PhD candidate, Monash University
Schizophrenia is a debilitating, chronic, psychiatric disorder that distorts the normal functioning of the brain and impedes the ability to function normally. Symptoms of schizophrenia usually begin in young adulthood and are broadly categorised into three groups; positive, negative and cognitive. Positive symptoms include delusions (i.e. a belief or conviction where content is untrue), hallucinations (i.e. a perceptual experience in the absence of external environmental stimuli) and disordered thoughts and speech. Negative symptoms are a reduction or loss of normal activity and include apathy (i.e. lack of interest or enthusiasm), anhedonia (i.e. inability to feel pleasure in normally enjoyable activities) and a lack of motivation or desire. Lastly, cognitive deficits are widely reported in patients with schizophrenia, and often include deficits in the areas of working memory, attention and inhibition.
It is believed that the personality characteristics and symptoms observed in schizophrenia lie on a continuum, referred to as schizotypy and observed in the general population. The continuum theory recognises schizotypy as a suitable model for investigating schizophrenia as it mirrors the symptoms in a more subtle manner.
My research focuses on the cognitive symptoms across the schizotypy/schizophrenia continuum. Cognitive symptoms respond poorly to current treatment and contribute to an employment rate approximately half of that of the general population. It is therefore important to gain a better understanding of the underlying mechanisms of these symptoms. My research aims to identify genetic pathways and mutations, looking specifically at the glutamatergic system, that influence cognition across the schizotypy/schizophrenia continuum, which will hopefully allow for more targeted treatment of cognitive symptoms in the future.
Abstract: Schizotypy is defined as a time-stable multidimensional personality trait consisting of positive, negative, and disorganized facets. Schizotypy is considered as a model system of psychosis, as there is considerable overlap between the 2 constructs. High schizotypy is associated with subtle but fairly widespread cognitive alterations, which include poorer performance in tasks measuring cognitive control. Similar but more pronounced impairments in cognitive control have been described extensively in psychosis. We here sought to provide a quantitative estimation of the effect size of impairments in schizotypy in the updating, shifting, and inhibition dimensions of cognitive control. We included studies of healthy adults from both general population and college samples, which used either categorical or correlative designs. Negative schizotypy was associated with significantly poorer performance on shifting (g = 0.32) and updating (g = 0.11). Positive schizotypy was associated with significantly poorer performance on shifting (g = 0.18). There were no significant associations between schizotypy and inhibition. The divergence in results for positive, negative, and disorganized schizotypy emphasizes the importance of examining relationships between cognition and the facets of schizotypy rather than using the overall score. Our findings also underline the importance of more detailed research to further understand and define this complex personality construct, which will also be of importance when applying schizotypy as a model system for psychosis.
Pub.: 20 Mar '18, Pinned: 11 May '18
Abstract: The personality characteristics and symptoms observed in schizophrenia are postulated to lie on a continuum, with non-clinical manifestations referred to as schizotypy. High schizotypy behaviours are argued to correspond with the three main clusters of symptoms in schizophrenia: positive, negative and cognitive/disorganised symptoms, yet there is limited empirical evidence to support this. This study aimed to investigate whether schizotypy dimensions significantly correlate with their respective schizophrenia symptomatology in the largest sample to date. A total of 361 adults (103 patients with schizophrenia/schizoaffective disorder and 258 healthy controls) were assessed for schizotypy using the Oxford-Liverpool Inventory of Feelings and Experiences. The MATRICS Consensus Cognitive Battery supplemented by the Stroop task and Wisconsin Card Sorting Test was administered to all participants to obtain objective measurements of cognition. Schizophrenia symptomatology was assessed using the Positive and Negative Syndrome Scale in patients only. The results demonstrated significant correlations between the Oxford-Liverpool Inventory of Feelings and Experiences positive and negative subscales and their respective Positive and Negative Syndrome Scale subscales only, indicating that positive and negative schizotypy dimensions across patients and controls accurately reflect the respective schizophrenia symptomatology observed in patients. Cognitive performance did not correlate with cognitive/disorganised symptom dimensions of the Oxford-Liverpool Inventory of Feelings and Experiences or the Positive and Negative Syndrome Scale, indicating that cognitive impairment is an independent symptom dimension that requires objective cognitive testing. Collectively, the findings provide empirical evidence for the continuum theory and support the use of schizotypy as a model for investigating schizophrenia.
