2009), increased efficiency of early auditory processing (Adcock et al., 2009), and normalized sensory gating (Popov et al., 2011). One study, however, failed to find improvements in cognitive and electrophysiological (P300 and Auditory Steady State Response) outcome measures (Rass et al., 2012). Fewer studies have reported on structural brain changes; one study reported increased gray matter volume as a result of CCR and enriched supportive therapy after 2 years (Eack et al., 2010). Using a spatial meta-analytic approach known as activation likelihood estimation (ALE), Ramsay and Macdonald, (2015) found cognitive remediation generally increased neural activation in areas of the lateral and medial prefrontal cortex, parietal cortex, the insula, and the caudate and thalamus. Despite the heterogeneity in treatment approaches, it is encouraging that CRT influences brain regions known to support working memory, cognitive control, and emotional functioning.   105 Another area in which cognitive remediation has demonstrated effectiveness is improving competitive employment outcomes (McGurk et al., 2005). Unemployment rates among those with serious mental illness are high, generally estimated to be 70-90%, even though most people want to work (Westcott, Waghorn, McLean, Statham, & Mowry, 2015). Among those who fail to find employment, cognitive dysfunction is often a significant challenge (Green et al., 2004; Kurtz et al., 2008; McGurk & Mueser, 2004). When compared with employment interventions alone, programs that incorporate cognitive remediation have shown a variety of vocational benefits, (e.g. more likely to work, held more jobs, worked more weeks, and earned more in wages) that are maintained even at 3-year follow-up (M. D. Bell, Bryson, Greig, Fiszdon, & Wexler, 2005; Kurtz & Nichols, 2007; McGurk, Twamley, et al., 2007). When supportive employment program was augmented with cognitive remediation, employment rate for low-functioning patients with schizophrenia increased from 20% to 49% over 2 years (M. D. Bell et al., 2014). The addition of CRT to IPS non-responders improved employment outcome with a number needed-to-treat (NNT) of 4 over a 2 year period (McGurk et al., 2015). The Cognitive Remediation Experts Workshop included social cognition as one of the cognitive processes that cognitive remediation aims to target. Since social cognitive processes are a unique area of functioning that may rely on neurocognition (e.g., attention), cognitive remediation has the potential to improve social cognition through improved neurocognition. A meta-analysis of social cognitive training for schizophrenia found moderate-to-large effects on emotion recognition, small to moderate effect on ToM, but no effect on social perception or attribution bias (Kurtz & Richardson, 2012). While social cognitive training is a distinct type of psychosocial intervention, it shares elements with social skills training and cognitive remediation. Social cognitive treatments focuses on remediating impairments or deficits in how  106 social information is processed (e.g., how other people’s mood states or thoughts are perceived) while neurocognitive remediation focus on nonsocial cognitive domains such as attention, memory, and problem solving (Fiszdon & Reddy, 2012). Recent trends in cognitive remediation research include delineation of techniques that enhance transfer of cognitive skills to functional skills, and integrating cognitive remediation with skills training to promote generalization (Sapperstein & Kurtz, 2013). A recent pilot study by Lindenmayer et al., (2013) found that cognitive remediation with emotion perception training resulted in greater improvements in emotion recognition and social functioning. Within social cognition, irony comprehension is an important skill that directly affects patients’ community functioning (Couture et al., 2006), yet to my knowledge, no previous studies have examined the effect of cognitive remediation on irony comprehension. Thus far, the domains of social cognition that have received the most attention are facial affect recognition and ToM that did not include irony comprehension (Kurtz & Richardson, 2012).  As the evidence for the efficacy of cognitive remediation accumulates, translational research examining the effectiveness of implementing CCR in the larger clinical community is needed. Efficacy studies of CCR attempt to maximize internal validity by using restrictive inclusion and exclusion criteria to create homogeneous samples (Nathan, Stuart, & Dolan, 2000). In contrast, I examined the effectiveness of CCR with particular emphasis on acceptability and compliance to determine the generalizability of CCR gains within a local vocational rehabilitation program for youths and adults who have a mental health disability, and also in an early psychosis clinic. A multi-dimensional outcome assessment, which included neuropsychological evaluation and event related potentials to measure functional and cognitive  107 outcomes was conducted. In particular I focused on two aspects of social cognition - irony comprehension and ToM - to examine the generalizability of CCR to improving social cognition.   3.1 Objectives  The main objective of the pilot study was to assess the feasibility of implementing a cognitive remediation program in an outpatient vocational rehabilitation setting for youths and adults who have either a mental health disability or who are in an early psychosis intervention clinic. The secondary objective of the study was to examine cognitive effects as a result of cognitive remediation. In addition, the study will examine whether neurocognitive training impacts distal outcome measures such as social cognition, and in particular, a novel measure of irony comprehension. Furthermore, the effectiveness of cognitive remediation was examined to determine whether it warranted larger scale implementation.  3.2 Outcomes  The three main outcomes of the pilot study were feasibility, effectiveness, and electrophysiological assessments. The feasibility outcomes were: retention of participants in the study, number of sessions completed during the course of the study, and completion rate of primary outcome measures. The effectiveness outcomes were: neurocognitive and social cognitive measures. Electrophysiological assessment included the P300 elicited during an auditory oddball paradigm, and the N400 and P600 elicited during a verbal irony comprehension task. The P300 was included to examine modality specific effects of auditory training. The ERP analysis will examine mid-line sites as it has maximal activation.  108 3.3 Methods 3.3.1 Participants  The outpatient sample was recruited from the Early Psychosis Intervention program of Vancouver, BC, and also from Gastown Vocational Services in Vancouver, BC. Inclusion criteria for all participants were: 1) axis-I diagnosis of schizophrenia, or schizoaffective disorder obtained from the Structured Clinical Interview for DSM-IV (SCID-I; First et al., 1997) and chart review; 2) age between 18-55 years; 3) no history of neurological illness; 4) no loss of consciousness for > 5 minutes; 5) no current alcohol or drug dependence; 6) visual acuity of 20/30 or better (with correction). Informed consent was obtained for all participants. The protocol was approved by the Behavioural Research Ethics Board (BREB) of the University of British Columbia and Vancouver Coast Health Research Institute (VCHRI) ethics review board.  3.3.2 Materials  Clinical and Cognitive Assessment  The MATRICS Consensus Cognitive Battery (MCCB) consists of ten tests yielding seven cognitive domains and an overall composite score was used to assess neurocognitive functioning.   The Hinting Task (Corcoran et al., 1995) consists of ten short vignettes about the interactions of two characters, with one character dropping a hint to the other character. The participant must identify the meaning of the hint on the first try for two points, or after an additional hint for one point. The Hinting Task is scored out of 20 total points.     The Irony Comprehension Task consists of 100 vignettes ranging in length from three to five sentences, followed by a target sentence. The vignettes were neither imaginative nor highly fictional. They involved interactions between two characters in everyday life situations. The  109 vignettes were written to be largely unambiguous so that only one interpretation of the situation would be made. In the ironic discourse, the target sentence contained a response that is opposite in meaning to that which would be expected in the context. In the literal discourse, the target sentence corresponded with the preceding context. The final word in the target sentence determined whether the meaning of the discourse was ironic or literal.  Schizophrenia symptoms were assessed using the Positive and Negative Syndrome Scale (Kay et al., 1987). This instrument includes 30 items evaluating psychiatric symptoms. Items are rated on a scale from 1 (absent) to 7 (extreme).   