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P.3.011 Visual information processing abnormalities as biomarker of schizophrenia: an EEG study in schizotypy
Clinical neuropsychopharmacology escitalopram treated patients. We found that, in contrast to previous suggestions about dose adjustment [1], UM genotypes of both DMEs in GENDEP received a consistently lower dose of antidepressants over the 12week trial. As clinicians consider both efficacy and ADRs when titrating dose, it is unclear why those with a UM genotype received lower doses. It is possible that while the metabolites of both drugs have lower antidepressant efficacy than their parent compounds, they still contribute to their ADR profile. In that case, while subjects of UM genotype might not respond as well to a lower dose, they may also be not be able to tolerate a higher doses due to increased rate of ADRs. Further work is indicated to investigate this hypothesis. Disclosure statement: GENDEP was funded by a European Commission Framework 6 grant, Ref.: LSHBCT-2003–503428. Lundbeck provided both nortriptyline and escitalopram. Roche Molecular Systems (USA) supplied the AmpliChip CYP450 Test® microarrays and associated support. GlaxoSmithKline and the Medical Research Council (UK) contributed by funding add-on projects in the London centre. In its latter stages, GENDEP received additional funding at the Institute of Psychiatry site from the Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and the Institute of Psychiatry, King’s College London (NIHR, Department of Health, UK). However, the funders had no role in the design and conduct of the study, or in data collection, analysis, interpretation or writing of this report. Reference(s) [1] Kirchheiner, J., Nickchen, K., Bauer, M., Wong, M.L., Licinio, J., Roots, I. et al. 2004 Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry; 9(5):442–473. [2] Uher, R., Maier, W., Hauser, J., Marusic, A., Schmael, C., Mors, O. et al. 2009 Differential efficacy of escitalopram and nortriptyline on dimensional measures of depression. Br J Psychiatry; 194(3):252– 259. [3] Von Moltke, L.L., Greenblatt, D.J., Giancarlo, G.M., Granda, B.W., Harmatz, J.S., Shader, R.I. 2001 Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos; 29(8):1102–1109.
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P.3.011 Visual information processing abnormalities as biomarker of schizophrenia: an EEG study in schizotypy I. Koychev1 ° , W. El-Deredy2 , C. Haenschel3 , 1 J.F.W. Deakin1 . The University of Manchester, Neuroscience and Psychiatry Unit, Manchester, United Kingdom; 2 The University of Manchester, School of Psychology, Manchester, United Kingdom; 3 The University of Bangor, School of Psychology, Bangor, United Kingdom Purpose of the study: We aimed to clarify the importance of early visual deficits for the formation of cognitive deficits in the schizophrenia spectrum. We carried out an event-related potential (ERP) study using a working memory task on a sample of volunteers exhibiting high and low levels of schizophrenia-like personality traits. The hypothesis was that the high schizotypes would have early visual deficits (P1 component reduction) and working memory similar to the ones observed in schizophrenia [1] and their first-degree relatives [2]. We also hypothesized that the working memory deficits will be more pronounced on tasks that allow only short stimulus presentation, but will be more difficult to demonstrate in tasks that allow ample time for stimulus processing. Methods: A 64 channel electroencephalographic kit was used to obtain event-related potentials. The participants completed a visual delayed discrimination task, where they were shown stimuli briefly (400 ms) and compared them to target cues presented after a 6 second delay period. We also recorded their performance on a clinical cognitive battery (CANTAB) testing memory (Paired associate learning task − PAL) and the central executive (Intra- and extra-dimensional reversal task − IED) functions. Results: The two groups did not differ in their reaction time to the task (F(1,36) = 1.102, p = 0.301) and it increased with the working memory load (F(2,72) = 108.327, p < 0.001). However the performance on the task was significantly worse in the high schizotypes group, as they identified correctly a lower number of target cues (F(1,36) = 4.841, p = 0.034). Also, the P1 ERP component was significantly reduced in the high schizotypes’ sample, both in the encoding (F(1,36) = 5.026, p = 0.034, effect size 0.0351) and retrieval (F(1,36) = 5.140, p = 0.029, effect size 0.353) phases of the task. None of the later components (N1, P2) was significantly different between the groups (F(1,36) = 0527, p = 0.472 and F(1,36) = 0.268, p = 0.608, respectively). The two groups did not differ also in terms of their performance on the CANTAB battery