Pub.: 01 May '18, Pinned: 11 May '18
Abstract: Historically, various lines of evidence have converged on the view that the brain expends much of its neural resources on inhibiting its own activity in a critical step towards the cognitive control of behaviour. The loss of inhibitory control is widely reported in neurological and psychiatric disorders; however, the consequences of reduced inhibition in terms of wider cognitive effects on cognitive control operations such as planning, abstract thought, working memory and the ability to appreciate the perspective of others ('theory of mind') has been widely overlooked. The antisaccade paradigm examines the conflict between a prepotent stimulus that produces a powerful urge to fixate the target, and the overriding goal to 'look' in the opposite direction. In this chapter we illustrate how this paradigm is increasingly used to explore the relationship of inhibitory control and cognition in Parkinson's disease, schizophrenia and healthy participants. Evidence is presented that is consistent with the theory of cognitive inhibition as a distinct process that can be dissociated from working memory. We conclude that the inhibitory control of saccadic eye movement should be studied in the wider context of cognitive operations.
Pub.: 02 Jan '03, Pinned: 26 Mar '18
Abstract: Several forms of eye movement dysfunction (EMD) are regarded as promising candidate endophenotypes of schizophrenia. Discrepancies in individual study results have led to inconsistent conclusions regarding particular aspects of EMD in relatives of schizophrenia patients. To quantitatively evaluate and compare the candidacy of smooth pursuit, saccade and fixation deficits in first-degree biological relatives, we conducted a set of meta-analytic investigations. Among 18 measures of EMD, memory-guided saccade accuracy and error rate, global smooth pursuit dysfunction, intrusive saccades during fixation, antisaccade error rate and smooth pursuit closed-loop gain emerged as best differentiating relatives from controls (standardized mean differences ranged from .46 to .66), with no significant differences among these measures. Anticipatory saccades, but no other smooth pursuit component measures were also increased in relatives. Visually-guided reflexive saccades were largely normal. Moderator analyses examining design characteristics revealed few variables affecting the magnitude of the meta-analytically observed effects. Moderate effect sizes of relatives v. controls in selective aspects of EMD supports their endophenotype potential. Future work should focus on facilitating endophenotype utility through attention to heterogeneity of EMD performance, relationships among forms of EMD, and application in molecular genetics studies.
Pub.: 22 Oct '08, Pinned: 26 Mar '18
Abstract: Poor performance on the antisaccade task has been proposed as a candidate endophenotype in schizophrenia. Caveats to this proposal, however, include inconsistent findings in first-degree relatives of individuals with schizophrenia, and substantial heterogeneity in individuals with the disorder. In this study, we examined antisaccade performance in patients and relatives, and sought to establish whether antisaccade measures could differentiate between two patients clusters identified in the Western Australian Family Study of Schizophrenia with either pervasive cognitive deficits (CD) or cognitively spared (CS). Ninety-three patients (CD=47, CS=46), 99 relatives and 62 healthy controls carried out a standard antisaccade task. Results showed: (i) significantly greater error rate, and prolonged latencies to correct responses and self-correction saccades in patients compared with controls; (ii) high error rates in relatives of poorly performing patients; (iii) longer latencies of self-correction saccades in relatives compared to controls; and (iv) higher error rate and longer latencies of self-correction saccades in the CD subgroup compared with CS. Unaffected relatives as a group were unimpaired in error rate as compared to healthy controls. These findings suggest that the antisaccade error rate and latency of self-correction saccades are useful measures in specific applications of genetic research in schizophrenia, without fully meeting endophenotype co-familiality requirements.
Pub.: 20 Sep '11, Pinned: 26 Mar '18
Abstract: Increased catechol-O-methyltransferase activity associated with variation in catechol-O-methyltransferase valine158 methionine genotypes may result in reduced dopamine neurotransmission in the prefrontal cortex and thus contribute to the poor performance of frontally mediated cognitive tasks and the occurrence of associated negative symptoms observed in patients with schizophrenia; however, reported associations between catechol-O-methyltransferase valine158 methionine genotypes and measures of cognition have not been consistent.Catechol-O-methyltransferase genotyping, measures of schizotypy, cognitive measures of memory and attention, as well as the antisaccade eye movement task, a measure sensitive to prefrontal cortical function, were obtained in a sample of 543 young men representative for that age group (mean age 21 years).None of the cognitive measures was associated with catechol-O-methyltransferase valine158 methionine genotypes; however, there was an effect of high-activity allele loading on schizotypy, in particular the negative and disorganization dimensions.Previously reported inconsistencies in the relationship between catechol-O-methyltransferase valine158 methionine genotypes and cognition were not resolved; however, catechol-O-methyltransferase genotype may affect expression of negative schizotypy by direct or indirect effects on central dopamine neurotransmitter signaling.