Electrophysiological Assessment   The EEG was recorded from 32 electrode sites using Brain Vision QuickAmps. Data were captured at 1000 Hz using a common average reference and all impedances were kept below 10 kΩ. Eye blink activity was recorded using bipolar electrodes placed above and below the left eye and on each temple for offline eye-blink correction (Gratton et al., 1983). Epochs with voltage exceeding ± 100 V at any site were automatically excluded from further analyses. Only trials in which participants provided a correct response were analyzed further.   Data for ERP analysis were filtered using a .01-30 Hz (12 dB/octave) Butterworth zero phase filters except for the vertical and horizontal EOG channels, which were filtered using a .5-1 Hz (12 dB/octave) filter. Data were segmented with a 200 msec baseline and a 1000 msec epoch from the onset of the critical word.   The N400 component was quantified as the mean activity (μV) within the 300-500 msec window and the P600 component as the mean activity within the 500-800 msec window (Herten et al., 2005; Osterhout & Holcomb, 1992). The N400 and P600 were analyzed using repeated-measures analyses of variance to assess the effects of conditions (ironic and literal), regions of  110 interest (frontal, central, parietal and occipitals) and laterality (left, central, and right). Latency analysis was carried out using automatic peak detection of the largest negative value within the N400 window and the largest positive value within the P600 window. The N400 is an evoked potential elicited during language processing and is thought to reflect semantic processing. SZ typically show prolonged N400 latency and a smaller N400 effect. The P600 event-related potential is elicited by syntactic as well as semantic anomalies and is thought to reflect the integration of information into a coherent sentence representation. P600 amplitude is also typically reduced in SZ (Dima, Dillo, Bonnemann, Emrich, & Dietrich, 2011).    The P300 ERPs were elicited by 86 dB SPL tone-pips presented binaurally for 50 ms with a random interstimulus interval between 1000-3000 ms. Participants were presented with 75 high-pitched tones (1500 Hz) randomly interspersed among 425 distractor tones (1000 Hz). The quantification of the P300 ERPs only examined responses to high-pitched tones. The P300 amplitude is typically reduced in SZ (Jeon & Polich, 2003; Mathalon, Ford, & Pfefferbaum, 2000; McCarley et al., 1993).  3.3.3 Interventions  Participants in the computerized cognitive remediation (CCR) group received the Posit Science Brain Fitness auditory training program. The program is commercially available and consists of six exercises that focus on auditory processing, processing speed, and verbal memory in an adaptive design. The program corresponds to the restorative model of cognitive remediation in that it focuses on strengthening neural networks at the sensory level, and on gradually building upon these foundations in successively more complex tasks (Medalia & Bellucci, 2012). It was hypothesized that EEG results may be sensitive to cognitive remediation protocols that focus on changing cognition by strengthening neural networks at the sensory level.   111  Participants completed 1-hour training session twice a week for 12 weeks for a total of 24 hours of training. The number of training hours varies widely in the literature, ranging from 20 hours to 100 hours (Fisher et al., 2009; Kurtz, Seltzer, Shagan, Thime, & Wexler, 2007; Lindenmayer et al., 2008). I based the training program after Keefe et al., (2012) who found improved cognitive functioning after approximately 12 weeks of training and approximately 20 sessions. However, those improvements were not statistically significant after 40 sessions. Likewise, Lindenmayer et al., (2008) and McGurk, Mueser, Feldman, Wolfe, & Pascaris, (2007) found significant improvements in overall cognitive functioning after approximately 24 sessions.   In addition to the CCR training, participants in the treatment group attended a 2-hour group meeting led by an occupational therapist once a week wherein they discussed their CCR progress, learned about different cognitive domains and developed ways to generalize their CCR gains. Participants self-selected whether they would like to participate in the treatment group or be in the wait-list control group. Participants in the waitlist control group received treatment as usual and were given the option of CCR upon completion of the study. Random assignment was not used in the study because there was strong interest in treatment from participants in the outpatient vocational rehabilitation setting.   The pre- and post-assessments were completed within 2 weeks of starting and ending the intervention. For each of the pre- and post-assessments participants received $10/hr to help compensate for effort and transportation costs. Participants were not paid for participation in the CCR group but received limited reimbursement for transportation costs.   3.3.4 Data Analysis   The data were analyzed using repeated measures ANOVA with time as a within-subjects factor and group as a between-subjects factor. Mauchly’s Test of Sphericity was used to test the  112 assumption of sphericity. A Greenhouse-Geisser correction was applied when sphericity was violated. 3.4 Results  Overall, a total of 29 participants were enrolled in the study and 21 participants were included in the analysis (11: Treatment; 10: Wait List Control). Demographic and clinical characteristics are described in Table 3.1 and participant flow is reported in Figure 3.2. Participants in both groups did not differ in age or education level at baseline. All participants in the treatment condition and eight in the wait list control condition were prescribed atypical antipsychotic medication. There were no differences in CPZ equivalents between the groups. CPZ equivalents were not correlated with reaction time data, social cognitive outcome measures or ERP measures (all p’s > 0.05). The two treatment groups did not differ at baseline on clinical, neurocognitive, or social cognitive outcome measures (all p’s > 0.05).       113 Table 3.1  Descriptive Statistics at Baseline for Study 3 Variable Treatment (n=11) Wait List Control (n=10) Male (n) Medication Status   Atypical Antipsychotic   Typical Antipsychotic  Ethnicity   Asian   Caucasian   Hispanic   Black   Other 4  11 0  7 4 0 0 0 7  8 2  3 4 1 1 1  Mean (SD) Mean (SD) Age 29.82 (8.76) 30.60 (5.80) Education (yrs) 13.20 (1.23) 12.44 (2.55) CPZ Equivalents 204.04 (186.87) 232.14 (105.33) PANSS Positive 10.73 (3.52) 13.70 (4.45) PANSS Negative  13.36 (4.57) 11.20 (5.61) PANSS General  27.00 (8.54) 25.60 (5.97)   Note. CPZ = Chlorpromazine; PANSS = Positive and Negative Syndrome Scale.        114  Figure 3.2 Consolidated Standards of Reporting Trials (CONSORT) chart    115  Overall, the rate of attrition was moderate with 3 participants lost to follow-up, 2 hospitalized, 1 refused follow-up assessment, and 1 participant discontinued due to newfound employment. Those that were in the treatment group had a high rate of session completion; 10/14 completed 100% of their sessions. The overall percentage of sessions completed was 93%.   Outcome measures are reported in Table 3.2. There were no Group x Time interactions on the primary outcome measures (MCCB, Hinting Task, Irony Comprehension Task) or symptom measures to suggest a differential effect of treatment (all p’s > 0.05). Participants showed neurocognitive deficits across all domains of the MCCB with the composite score falling between 1 and 2 standard deviations below the normative mean for the MCCB. Speed of processing (BACS: Symbol Coding, Category Fluency: Animal Naming. Trail Making Test: Part A) and attention/vigilance (CPT-IP) were the domains that showed the most impairments, while working memory (WMS-III: Spatial Span and Letter-Number Span) showed the least impairment. Both the treatment and control groups performed well on social cognitive measures at baseline (Irony Comprehension = 87%; Hinting Task = 75%) and at follow-up (Irony Comprehension = 90%; Hinting Task = 79%). Repeated measures ANOVA with time, electrode sites, and condition as a within subjects factor factor and treatment group as a between subjects factor revealed no interactions or main effects for the P300, the N400 or the P600 (all p’s > 0.05). The P300 ERPs for the auditory oddball task at parietal sites for the treatment and wait list control group are reported in Figure 3.3. The ERPs for the Irony Comprehension Task for participants in the treatment and wait list control groups are reported in  Figure 3.4 and Figure 3.5 respectively.    