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(number of errors in PAL: F(1,37) = 0.607, p = 0.441 and in IED: F(1,37) = 1.515, p = 0.226). Conclusion: The study confirmed the hypothesis that the P1 component is reduced in individuals at risk of psychosis. The deficits were related to poorer performance on working memory in a task with short stimulus presentation times. Importantly, the two groups did not differ in central executive and memory tasks (CANTAB battery) that allowed longer stimulus duration. This could indicate that the observed abnormalities are particularly relevant to processes where swift object recognition is required. The origin of the early visual deficits has been hypothesized to be due to abnormal NMDA transmission in the optic nerve [3] or inefficient top-down activation of the visual cortex [1]. This study confirmed that, the deficit is not due to the overt clinical phenotype, but is rather characteristic of the schizophrenia spectrum and could represent a promising biomarker for drug efficacy. Reference(s) [1] Haenschel, C., R. A. Bittner, et al. (2007). Contribution of impaired early-stage visual processing to working memory dysfunction in adolescents with schizophrenia: a study with event-related potentials and functional magnetic resonance imaging. Arch Gen Psychiatry 64(11): 1229−40. [2] Yeap, S., S. P. Kelly, et al. (2006). Early visual sensory deficits as endophenotypes for schizophrenia: highdensity electrical mapping in clinically unaffected first-degree relatives. Arch Gen Psychiatry 63(11): 1180−8. [3] Javitt, D.C. (2009). When doors of perception close: bottom-up models of disrupted cognition in schizophrenia. Annu Rev Clin Psychol 5: 249−75. P.3.012 Corticostriatal white matter development is changed in autism M. Langen1 ° , R.C.W. Mandl2 , H.E. Hulshoff Pol2 , H. van Engeland1 , S. Durston1 . 1 University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience − Department of Child and Adolescent Psychiatry, Utrecht, The Netherlands; 2 University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience − Department of Psychiatry, Utrecht, The Netherlands Background: Repetitive and stereotyped behaviour is one of the defining symptom clusters in Autism Spectrum Disorders (ASD) and forms a prominent impairment for many individuals with this disorder. MRI-studies have implicated striatum, and especially developmental trajectories of striatum, in this behaviour [1]. However, to
date, no studies have focused on developmental changes in corticostriatal white matter. Purpose of the study: In the current study we set out to investigate age-related changes in the microstructural integrity of corticostriatal white matter in autism, using both diffusion tensor and magnetisation transfer imaging. Methods used: Measures of white matter integrity from diffusion weighted and magnetisation transfer brain images were investigated in 69 individuals (29 subjects with high-functioning autism and 40 typically developing, matched controls) aged between 7 and 14 years. Measurements included fractional anisotropy (FA) values and magnetisation transfer ratio (MTR) of corticostriatal white matter as well as of total brain white matter. The combination of DTI and MTI allows for an assessment of white matter integrity, where information on the directionality and coherence of white matter tracts (FA) is combined with information regarding the macromolecule content, which is often taken as a proxy for myelination level (MTR) [2]. Summary of results: We show age-dependent changes in corticostriatal white matter in subjects with autism between 7 and 14 years of age: In this age range, corticostriatal MTR decreased in autism, while it did not change in controls (GLM multivariate analysis for corticostriatal MTR: interaction between group and age (F = 5.286; p = 0.008); confirmed by correlational analyses between age and corticostriatal MTR for the separate diagnostic groups). This suggests that changes in the myelination of corticostriatal tracts may be occurring in autism. Furthermore, while corticostriatal