Pub.: 29 Sep '04, Pinned: 26 Mar '18
Abstract: Schizotypy is a range of perceptual experiences and personality features related to risk and familial predisposition to psychosis. Despite evidence that schizotypy is related to psychosis vulnerability, very little is known about the expression of schizotypal traits in individuals with a psychotic disorder, and their relationship to clinical symptoms, cognition, and psychosocial functioning.59 healthy subjects and 68 patients with a psychotic disorder (47 schizophrenia spectrum disorder; 21 bipolar disorder with psychotic features) completed four schizotypy scales, the Perceptual Aberration Scale, the Revised Physical and Social Anhedonia Scales, and the Schizotypal Personality Questionnaire, a brief neuropsychological assessment, and a self-report measure of quality of life. Clinical symptoms of psychosis were quantified in patients with the Positive and Negative Syndrome Scale (PANSS).Psychosis patients scored higher than healthy subjects on all schizotypy scales. Correlations between schizotypy and PANSS scores were modest, ranging from r=.06 to r=.43, indicating that less than 20% of the variance in self-reported schizotypy overlapped with clinical symptoms. After controlling for clinical symptoms, patients with schizophrenia spectrum disorders reported higher levels of cognitive-perceptual disturbances and negative traits than patients with bipolar disorder. Elevated schizotypy was associated with lower cognitive functioning and self-reported quality of life.Schizotypal personality traits are markedly elevated in psychotic disorders, especially schizophrenia spectrum disorders, relatively weakly correlated with positive and negative psychotic symptoms, and associated with greater cognitive impairment and lower quality of life. Assessing schizotypy in patients with psychosis may be useful for predicting functional outcome and differential diagnosis.
Pub.: 24 May '15, Pinned: 26 Mar '18
Abstract: Schizotypy is a term that refers to a continuum of personality characteristics, emerging from mental states ranging from organized and normal to unorganized and disordered; with the latter tending to include individuals with high schizotypal scores as well as those diagnosed with schizotypal personality disorder. Evidence from psychophysiological studies has found a relative weakness in the inhibitory functioning, including prepulse inhibition (PPI), sensory gating (SG), and antisaccade eye movement (AEM) in schizotypy and schizophrenia. As schizotypy and schizophrenia are in the same spectrum, understanding the nature of sensory and motor inhibitory weakness associated with schizotypy will optimize the prevention and intervention for both schizotypy and schizophrenia populations. This review aims at examining the deficits of sensory gating, saccade control, and prepulse inhibition in schizotypy; examining the relationship between the three measures and schizotypal symptoms and traits; examining the effect of nicotine on the three measures; and examining the relevant brain regions to the three measures. We searched multiple databases (such as MEDLINE, Pubmed, PsychINFO, Google Scholar) using combinations of the keywords: schizotypy, schizotypal personality disorder, prepulse inhibition, sensory gating and antisaccade for articles published in English since 1980. We found that three measures (SG, PPI and AEM) are associated with major schizotypal symptoms, suggesting that three measures could be used to predict the disease etiology and prognosis. Secondly, the three measures are modulated by nicotine administration at a certain level, providing a potential tool to study the role of nicotine in the cognition and symptom improvement in schizotypy. Thirdly, brain-imaging studies have localized activity in brain regions associated with sensory gating, saccade control, and prepulse inhibition, narrowing the search for brain regions to target for the treatment and prevention of schizotypy. Overall, the three measures are suggested to be a valuable tool to study the inhibitory deficits in schizotypy, and maybe used as a tool for the prevention and treatment of schizotypy as well.
Pub.: 13 Feb '17, Pinned: 26 Mar '18
Abstract: Cortical glutamatergic dysfunction is thought to be fundamental for psychosis development, and may lead to structural degeneration through excitotoxicity. Glutamate levels have been related to gray matter volume (GMV) alterations in people at ultra-high risk of psychosis, and we previously reported GMV changes in individuals with high schizotypy (HS), which refers to the expression of schizophrenia-like characteristics in healthy people. This study sought to examine whether GMV changes in HS subjects are related to glutamate levels.We selected 22 healthy subjects with HS and 23 healthy subjects with low schizotypy (LS) based on their rating on a self-report questionnaire for psychotic-like experiences. Glutamate levels were measured in the bilateral anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, and GMV was assessed using voxel-based morphometry.Subjects with HS showed GMV decreases in the rolandic operculum/superior temporal gyrus (p FWE = 0.045). Significant increases in GMV were also detected in HS, in the precuneus (p FWE = 0.043), thereby replicating our previous finding in a separate cohort, as well as in the ACC (p FWE = 0.041). While the HS and LS groups did not differ in ACC glutamate levels, in HS subjects ACC glutamate was negatively correlated with ACC GMV (p FWE = 0.026). Such association was absent in LS.Our study shows that GMV findings in schizotypy are related to glutamate levels, supporting the hypothesis that glutamatergic function may lead to structural changes associated with the expression of psychotic-like experiences.