116 Table 3.2 Cognitive and Clinical Measures at Baseline and Post Treatment for Study 3   Treatment Wait List Control    Baseline After Training  Baseline After Training Cognitive Domains   T-Score (SD)  T-Score (SD) T-Score (SD)  T-Score (SD) TMT 38.90 (11.51) 38.80 (9.95) 40.00 (7.76) 41.44 (9.90) BACS 33.60 (9.95) 35.30 (11.66) 37.00 (14.75) 32.33 (11.83) HVLTR 40.40 (14.82) 43.70 (12.95) 44.78 (9.23) 43.89 (9.19) WMS-III 43.30 (15.23) 41.90 (10.62) 44 (7.83) 51.56 (7.09) LNS 45.60 (11.25) 45.00 (18.26) 41.44 (11.90) 42.89 (9.32) NAB 42.40 (8.99) 46.30 (8.93) 39.67 (7.45) 41.89 (7.17)  BVMT-R 34 (16.90) 40.70 (13.51) 43.11 (8.02) 47.78 (11.03) FLUENCY 40.60 (8.41) 43.40 (7.41) 42.67 (10.49) 39.11 (11.91) MSCEIT 40.80 (8.15) 36.20 (11.92) 41.78 (13.02) 38.22 (13.64) CPT 40.10 (9.36) 41.20 (7.07) 35.44 (8.90) 32.00 (6.89) MCCB Composite 32.50 (14.98) 35.20 (16.63) 34.44 (10.75) 34.78 (10.22)  Hinting Mean (SD) 14.30 (3.71) Mean (SD) 15.80 (3.99) Mean (SD) 16.10 (2.69) Mean (SD) 15.90 (3.48) Irony Comprehension 87.20 (14.10) 90.80 (6.60) 87.00 (9.94) 89.10 (7.36) Clinical Domains  PANSS Positive 10.73 (3.52) 11.18 (4.77) 13.70 (4.45) 14.30 (5.66) PANSS Negative 13.36 (4.57) 12.64 (4.52) 11.20 (5.61) 12.40 (6.31) PANSS General 27.00 (8.54) 27.55 (6.23) 25.60 (5.97) 26.20 (7.47) Note. TMT = Trail Making Test: Part A; BACS = Brief Assessment of Cognition in Schizophrenia: Symbol Coding; HVLTR = Hopkins Verbal Learning Test-Revised; WMS-III = Wechsler Memory Scale: Spatial Span; LNS = Wechsler Memory Scale: Letter-Number Span; NAB = Neuropsychological Assessment Battery: Mazes; BVMT-R = Brief Visuospatial Memory Test-Revised; Fluency = Category Fluency: Animal; MSCEIT = Mayer-Salovey-Caruso Emotional Intelligence Test: Managing Emotions; CPT = Continuous Performance Test: Identical Pairs. T-Score standardizations of the MCCB was based on a sample of 176 schizophrenia and schizoaffective outpatients and 300 community residents in the U.S.   117  Treatment (n=11)        Treatment (n=11)     Time   Wait List Control (n=10)     Time Figure 3.3 P300 for the auditory oddball task in study 3.    118          Figure 3.4 ERPs of the ICT for participants in the treatment group in study 3.  119                               Figure 3.5 ERPs of the ICT for participants in the wait list control group in study 3.   120 3.5 Discussion  The need for effective treatment that targets cognitive functioning to improve the quality of life for individuals with schizophrenia is as important as reduction in symptoms. Equally important is the remediation of social cognitive deficits to improve interpersonal relationships and community functioning. Social cognition is strongly associated with social functioning and plays an important role in social and community integration, work life, and interpersonal relationships (Couture et al., 2006). The current pilot study examined the effectiveness of CCR in improving neurocognition as well as its ability to generalize to social cognition. The program employed a neuroplasticity-based intervention and a cognitive adaptive training procedure, which have the potential to maximize improvements in functional outcome (Velligan et al., 2008).   It has been proposed that social cognition may serve as a mediating variable between neurocognition and community functioning (Schmidt, Mueller, & Roder, 2011). This implies that impairment in neurocognition may negatively impact social cognition and exert negative influence on functional outcomes. The intervention failed to improve neurocognition, and as a result no generalization to social cognition was observed. It may be the case that social cognition mediates the relationship between neurocognition and functional outcomes; however, the null results do not allow us to make conclusive statements regarding this relationship.   Potential reasons for the null results in the study include: age of participants, lack of statistical power, and choice of training module. First, the mean age of subjects in studies which showed positive results ranged from 37 (Keefe et al., 2012) to 43 (Vinogradov et al., 2009). The mean age of subjects in studies that showed negative results ranged from 19 (Piskulic et al., 2015) to 37-45 (Rass et al., 2012). While our sample was indeed younger than the studies that  121 showed positive results, the null finding by Rass et al., (2012) whose sample had comparable age to Keefe et al. (2012) and Vinogradov et al. (2009) suggests that age may not be the sole contributing factor. Second, the small sample size in the current study may not have produced sufficient power to detect the small-to-moderate effect sizes of training found in previous studies (Wykes et al., 2011). Third, it is possible that the choice of auditory training may have affected the results. However, several authors found positive effects of auditory training on cognitive functioning compared to control (Fisher et al., 2009; Keefe et al., 2012; Vinogradov et al., 2009). Related to choice of training module, our study used auditory training while our social cognitive tasks were mostly visual. To examine modality specific effects of auditory training, the oddball paradigm (an auditory task) and the P300 was included in the study. Participants in the auditory training program did not improve performance on the auditory oddball paradigm task, and performance did not generalize to the visual tasks.  A limitation to the current study is that participants self-selected to condition and were not randomized. Randomized controlled trial minimizes allocation and selection bias by assigning participants to the treatment or control groups using chance to determine assignment. One potential drawback to self-selection is that participants who selected the treatment condition may have more intrinsic motivation to complete the cognitive remediation. This potential difference in motivation level may be problematic if our study had found improvement on cognition as a result of training. However, the lack of significant difference between the two groups, despite potential motivational differences, is unlikely to be a confounding variable in our null findings.   Overall, the attrition rates were low and the majority of participants completed all their training sessions. Participants were self-selected to the treatment group and had high levels of  122 motivation to complete training. In addition they provided positive feedback about the CCR and the group. However, cognitive and symptom variables did not show improvements with CCR. Several factors may have contributed to the null findings. First, the intensity of the training regimen may have been insufficient to detect an effect of CCR. However, the number of training session in this study (24) is consistent with other studies that found small improvements after 20 training sessions (Keefe et al., 2012). Other studies that utilized 40 training sessions found no improvements on cognitive or electrophysiological measures in SZ patients (Rass et al., 2012) or in patients with high risk of psychosis (Piskulic, Barbato, Liu, & Addington, 2015). Second, this was an effectiveness study and significant improvements in cognition may not have been detected due to small sample sizes. A similar study of computer-based training within a vocational rehabilitation program of comparable sample size found that visual training only improved visual memory impairment (Surti et al., 2011) and that it failed to generalize to all memory tasks. Likewise, training that focused on verbal strategy improved verbal working memory but not non-verbal working memory, visual learning, or speed of processing (D’Amato et al., 2011). Taken together, this and other studies question the treatment benefits and generalizability of CCR, in its current form, in schizophrenia. While I demonstrated both feasibility and tolerance of CCR combined with psychosocial rehabilitation in a community vocational rehabilitation setting, future studies are needed to identify and refine the essential elements of successful treatment using computerized neuroplasticity-based interventions.   123 Chapter 4: General Discussion  My dissertation focused on two lines of inquiry. First, what neural mechanisms are involved in social cognitive deficits in schizophrenia spectrum disorders? Second, what is the effectiveness of a computerized cognitive remediation program in targeting neurocognitive and social cognitive deficits in patients with schizophrenia? These questions were addressed in three studies.   In Chapter 2 I examined whether electroencephalography (EEG) is sensitive to the processing of irony, an important index of social cognition. In the first study, patients with schizophrenia spectrum disorders exhibited impaired social cognition, across the 3 domains of social cognition – irony comprehension (behavioural data from the ICT), understanding indirect speech (Hinting Task), and emotional intelligence (MSCEIT). Along with impaired performance on social cognitive tasks, patients with schizophrenia had overall slower reaction time compared to healthy controls on the ICT. There was also a marginal main effect of condition whereby the reaction time of all participants was longer to ironic statements compared to literal statements, although the interaction between group and condition was not significant.    