FA was independent of total white matter FA for controls, it was not for subjects with autism (GLM multivariate analysis for corticostriatal FA: interaction between group and total white matter FA (F = 3.736; p = 0.030); confirmed by correlational analyses between corticostriatal FA and FA in total white matter for the separate diagnostic groups). This suggests that corticostriatal development in this agerange may occur somewhat independently of overall white matter in controls, but less so in autism. Finally, corticostriatal MTR was associated with the severity of repetitive behaviour (r = 0.516 p = 0.007), suggesting that these developmental changes in autism may be related to the repetitive behaviour that characterises the disorder. Conclusions: This study combined information on white matter directionality (FA) and myelination (MTR) to investigate corticostriatal white matter in autism. We found changes in corticostriatal white matter development, where indirect indexes of myelin content decline between the ages of 7 and 14 years for these subjects. Furthermore, measures of corticostriatal white matter directionality and
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P.3.011 Visual information processing abnormalities as biomarker of schizophrenia: an EEG study in schizotypy I. Koychev1 ° , W. El-Deredy2 , C. Haenschel3 , 1 J.F.W. Deakin1 . The University of Manchester, Neuroscience and Psychiatry Unit, Manchester, United Kingdom; 2 The University of Manchester, School of Psychology, Manchester, United Kingdom; 3 The University of Bangor, School of Psychology, Bangor, United Kingdom Purpose of the study: We aimed to clarify the importance of early visual deficits for the formation of cognitive deficits in the schizophrenia spectrum. We carried out an event-related potential (ERP) study using a working memory task on a sample of volunteers exhibiting high and low levels of schizophrenia-like personality traits. The hypothesis was that the high schizotypes would have early visual deficits (P1 component reduction) and working memory similar to the ones observed in schizophrenia [1] and their first-degree relatives [2]. We also hypothesized that the working memory deficits will be more pronounced on tasks that allow only short stimulus presentation, but will be more difficult to demonstrate in tasks that allow ample time for stimulus processing. Methods: A 64 channel electroencephalographic kit was used to obtain event-related potentials. The participants completed a visual delayed discrimination task, where they were shown stimuli briefly (400 ms) and compared them to target cues presented after a 6 second delay period. We also recorded their performance on a clinical cognitive battery (CANTAB) testing memory (Paired associate learning task − PAL) and the central executive (Intra- and extra-dimensional reversal task − IED) functions. Results: The two groups did not differ in their reaction time to the task (F(1,36) = 1.102, p = 0.301) and it increased with the working memory load (F(2,72) = 108.327, p < 0.001). However the performance on the task was significantly worse in the high schizotypes group, as they identified correctly a lower number of target cues (F(1,36) = 4.841, p = 0.034). Also, the P1 ERP component was significantly reduced in the high schizotypes’ sample, both in the encoding (F(1,36) = 5.026, p = 0.034, effect size 0.0351) and retrieval (F(1,36) = 5.140, p = 0.029, effect size 0.353) phases of the task. None of the later components (N1, P2) was significantly different between the groups (F(1,36) = 0527, p = 0.472 and F(1,36) = 0.268, p = 0.608, respectively). The two groups did not differ also in terms of their performance on the CANTAB battery
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(number of errors in PAL: F(1,37) = 0.607, p = 0.441 and in IED: F(1,37) = 1.515, p = 0.226). Conclusion: The study confirmed the hypothesis that the P1 component is reduced in individuals at risk of psychosis. The deficits were related to poorer performance on working memory in a task with short stimulus presentation times. Importantly, the two groups did not differ in central executive and memory tasks (CANTAB battery) that allowed longer stimulus duration. This could indicate that the observed abnormalities are particularly relevant to processes where swift object recognition is required. The origin of the early visual deficits has been hypothesized to be due to abnormal NMDA transmission