Pub.: 05 Dec '17, Pinned: 26 Mar '18
Abstract: Schizotypal traits are expressions of underlying vulnerability to psychotic disorders which have a potential impact on mental health status, neurocognition, quality of life, and daily functioning. To date, little research has examined epidemiologic landscape of schizotypal traits at the cross-national level. Our aim was to study the expression of schizotypal traits by sex, age, and country in a combined sample gathered from 12 countries. A total of 27,001 participants completed the Schizotypal Personality Questionnaire (SPQ). The mean age of participants was 22.12 (SD=6.28); 37.5% (n=10,126) were males. Schizotypal traits varied according to sex, age, and country. Females scored higher than males in the positive dimension, whereas males scored higher in the disorganization dimension. By age, a significant decrease in the positive schizotypal traits was observed. Epidemiological expression of schizotypal traits varied by country. Moreover, several interactions by sex, age, and country were found. This pattern is similar to those found in patients with psychosis and psychotic-like experiences. These findings provide new insights and the opportunity to explore the phenotypic expression of schizotypal traits at cross-national level. Copyright © 2018. Published by Elsevier B.V.
Pub.: 24 Mar '18, Pinned: 26 Mar '18
Abstract: Cognitive performance in healthy persons varies widely between individuals. Sex differences in cognition are well reported, and there is an emerging body of evidence suggesting that the relationship between dopaminergic neurotransmission, implicated in many cognitive functions, is modulated by sex. Here, we examine the influence of sex and genetic variations along the dopaminergic pathway on aspects of cognitive control. A total of 415 healthy individuals, selected from an international consortium linked to Brain Research and Integrative Neuroscience Network (BRAINnet), were genotyped for two common and functional genetic variations of dopamine regulating genes: the catechol-O-methyltransferase [COMT] gene (rs4680) and the dopamine receptor D2 [DRD2] gene (rs6277). Cognitive measures were selected to explore sustained attention (using a continuous performance task), switching of attention (using a Trails B adaptation) and working memory (a visual computerised adaptation of digit span). While there were no main effects for genotype across any tasks, analyses revealed significant sex by genotype interactions for the capacity to switch attention. In relation to COMT, superior performance was noted in females with the Val/Val genotype and for DRD2, superior performance was seen for TT females and CC males. These findings highlight the importance of considering genetic variation in baseline dopamine levels in addition to sex, when considering the impact of dopamine on cognition in healthy populations. These findings also have important implications for the many neuropsychiatric disorders that implicate dopamine, cognitive changes and sex differences.
Pub.: 17 Dec '14, Pinned: 26 Mar '18
Abstract: Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia.We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated.The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected.The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.
Pub.: 06 Mar '07, Pinned: 26 Mar '18
Abstract: Recent work shows promising associations between schizophrenia and polymorphisms in neuregulin-1 (NRG1) and a large literature also finds strong familial relationships between schizophrenia and cognitive deficits. Given the role of NRG1 in glutamate regulation and glutamate's effect on cognition, we hypothesized that cognitive deficits may be related to variation within NRG1, providing a possible mechanism to increase risk for schizophrenia.This study examined the associations between NRG1, cognition, and schizophrenia using a multigenerational multiplex family sample (total N=419, 40 families), including 58 affected participants (schizophrenia or schizoaffective disorder-depressed type) and their 361 unaffected relatives. Participants were genotyped for 40 NRG1 single nucleotide polymorphisms (SNPs), chosen largely based on previous associations with schizophrenia. All participants completed structured diagnostic interviews and a computerized neurocognitive battery assessing eight cognitive domains. Variance component quantitative trait analyses tested for associations between individual NRG1 SNPs and cognitive performance in the total sample, a subsample of healthy participants with no Diagnostic and Statistical Manual of Mental Disorders diagnosis, and using general intelligence as a covariate.Effect sizes (within-family β coefficients) ranged from 0.08 to 0.73, and 61 of these associations were nominally significant (P≤0.05), with 12 associations at P≤0.01, although none achieved the modified Bonferroni significance threshold of P<0.0003. Attention was the most frequently nominally associated domain and rs10503929, a nonsynonymous SNP, was the most frequently nominally associated SNP.Although not significant experiment-wise, these findings suggest that further study of the associations between variation in NRG1 and cognition may be productive.