All three measures of social cognition were moderately correlated, indicating that they measured similar/related constructs. However, only the Hinting Task, a measure of indirect speech, was inversely correlated with negative symptoms of schizophrenia. Neural correlates of irony comprehension, as indexed by the N400, showed hemispheric differences in the interpretation of ironic sentences in healthy controls but not in patients with schizophrenia. However the results of the N400 were in the opposite direction than was predicted. Similarly, there were no differences between P600 amplitude in response to literal and ironic statements, which was contrary to my hypothesis.   124  Given the paradoxical findings of study 1, I wanted to see if the findings could be replicated in a larger healthy sample. In addition to this objective, study 2 was also designed to examine the dimensionality of schizophrenia symptoms and investigate whether the relationship between symptoms of schizophrenia and performance on social cognitive tasks would also hold for those with subclinical traits along the schizophrenia spectrum. Similar to study 1, only Hinting Task performance was inversely correlated with schizotypal traits. Unlike in study 1, literal statements exhibited larger amplitudes than ironic statements in healthy controls for the P600 but not the N400. Findings from study 2 did not clarify the relationship between irony comprehension and its related neural markers. These two studies suggest that irony comprehension may be sensitive to how patients with schizophrenia interpreted irony compared to controls, however further research is needed to examine the direction and timing of these effects.   Difficulties in understanding irony are part of the social cognitive deficits characteristic of schizophrenia. Although a number of studies have reported difficulties in irony comprehension in patients with schizophrenia (Kosmidis, Aretouli, Bozikas, Giannakou, & Ioannidis, 2008; Mo et al., 2008) only two studies have examined the neural correlates of irony comprehension. In the first study, using fMRI, Rapp and colleagues (2013) showed that the posterior medial prefrontal and right temporal regions played a role in defective irony comprehension in female patients with schizophrenia. In addition, they found that SZ patients made more errors on a behavioural measure of irony comprehension than HC, which is consistent with the current finding. In the second study, Varga and colleagues (2013), found that patients with schizophrenia performed significantly worse in the irony comprehension task than healthy controls and the two groups had markedly different brain activation patterns, as  125 measured by fMRI. Interestingly, they found that the addition of a short linguistic help (additional information about the emotional state of the speaker) improved patient’s performance and the statistically significance group difference disappeared. An example of a response in the short linguistic help condition is: “Joe angrily remarks” or “Rose disappointedly remarks”. Notably, the linguistic help also resulted in no significant differences in the BOLD responses between schizophrenia patients and healthy control. The current study was the first to examine the neural correlates of irony comprehension in patients with schizophrenia using EEG. Collectively these results suggest that irony comprehension reflects a combination of two components: the N400, which indexes effortful semantic processing and the P600, which indexes a general context updating process.   The reaction time data from the ICT showed a trend in which all participants had longer reaction times to ironic statements compared to literal statements. This general trend in the data provides partial support for the Standard Pragmatic Model suggesting that the meaning of an ironic sentence must initially be evaluated and rejected, potentially resulting in longer processing time compared with a literal sentence. However, this reaction time finding was only at a trend level and until replicated with significant findings, must be interpreted with caution. Integration between the Standard Pragmatic Model and the majority of the literature regarding delayed reading rates in those with schizophrenia would suggest a differential deficit by patients with schizophrenia of longer reaction times to ironic statements. We found the delayed reading time in those with schizophrenia but did not find the expected the interaction therefore the overall slowed reaction time was not a function of differential processing of ironic compared to literal statements by schizophrenia patients.   126  The pattern of abnormalities of the N400 and P600 also provide partial support for the two neurobiological models put forth by Brouwer & Hoeks (2013) and Lau et al., (2008). These models suggest that the processing of irony consists of activating the lexical information associated with a word, which generates the N400. Then the retrieval of lexical representations based on the top-down information integrates this information with prior context into an updated representation of the intended meaning, which generates the P600. The healthy controls in study 1 showed differences in the activation of lexical information for ironic and literal sentences for the occipital and parietal sites in N400, which is consistent with the visual modality of the Irony Comprehension Task, although the pattern observed did not conform to my hypotheses. As processing of lexical information progresses, the information travels toward the frontal and central areas of the brain where top-down integration occurs with contextual information as reflected in significant differences at P600. In contrast, patients with schizophrenia did not show differences in the retrieval of lexical information related to irony (no N400 effect). Impairment in the retrieval of lexical information may underlie this poorer performance in patients with schizophrenia.   Among the three measures of social cognition used in these studies, the Hinting Task was the most sensitive to symptoms of schizophrenia. Hinting Task scores correlated with symptom measures of schizophrenia in study 1 and schizotypal personality traits in study 2. One possible explanation for this finding is task constraints; the Hinting Task relied heavily on verbal working memory which has been shown to be a core impairment in schizophrenia (Green, 1996; Silver, Feldman, Bilker, & Gur, 2003). In addition, the Hinting Task was difficult, as it required the participants to generate a response by understanding the perspective of the speaker whereas the Irony Comprehension Task and the MSCEIT were in a dichotomous and multiple choice format,  127 respectively, which only required recognition. The detection of irony has been found to be easier than justifying ironic responses in children with autism spectrum disorder such that they can correctly detect irony but have difficulty explaining ironic responses (Happé, 1993; Leekam & Prior, 1994). Another possible explanation may be that the Hinting Task is tapping into executive control processes responsible for effortful retrieval and verbal expression skills. Verbal fluency, which requires lexical access speed, updating, and inhibition ability are consistently impaired in schizophrenia (Henry & Crawford, 2005). Furthermore, ToM performance is associated with verbal fluency measures (Woodward et al., 2009). Overall, the robustness of the Hinting Task in these studies is consistent with the results and initial psychometric study of the Social Cognition Psychometric Evaluation (SCOPE) project which found that the Hinting Task showed the strongest psychometric properties across all evaluation criteria and is recommended for use in clinical trials (Pinkham, Penn, Green, & Harvey, 2016). The Hinting Task showed adequate test-retest reliability, small practice effects, limited floor/ceiling effects, and distinguished patient performance from controls (Pinkham et al., 2016). The strong psychometric properties of the Hinting Task combined with its robustness in the current studies provide further support for a growing consensus that the Hinting Task is a reliable and valid measure of ToM skills.   Collectively, the studies in the dissertation strengthen our understanding of the relationship between symptoms of schizophrenia and social cognition and lend preliminary empirical support for Frith’s neuropsychological model of schizophrenia. I found that patients with more severe negative symptoms had more impaired ToM, at least as measured by the Hinting Task. Furthermore, healthy undergraduate students with higher schizotypy traits had poorer understanding of ToM, as measured by the Hinting Task, but not the MSCEIT or ICT. Together these findings suggest that poor ToM abilities reflect an underlying trait and show  128 promise as a potential endophenotype for schizophrenia. The concept of endophenotype has been used to identify disease related processes that could mark the path between genotype and the behaviours of interest. However, further studies that examine ToM abilities in family members of patients with schizophrenia are needed to support the classification of ToM as an endophenotype.   