in the optic nerve [3] or inefficient top-down activation of the visual cortex [1]. This study confirmed that, the deficit is not due to the overt clinical phenotype, but is rather characteristic of the schizophrenia spectrum and could represent a promising biomarker for drug efficacy. Reference(s) [1] Haenschel, C., R. A. Bittner, et al. (2007). Contribution of impaired early-stage visual processing to working memory dysfunction in adolescents with schizophrenia: a study with event-related potentials and functional magnetic resonance imaging. Arch Gen Psychiatry 64(11): 1229−40. [2] Yeap, S., S. P. Kelly, et al. (2006). Early visual sensory deficits as endophenotypes for schizophrenia: highdensity electrical mapping in clinically unaffected first-degree relatives. Arch Gen Psychiatry 63(11): 1180−8. [3] Javitt, D.C. (2009). When doors of perception close: bottom-up models of disrupted cognition in schizophrenia. Annu Rev Clin Psychol 5: 249−75. P.3.012 Corticostriatal white matter development is changed in autism M. Langen1 ° , R.C.W. Mandl2 , H.E. Hulshoff Pol2 , H. van Engeland1 , S. Durston1 . 1 University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience − Department of Child and Adolescent Psychiatry, Utrecht, The Netherlands; 2 University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience − Department of Psychiatry, Utrecht, The Netherlands Background: Repetitive and stereotyped behaviour is one of the defining symptom clusters in Autism Spectrum Disorders (ASD) and forms a prominent impairment for many individuals with this disorder. MRI-studies have implicated striatum, and especially developmental trajectories of striatum, in this behaviour [1]. However, to
date, no studies have focused on developmental changes in corticostriatal white matter. Purpose of the study: In the current study we set out to investigate age-related changes in the microstructural integrity of corticostriatal white matter in autism, using both diffusion tensor and magnetisation transfer imaging. Methods used: Measures of white matter integrity from diffusion weighted and magnetisation transfer brain images were investigated in 69 individuals (29 subjects with high-functioning autism and 40 typically developing, matched controls) aged between 7 and 14 years. Measurements included fractional anisotropy (FA) values and magnetisation transfer ratio (MTR) of corticostriatal white matter as well as of total brain white matter. The combination of DTI and MTI allows for an assessment of white matter integrity, where information on the directionality and coherence of white matter tracts (FA) is combined with information regarding the macromolecule content, which is often taken as a proxy for myelination level (MTR) [2]. Summary of results: We show age-dependent changes in corticostriatal white matter in subjects with autism between 7 and 14 years of age: In this age range, corticostriatal MTR decreased in autism, while it did not change in controls (GLM multivariate analysis for corticostriatal MTR: interaction between group and age (F = 5.286; p = 0.008); confirmed by correlational analyses between age and corticostriatal MTR for the separate diagnostic groups). This suggests that changes in the myelination of corticostriatal tracts may be occurring in autism. Furthermore, while corticostriatal FA was independent of total white matter FA for controls, it was not for subjects with autism (GLM multivariate analysis for corticostriatal FA: interaction between group and total white matter FA (F = 3.736; p = 0.030); confirmed by correlational analyses between corticostriatal FA and FA in total white matter for the separate diagnostic groups). This suggests that corticostriatal development in this agerange may occur somewhat independently of overall white matter in controls, but less so in autism. Finally, corticostriatal MTR was associated with the severity of repetitive behaviour (r = 0.516 p = 0.007), suggesting that these developmental changes in autism may be related to the repetitive behaviour that characterises the disorder. Conclusions: This study combined information on white matter directionality (FA) and myelination (MTR) to investigate corticostriatal white matter in autism. We found changes in corticostriatal white matter development, where indirect indexes of myelin content decline between the ages of 7 and 14 years for these subjects. Furthermore, measures of corticostriatal white matter directionality and