Pub.: 21 Dec '11, Pinned: 26 Mar '18
Abstract: The glutamatergic system is essential for learning and memory through its crucial role in neural development and synaptic plasticity. Genes associated with the glutamatergic system, including metabotropic glutamate receptor (mGluR or GRM) genes, have been implicated in the pathophysiology of schizophrenia. Few studies, however, have investigated a relationship between polymorphism of glutamate-related genes and cortical function in vivo in patients with schizophrenia. We thus explored an association between genetic variations in GRM3 and brain activation driven by a cognitive task in the prefrontal cortex in patients with schizophrenia.Thirty-one outpatients with schizophrenia and 48 healthy controls participated in this study. We measured four candidate single nucleotide polymorphisms (rs274622, rs2299225, rs1468412, and rs6465084) of GRM3, and activity in the prefrontal and temporal cortices during a category version of a verbal fluency task, using a 52-channel near-infrared spectroscopy instrument.The rs274622 C carriers with schizophrenia were associated with significantly smaller prefrontal activation than patients with TT genotype. This between-genotype difference tended to be confined to the patient group. GRM3 polymorphisms are associated with prefrontal activation during cognitive task in schizophrenia.
Pub.: 29 Apr '15, Pinned: 26 Mar '18
Abstract: The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of 'low schizotypes' was significantly different from 'high schizotypes' with 'average schizotypes' having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes.
Pub.: 18 May '16, Pinned: 26 Mar '18
Abstract: Previous research has shown mild forms of the neurocognitive impairments seen in schizophrenia among healthy individuals exhibiting high schizotypal traits. This study aimed to explore associations between schizotypy and cognitive performance in an adult community sample. Ninety-five females and 79 males completed the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE), which measures four separable aspects of schizotypy: cognitive disorganization, unusual experiences, introvertive anhedonia, and impulsive non-conformity. Subsequently, participants were administered a neurocognitive battery incorporating measures of executive skills including inhibition, cognitive flexibility, reasoning, and problem solving along with measures of attention and processing speed and both verbal and spatial working memory. In line with predictions, the current study found that higher scores on the subscales of unusual experiences, cognitive disorganization, and impulsive non-conformity related to worse performance on a measure of inhibition. Additionally, as introvertive anhedonia increased, both attention and processing speed and reasoning and problem-solving performance became more impaired. In conclusion, this study extends schizotypy literature by examining the subscales of the O-LIFE, and enables inferences to be drawn in relation to cognitive impairment in schizophrenia.
Pub.: 18 Jun '15, Pinned: 26 Mar '18
Abstract: Myles, J.B., S. Rossell, A. Phillipou, Thomas, E and C. Gurvich. A systematic review of saccadic eye movements across the schizophrenia continuum: Characterisation, pathophysiology and genetic associations. NEUROSCI BIOBEHAV REV 21(1) XXX–XXX, 2015.
Pub.: 01 Dec '16, Pinned: 26 Mar '18
Abstract: Thomas, E.H.X., K. Bozaoglu, S.L. Rossell and C. Gurvich. The Influence of the Glutamatergic System on Cognition in Schizophrenia: A Systematic Review. NEUROSCI BIOBEHAV REV 21(1) XXX-XXX, 2016. Previous literature showing the role of the glutamatergic system on cognition in schizophrenia has been inconclusive. 44 relevant pharmacological, candidate gene and neuroimaging studies were identified through systematic search following PRISMA guidelines. To be included, studies must have observed at least one objective measure of cognitive performance in patients with schizophrenia and either manipulated or measured the glutamatergic system. Of the cognitive domains observed, memory, working memory and executive functions appear to be most influenced by the glutamatergic pathway. In addition, evidence from the literature suggests that presynaptic components synthesis and uptake of glutamate is involved in memory, while postsynaptic signaling appears to be involved in working memory. In addition, it appears that the glutamatergic pathway is particularly involved in cognitive flexibility and learning potential in regards to executive functioning. The glutamatergic system appears to contribute to the cognitive deficits in schizophrenia, whereby different parts of the pathway are associated with different cognitive domains. This review demonstrates the necessity for cognition to be examined by domain as opposed to globally.
Pub.: 18 Apr '17, Pinned: 26 Mar '18