Chapter 3 examined whether cognitive remediation impacted neurocognitive functioning, and whether improvements generalized to social cognition and emotional processing. I found that patients in the cognitive remediation group did not show improvements in neurocognition nor did cognitive training generalize to improvements in social cognition. Electrophysiological results were consistent with behavioural results and showed no significant neural changes as a result of cognitive remediation. These findings suggest that neuroplasticity-based interventions had limited effects on neurocognition.   The efficacy of computerized cognitive remediation has been demonstrated by several reviews (McGurk, et al., 2007; Wykes et al., 2011), however these studies display huge variation in sample characteristics and models of intervention, making it difficult to determine how to best implement this type of treatment. Cognitive remediation is promising, cost-effective and is valued by patients, but much more research is needed to determine the mechanisms of action (Wykes & Huddy, 2009). Understanding which treatment components successfully lead to which neurocognitive improvements, and which lead to none (as this one), would help us determine the most effective treatments that also incorporate individual differences, such as duration of illness and severity level.    129 4.1 Limitations  There are a number of caveats that need to be taken into consideration when interpreting the conclusions above. The limitations of the individual studies have been addressed in their corresponding chapters and I will outline general points of consideration relevant to the dissertation below.   The schizophrenia patients in study 1 were relatively young, stable, medicated, and predominantly male. Although the sample was relatively young, it was not exclusively a first episode sample. Thus, the findings may not be generalizable to older more chronic patients with schizophrenia. The sample characteristics in the studies were a reflection of sample recruitment, namely from the Vancouver Early Psychosis Intervention Program and Gastown Vocational Services. These clinics are focused on the identification of the early stages of psychosis and on targeting treatment to promote functional recovery. Therefore, the sample reflects real-world clinical settings from programs that aim to enhance treatment effectiveness and maximize chance of recovery. Longitudinal data suggest two separate periods of time when everyday functioning in schizophrenia patients appears to deteriorate. Patients with schizophrenia seem to deteriorate most around the first psychotic episode, and again at around 65 years of age (Harvey, 2014). This suggests that these two critical periods warrant aggressive intervention to ameliorate the cognitive decline. Study 3 focused on the first period of decline, treatment of older patients in the second period of decline was outside the scope of this study. However, one study has found that younger patients benefited more from cognitive remediation than an older cohort (Wykes et al., 2009).   The relatively young samples in these studies were reasonably high functioning. Therefore, ceiling effects may have contributed to some of the null findings in the treatment  130 study. This was especially true for measures of social cognition in which participants with schizophrenia were scoring in the top range (e.g., mean score on Irony Comprehension was 86%). This lack of variance may have minimized treatment effects, and thus results should be interpreted with caution. On the other hand, ceiling effects were less of an issue in terms of neurocognition as patients with schizophrenia consistently scored at least one standard deviation below the mean.    The relationship between intellectual functioning and social cognition was not investigated in the current study. There is an ongoing debate regarding the association between Theory of Mind and other aspects of cognition. Previous studies have found that IQ and verbal IQ did not explain the deficit of metaphor and irony comprehension (Mitchley et al., 1998; Mo et al., 2008). Similarly, impairment in ToM was found to be non dependent on IQ (Gavilán & García-Albea, 2011; Varga et al., 2013). However, Brune (2003) found that the ToM impairment in the schizophrenia group relative to control became non-significant when IQ was controlled for. Yet other researchers have suggested that ToM impairments in schizophrenia are specific and not a reflection of general cognitive deficits (Pickup & Frith, 2001). Unfortunately, the lack of information on general cognitive functioning in the current studies does not allow an elucidation on the association between social cognition and intellectual functioning. Future studies should include measures of intellectual functioning so that the relationship between social cognition and intellectual functioning can be assessed.  One factor that may influence lexical and semantic processing, and one that I did not examine in the studies, is thought disorder. Although we did not measure thought disorder formally, items on the PANSS such as “Unusual Thought Content” and “Conceptual Disorganization” suggest that the schizophrenia patient sample was relatively free of thought  131 disorder and only one patient had a rating of “moderate severe” on “Conceptual Disorganization”. The relationship between thought disorder and semantic priming studies in ERP is inconsistent. Many ERP priming studies (Mathalon et al., 2002; Mitchell et al., 1991; Nestor et al., 1997; Niznikiewicz et al., 1997) but not all (Spitzer, Braun, Hermle, & Maier, 1993) found no significant relationship between severity of thought disorder and N400 measures of priming. One possible reason for the difference may be ways in which thought disorder is measured (Holzman, Shenton, & Solovay, 1986). Thus, future studies should include a formal measure of thought disorder to fully assess the contribution of thought disorder to semantic processing.   The reliability of the assessments used in the study also needs to be taken into consideration. The test battery in study 3 included the MATRICS Consensus Cognitive Battery (MCCB), which is a standardized battery that has been recommended by the NIMH for use in assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. Overall, the MCCB has good test-retest reliabilities with an r value above 0.70 (Nuechterlein et al., 2008). The lack of good psychometric properties for the social cognitive measures have been noted by Yager and Ehmann, (2006) and demonstrated in a recent survey of experts in the Social Cognition Psychometric Evaluation (SCOPE) study (Pinkham et al., 2014). Similarly, the Irony Comprehension task was created in my lab and further research is required to determine its reliability and validity.  A final consideration is the sample size and power of these studies. A power analysis was calculated to determine the adequate number of participants required to power the first two studies. However, the third study was a pilot study, and thus a power analysis was not undertaken. With insufficient power, the possibility of committing a type II error is increased.  132 One of the main goals of the third study was to determine practicality and tolerability of treatment. More research is needed to determine the active ingredients of CCR and to identify the essential elements of successful treatment.  4.2 Future Directions  Several models of social cognitive training are available including: proof of concept, targeted treatments, and broad-based treatments (Horan, Kern, Green, & Penn, 2008). Proof of concept is single-session, laboratory-based treatment aimed at improving a specific social cognitive skill, such as emotion perception (Penn & Combs, 2000). Targeted treatments focus on specific domains of social cognition and require multiple sessions (Fiszdon & Reddy, 2012). Broad-based programs focus on multiple social cognitive processes in conjunction with cognitive remediation and/or skills training (Roder, Mueller, & Schmidt, 2011). The current study focused on the third model of broad based training in multiple domains in conjunction with cognitive remediation. There was no improvement in cognition, and therefore no gain to generalize from neurocognition to social cognition. Further research is needed to investigate whether targeted social cognition training such as proof of concept and targeted treatments may yield more promising results.   The cognitive remediation program used in this study represented a neuroplasticity-based intervention which was derived from basic research on neuroplasticity and showed demonstrable effects in fronto-temporal networks in patients with chronic schizophrenia (Adcock et al., 2009; Fisher et al., 2015, 2009; Vinogradov, Fisher, Holland, et al., 2009). A recent review of higher-level cognitive remediation for psychosis found improved neurocognition across domains, and these improvements generalized to work, social, and independent living skills (Reddy et al., 2014). Significantly fewer studies have examined neuroplasticity-based interventions. The ones  133 that did found that neuroplasticity-based interventions did not generalize across domains of cognition (Reddy et al., 2014). Future studies are needed to examine whether improvements in higher-level cognitive remediation can be measured physiologically via electroencephalography to understand the neural mechanisms involved. In addition, further research is required to examine minimally necessary and sufficient dosage, as well as frequency of treatment in neuroplasticity-based interventions.  4.3 Overall Summary and Conclusions  The results of this dissertation contribute to the understanding of social cognition - in particular, irony comprehension and ToM in schizophrenia-related disorders - in three ways. First, patients with schizophrenia processed ironic statements differently than did healthy controls, and this was reflected in behavioural measures and to a smaller degree, ERP measures. While it is generally known that patients with schizophrenia have difficulty with irony comprehension, the allocation of different cognitive resources during the on-line processing of irony is generally not well understood. The EEG study revealed that the understanding of irony is complex and effortful, showing hemispheric differences in the N400 component between schizophrenia patients and healthy controls, although not in the way hypothesized. In addition, the P600 effect was involved in the decoding of ironic statements in a larger sample of healthy controls, suggesting that irony comprehension reflects both semantic integration processes and a general updating or reanalysis processes. Differences in N400 and P600 amplitude between ironic and literal statements were not reliably evoked in the studies, and it is not clear why irony comprehension is associated with the N400 in some and the P600 in others. Second, symptoms of schizophrenia were correlated with social cognition such that patients with more severe negative symptoms performed worse on ToM tasks, as measured by the Hinting Task. This is  134 consistent with other studies showing more severe social cognitive deficits in those with predominately negative symptoms (Fett & Maat, 2013; Sergi et al., 2007). Third, computerized cognitive remediation revealed no improvement in neurocognition and there was no generalization to social cognition. In order to ameliorate the negative impact of social cognition on symptoms and functional outcome, future studies need to address whether targeted social cognitive treatments can yield improvements across social cognitive domains, or whether they generalize to social functioning. Overall the studies I have presented provide a first step toward understanding the link between behavioural and neural correlates of social cognition, as reflected in irony comprehension and its relationship with schizophrenia related disorders.     135 References Abu-Akel, A. (1999). Impaired theory of mind in schizophrenia. 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Cognitive Neuropsychiatry, 16(1), 71–91. http://doi.org/10.1080/13546805.2010.492693     185 Appendices  Appendix A  : Item samples from the Hinting Task      186  Appendix B  : Item samples from the MSCEIT        187 Appendix C  : Item samples from the Schizotypal Personality Questionnaire (SPQ)     188 Appendix D  : Positive and Negative Syndrome Scale (PANSS)  PANSS Item  Positive  P1 Delusions P2 Conceptual disorganization P3 Hallucinations P4 Hyperactivity P5 Grandiosity P6 Suspiciousness/persecution P7 Hostility  Negative N1 Blunted affect N2 Emotional withdrawal  N3 Poor rapport N4 Passive/apathetic social withdrawal N5 Difficulty in abstract thinking N6 Lack of spontaneity and flow of conversation  N7 Stereotyped thinking General Psychopathology Score  G1 Somatic concern G2 Anxiety G3 Guilt feelings G4 Tension  G5 Mannerisms and posturing G6 Depression G7 Motor retardation G8 Uncooperativeness G9 Unusual thought content G10 Disorientation G11 Poor attention G12 Lack of judgment and insight  G13 Disturbance of volition G14 Poor impulse control G15 Preoccupation G16 Active social avoidance       189 Appendix E  : EEG cap set up      190 Appendix F  : 32 channel standard EEG recording cap       191 Appendix G  : Items from the Irony Comprehension Task (ICT)   1. You have been working hard on your paper for English class. You ask your brother Tom to read it over and critique it. Your paper is very well written, and Tom says to you: “Your writing is excellent.”  2. You and Sam are good friends and are playing pool at your favorite bar. You miss an easy shot and Sam says: “You are playing terribly.”  3. Jordan, your best friend, drops in on your class to hear the presentation you’ve been working on. Your presentation goes well and the class was very interested in your topic. After, Jordan comments: “Your presentation was awful.”  4. You are really nervous before the final game of the basketball tournament. You play very well, making lots of baskets and practically winning the game for your team. After, your teammate Cameron says to you: “You played well.”  5. You have entered one of your paintings in a student art competition and place last in the competition. At an exhibition of all the entries, your good friend John comments on your painting: “Your painting is great.”  6. You and the rest of your band are excited about your first gig. Your brother Darrel is there to support you. The concert is horrible and nobody seems to like the music. After, Darrel says to you: “Your band sounds good.”  7. You and your best friend Robin are out for coffee and are discussing movies that you’ve seen. You start talking excitedly about a documentary you loved, but it was poorly done and all the critics trashed it. Robin agrees with the critics and says to you: “Your taste in movies is bad.”  8. You and Meredith have been in many of the same classes during your first three years at university. This term, you get to do a huge project together. You come up with a unique and creative way to present your project and Meredith says to you: “Your creativity is horrible.”   192 9. You have enrolled in a debate class with your friend Andy. At your first big debate, you get confused, mix up your words, and end up not knowing what to say. Andy says to you: “You debated poorly.”  10. You have just gotten your hair cut and styled at the salon. On your way home, it starts to rain. You have brought an umbrella, and when you arrive, your hair looks great. Your sister Erin says to you: “Your hair looks bad.”  11. You are at the flea market with your cousin Brian. You try on a hat and it makes your ears stick out. Brian says to you: “That hat looks great.”   12. You are taking a photography class with your friend Jim. For your class project, you decided to take pictures of a local courthouse. When you develop your pictures, the focus is perfect and they all look great. Jim says to you: “Your pictures turned out poorly.”  13. You are going to your Aunt’s dinner party and decide to bring her a gift. You pick out some lilies and head to the party. When you arrive, your aunt starts sneezing and you remember that she is allergic to lilies. Your cousin Christie says to you: “The flowers you picked are bad.”   14. You decide to wear a complicated costume to a Halloween party your best friend Emma is hosting. Your costume involves a lot of makeup and at the last minute it smears and looks awful. Emma says to you: “Your costume is great.”   15. You are at a wine store with your sister Ruth and decide to buy a red wine that you like to go with dinner. The wine clashes with the food and everyone gets sick from it. Ruth says to you: “The wine you picked is great.”   16. You decide to try salsa dancing with your good friend Emily. You have never really danced before but you end up doing great, nailing even the hardest moves after a little practice. Emily says to you: “Your dancing is great.”   17. You and Eric, your best friend since high school, decide to enter a tennis tournament together. You have been practicing for weeks and you play very well during the tournament, making it to the semi-finals. Eric says to you: “Your tennis skills are great.”   193 18. You have been trying to grow a bonsai tree for a couple of months. Currently the tree looks great, has a nice shape, and has a bunch of new leaves. Your friend Jodie says to you: “Your bonsai tree looks great.”   19. You have been working on a term paper all week. The day before it is due, you talk to your friend Kelly and realize that you need to reorganize everything. When you get it back, you have received an “A+”. Kelly says to you: “That paper must have been awful.”  20. You have been invited to a party by your co-worker Bob and are not sure how to dress. You decide to wear nice dress pants, a collared shirt, and a tailored jacket. When you arrive, everyone is dressed in the same type of clothes that you are wearing. Bob says to you: “You dressed poorly.”  21. You are going for a jog with your best friend Danny. After jogging for five kilometers, you decide to take a break to let Danny catch up. Danny says to you: “Your running is bad.”   22. You have planned a party at your favourite pub for your friend Jenna’s birthday. When you arrive at the pub they have your table ready, the band is playing, and you all have a great time. Jenna says to you: “This pub is bad.”   23. You and your best friend Tracey have been invited to a formal event. When you pick up your outfit from the store, the color is different than you had expected. It suits you better than the color you had ordered. Tracey says to you: “That colour makes you look bad.”   24. You have been redecorating your room. After you finish painting, you invite your friend Tania over to see what you have done. The paint starts to peel and the colors you used look awful with your furniture. Tania says to you: “Your room looks terrible.”   25. You and Alex, best friends since junior high, are shopping for clothes together. You try on a bright blue jacket and can see that it suits you very well. Alex says: “That looks awful.”   26. You have been out all weekend camping with your friends. On Sunday night, you get an awful night’s sleep and look very tired in the morning. Your roommate Anna says to you: “You look terrible.”   194 27. You are telling your friend Andrew about a new restaurant you love and you decide to meet there for lunch the next day. Andrew finds the food excellent and he compliments the restaurant. He says to you: “This restaurant is good.”  28. You are trying to install a new program on your friend Josh’s computer. You finish the installation successfully and find a way to free up more memory, speeding up his computer. Josh says to you: “Your computer skills are bad.”   29. You are sitting in class with your friend Thomas when the professor asks you a question. You do not know the answer and the professor is not impressed with your response. Thomas says to you: “Your answer was good.”   30. You are working on a term project with Meg, a girl you have been friends with for four years. You are in charge of making a poster for the project. The poster prints out perfectly and looks great. Meg says to you: “The poster looks bad.”   31. You have plans to go out with friends and decide to record a movie that is on TV while you are out. When you get home with your friend Allison, you find that the movie recorded perfectly and you both enjoy watching it. After the movie, Allison says to you: “That movie was terrible.”   32. You are working on an English project with your friend Tammy. You tell Tammy that you can memorize a 20-line poem in 5 minutes. You start to recite the poem but only recite a few lines before forgetting the rest. Tammy says to you: “Your memory is terrible.”   33. You have been asked to give a speech at a friend’s wedding. You spend a couple of hours working on your speech and it goes over very well at the wedding. Your friend Nathan says to you: “Your speech was bad.”   34. You have been asked to tutor your friend Carrie. You try your hardest and spend a lot of time on it but you have trouble explaining things and can’t seem to get anything across. In the end, Carrie gets a bad grade in the class. Carrie says to you: “Your teaching was good.”   35. You are working beside your friend Mark in statistics class. You are both having trouble getting your formulas to work. After a few minutes, Mark has figured out the answer, but  195 you are still working on it an hour later. Mark says to you: “Your statistics skills are good.”   36. You are at the pool with your friend Tim and decide to try a tricky dive. You step up to the edge and slip, doing a belly flop and splashing Tim in the process. Tim says to you: “That dive was great.”   37. Your friend Ian has convinced you to go to a karaoke bar. You get up to sing and don’t hit any of the notes, sounding awful. Ian says to you: “Your singing is great.”   38. You are studying for a math exam that is scheduled for tomorrow. You say to your sister Jill, “I’ll be glad when this midterm is over!” You receive 96% on your math exam, and Jill says to you: “Your math skills are terrible.”  39. You decide to try cooking a new recipe for your roommate Carl. You don’t have one of the ingredients, so you decide to improvise. The recipe turns out great and you both have seconds. Carl says to you: “That meal was good.”   40. You are getting ready for a first date and your friend Stacey is giving you tips. You come out wearing a red shirt that you think clashes terribly with the rest of your outfit. Stacey says to you: “You look terrible.”  41. You decided to throw a party and invited all of your friends. Everyone shows up and there is a lot of good food, good music, and good conversation. At the end of the party, your friend Kat says to you: “Your party was awful.”   42. You are playing chess with your friend Rob. You decide to try a risky move and end up backing him into a corner and winning the game. Rob says to you: “That move was great.”  43. You and Lindsey are best friends and roommates. Lindsey has to study for a final exam all weekend and needs quiet to study. You decide to invite a bunch of friends over to eat pizza and watch some movies. Lindsey says to you: “You are great.”   44. You and your partner are hosting a dinner party for your friends and colleagues. Your best friend Cynthia, who has barely touched her food, comes up to you and says: “The caterer you chose is good.”  196  45. You are asked to drive your friend Mary to the airport. Mary is worried that she might miss her flight so you drive very quickly, weaving wildly in traffic to make it on time. Mary says to you: “Your driving is bad.”  46. Your friend Jim has been sick for a week. You decide to cook Jim's favourite soup and deliver it to his house. When you give him the soup, Tim says to you: “You are nice.”   47. You are crossing the street with your friend Sarah. A car ran a red light and swerves at the last minute to avoid hitting you. Sarah says to you: “You are very lucky.”  48. You are late for a meeting and are scrambling to find a parking spot. The only spot available is the handicapped parking space. You decided to park there even though you don't have a handicapped sign. A passerby sees you doing this and says to you: “You are considerate.”  49. You take your father out to dinner at a fancy restaurant for Father's Day. After you ordered, you had to wait an hour before your meal was served. Your father tells you: “The service here is fantastic.”  50. You are waiting for the bus to arrive. When the bus finally pulls up to your stop 30 minutes late, the bus driver says to you: “The traffic is awful.”  51. You are going on vacation with your friend Todd. You are in charge of planning the travel schedule. Everything goes smoothly and you both have a great time. Todd says to you: “Your organization skills are awesome.”  52. You have been going to the gym every week for the last three months. You lost 30 lbs and are very happy with how you look. You run into your friend Anna who hasn't seen you since you lost your weight. Anna says to you: “You look superb.”  53. Your friend Jill is trying to fix a broken lamp and you offer to help her. You fixed the lamp and it works perfectly. Jill says to you: “Your handyman skills are poor.”  54. You are walking your dog when you run into your friend Bill. Your dog misbehaves and starts barking at Bill. Bill says to you: “Your dog training skills are awesome.”  197  55. You are asked to make a speech in front of your class. You are very nervous and you stutter throughout the speech. After your speech, your teacher tells you: “Your public speaking skills are great.”  56. Your friend Jane asks you to babysit while she runs an errand. When the baby wakes up from his nap, he starts crying very loudly, and nothing you try works to calm him down. When Jane returns to see her baby crying, she says to you: “Your babysitting skills are bad.”  57. You decided to join the school band. At the school concert, the band sounded wonderful and received a standing ovation. After the concert, your bandmate says to you: “Your playing was wonderful.”  58. You go to the library to borrow a book for a term paper, when you find out that you have $30 in overdue fees. The librarian says to you: “You are punctual.”  59. You are asked to substitute for an injured team-member in a baseball game. Everytime you are up to bat, you hit the ball out of the ballpark. After the game the coach says to you: “You played terribly.”  60. You forgot to wash the dishes last night after your mother reminded you to. Next morning she says to you: “Your memory is great.” 61. You are at the beach with your friend Kevin and you challenge him to a race. You lose to Kevin in the race and he says to you: “You are fast.”  62. You decide to try rollerblading and head to the park with your best friend Casey. You are doing pretty well when you start rolling down a hill towards a bunch of people. You lose control and end up running into two people and a tree before stopping. Casey says to you: “You are very skillful.”  63. Your brother James is coming for a visit and you agree to pick him up from the bus station. On the way, there is a ton of traffic and you hit all red lights. You make it there an hour after he does. James says to you: “You are always early.”  64. You are sitting on a bus with your best friend Lisa. The two of you are laughing and talking loudly. The person sitting next to you on the bus says: “You two are very quiet.”  198  65. You are sitting at the front of the bus. An elderly lady gets on the bus. You decide to stay in your seat instead of offering her your seat. The person sitting beside you says: “You are considerate.”  66. You are a guest at a wedding. You bought a very nice tuxedo for the occasion. Your date says to you: “You look fabulous.”  67. You decide to buy your mother a nice gift for her birthday. When she opens the gift she is very touched and says: “You are very thoughtful.”  68. A classmate of yours asks to borrow your notes because she missed the previous class. When you give her the notes she says: “You are generous.”  69. Your coworker has a family emergency and asks you to take his shift. Even though you are busy you agree to take his shift. Your coworker says to you: “You are helpful.”  70. A lady passing by you on the street drops her purse and its contents spill out. You help her pick everything up. The lady says to you: “You are helpful.”  71. At the local grocery store, you see an elderly lady struggling with her heavy shopping bags. You offer to help carry her bags to her car. She says to you: “You are kind.”  72. Your little brother Joey is assembling his bike. He is having trouble with the instructions. Although you are busy that day, you decide help Joey assemble his bike. Joey says to you: “You are selfish.”  73. You are sitting in the audience of a comedy club. The comedian makes offensive jokes, and you heckle him loudly. After the show, the comedian comes up and says to you: “You are very rude.”  74. You are strolling in a park with your friend Lea when you find a camera on a park bench. You put the camera in your pocket, intending to keep it. Later, a person approaches you and asks whether you have seen the camera he lost. You say no. After he leaves, Lea says: “You are honest.”   199 75. You are taking sunset pictures at the beach. The pictures turned out great and you decide to you show the pictures to your friend James. James says to you: “Your pictures are terrible.”  76. You are walking your dog in a park. Your dog is very sociable and likes to approach everybody. A passerby says to you: “Your dog is friendly.”  77. Your sister Mary is visiting your place, and notices that your pet goldfish is no longer in the fishbowl. You admit that it died when you forgot to change its water. Mary tells you: “You are horrid.”  78. You are in a mall when you spot a child looking lost. You help him find his parents. Afterwards, his parents say to you: “You are wonderful.”  79. You are watching a movie at the cinema with your friend Kate. You are not following the plot and keep asking Kate to clarify what is happening. The moviegoer sitting in front of you says: “You are annoying.”  80. You have neglected to mow your lawn for a month, and weeds are starting to sprout up all over the front yard. Your sister visits your place and says to you: “Your gardening skills are amazing.”  81. Your friend Cam invites you to a talk by his favourite author. The talk isn't particularly interesting, and you start dozing off in the middle. Cam nudges you and says: “You are attentive.”  82. You are going on a hike in the forest with your friend Nate. You have lots of energy and starts to walk faster. Nate who is tired says to you: “You are walking slowly.”  83. You are attending your friend Sandra's birthday party. You buy Sandra a watch that she wants but could not afford. Sandra says to you: “You are thoughtful.”  84. You are drinking wine at a dinner party hosted by your friend Elaine. You accidentally spill your drink all over the carpet, leaving an ugly stain. Elaine says to you: “You are clumsy.”   200 85. You are taking the Greyhound to go to the annual family reunion. You oversleep and miss your bus. You arrive 6 hours late to the reunion. Your brother says: “You are punctual.”  86. You are at an art gallery with your mother. You love the exhibit and praise every piece that you saw. Your mother says to you: “You are critical.”  87. You are at a zoo with your sister Sarah. Sarah wants to go see the spider exhibit. However you have a fear of spiders and tell Sarah you don't want to go. Sarah says to you: “You are a wimp.”  88. You have been working overtime often to finish up a big project. Your boss sees you at the office late at night, and says: “You are hardworking.”  89. You are working out at the gym. After you're done using a machine, you forget to wipe it for the next person to use. The person using it after you says: “You are inconsiderate.”  90. You are having lunch with your friend Ben. When you're done your meal, you throw your pop can into the garbage instead of recycling it. Ben says to you: “You are irresponsible.”  91. You and Michael are going on a trip. Michael is having money trouble and you offer to pay for his portion of the trip. Michael says to you: “You are generous.”  92. You forget to bring your lunch to work one day. You see your coworker's lunch in the fridge and decide to take it. He catches you in the act and says: “You are sneaky.”  93. You borrowed a pair of gloves from your friend Nick, and every time you meet him, you forget to bring the gloves along to return. After the sixth time, Nick says to you: “You are forgetful.”  94. You love chocolate chip cookies. At your office party, there is one chocolate chip cookie left. Although you really wanted the cookie, you offer it to your coworker. Your coworker says to you: “You are greedy.”   201 95. You are house-sitting for your friend Kay. Without asking Kay's permission, you hold a party at her place. She returns early from her trip, and finds her place a mess. Kay says to you: “You are disappointing.”  96. You are at your friend Jake's house. Jake has a big dog that barks and growls at everybody. Jake's dog bit you last time you were there but you decide to be nice and pet the dog. Jake says to you: “You are brave.”  97. You borrow your friend Ken's car for a date. You return the car with a full tank of gas. Ken says to you: “You are gracious.”  98. You are at a pharmacy filling a prescription for some cold medication. You have a runny nose, your eyes are red, and you feel terrible. The pharmacist says to you: “You look awesome.”  99. It is your first day at a new job and you are nervous. However, you work very hard and impress your boss and coworkers. At the end of the day your boss says to you: “You did excellent.”  100. You are at the hospital visiting your sick grandmother. You bring her a beautiful bouquet of her favourite flowers. Your grandmother says to you: “You are rude.”     202 Appendix H  : Sex differences analysis Table 4.1 One-Way ANOVA with Sex as the Dependent Variable in HC for Study 1   Male (n=10)  Female (n=15)   Variables M SD  M SD F p Irony Comprehension Task  90.50 11.19  93.73 7.14 .78 .39 Hinting Task 93.50 6.69  90.33 8.12 1.04 .32 MSCEIT Managing Emotion  93.75 3.41  96.43 8.08 .97 .34  Note. ANOVA = analysis of variance.     203 Table 4.2 One-Way ANOVA with Sex as the Dependent Variable in SZ for Study 1   Male (n=20)  Female (n=13)   Variables M SD  M SD F p Irony Comprehension Task  85.45 14.31  87.62 11.62 .21 .65 Hinting Task 72.75 18.60  77.69 18.10 .57 .46 MSCEIT Managing Emotion  85.45 11.88  89.91 10.09 1.25 .27 PANSS Positive 13.45 4.16  10.67 4.52 3.15 .09 PANSS Negative 13.70 4.76  12.0 4.92 .93 .34 PANSS General 27.65 7.34  27.18 10.85 .02 .89   Note. ANOVA = analysis of variance.    204 Table 4.3 One-Way ANOVA with Sex as the Dependent Variable for Study 2   Male (n=23)  Female (n=43)   Variables M SD  M SD F p Irony Comprehension Task  93.39 5.04  92.95 5.02 .11 .74 Hinting Task 90.22 11.23  88.84 9.25 .29 .59 MSCEIT Managing Emotion  101.10 16.73  98.00 10.83 .83 .37   Note. ANOVA = analysis of variance.  

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