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Eye tracking tests in families of schizophrenic patients
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VI. Genetics A. Intermediate Phenotypes A . 129. P R E F R O N T A L CORTEX INEFFICIENCY: POTENTIAL INTERMEDIATE PHENOTYPE IN SCHIZOPHRENICS AND THEIR SIBLINGS J.H. Callicott, M.F. Egan, V.S. M a t t a y , A. Bertolino, A. Bone, D.R. Weinberger CBDB N1MH. NIH. Bethesda. MD 20892
Intermediate phenotypes are a potentially powerful tool in the search for susceptibility genes in illnesses like schizophrenia by identifying fundamental, heritable physiological components of schizophrenia. Potentially intermediate phenotypes are those physiological characteristics present to a greater extent in the siblings of schizophrenics than a control population (i.e., increased relative risk). Previously, we found an increased relative risk for reduced hippocampal area neuronal integrity as reflected in IHMRSI measures of n-acetylaspartate (Callicott et al., 1998). We used echo-planar functional MRI and a parametric n-back working memory task to search for shared physiological characteristics in this same cohort of schizophrenic patients (n = 13), their siblings (n =23), and healthy controls (n = 18). Previously, we have found that schizophrenic patients showed a profound prefrontal cortical inefficiency - - requiring greater fMRI activation to achieve lower working memory accuracy - - which was predicted by the extent of DLPFC neuronal pathology (Callicott et al., in submission). fMRI data (zero, one, and two back) were analyzed as ordinal averages using SPM97. Unaffected siblings and healthy controls performed with similar accuracy. However, siblings showed a prefrontal activation pattern similar to schizophrenic patients - significantly hyperfrontal in spite of equal working memory accuracy. We have recently repeated this finding using a separate cohort of siblings (n = 29) and comrols (n = 24) and a spiral fMRI protocol. Though preliminary, these data suggest that prefrontal cortical inefficiency may represent the subtle effects of a shared susceptibility factor evident with functional neuroimaging, but leading to clinically manifest dysfunction when combined with other genetic and environmental factors in schizophrenia.
A . 130. E Y E T R A C K I N G TESTS IN FAMILIES OF SCHIZOPHRENIC PATIENTS C. Boudet, P. Denise, M.L. Bocca, P. Brazo, P. Abadie, C. R o u l l a n d , B. C h a b o t , P. Delamillieure, K. Benali, S. Dollfus Groupe de recherche sur les schizophrknies (UPRES JE 2014), Centre Esquirol, Centre Hospitalier Universitaire de Caen, Crte de Nacre. 14033 Caen, France
Most of the schizophrenic patients have eye disorders and their biological relatives demonstrate an increased
prevalence of eye tracking impairments. The aim of the study was to research if eye tracking disorders could be a vulnerability marker of schizophrenia. Methods: Fifteen DSM IV schizophrenic patients, nineteen parents of the probands without a schizophrenic spectrum diagnosis and two groups of healthy subjects matched in age and sex with the probands and with the parents were included in the study. Four eye movements tasks (smooth pursuit, pursuit of a pseudo-random stimulus, saccade and antisaccade) were used for the eye tracking evaluation. Results: Schizophrenic patients had significantly less successful antisaccades (p < 0.0001 ), more errors of antisaccades (p = 0.011 ), and their gain of pursuit for the pseudo-random stimulus was lower for the 0.4, 0.6 and 0.8 Hz frequencies (p =0.032, p = 0.032 and p = 0.046 respectively) than the healthy subjects, The relatives of probands had significantly more catch-up saccades during smooth pursuit than the healthy subjects (p =0.006) Conclusion: Patients with schizophrenia had eye tracking impairments for the antisaccade and for the pursuit of a pseudo-random task, their parents only had impairments for the smooth pursuit task but without defect of gain. These results did not allow us to sustain that eye tracking disorders are a marker of vulnerability of schizophrenia.
A . 131. H E R I T A B I L I T Y ESTIMATES FOR INDEPENDENT DOMAINS OF COGNITIVE DYSFUNCTION IN SCHIZOPHRENIA Michael F. Egan*, M D , Terry E. Goldberg, P h D , T o n y a Gscheidle, BA, Llewellyn Bigelow, M D , Daniel R. Weinberger, M D Clinical Brain Disorders Branch, N I M H Bldg 10, Rm4S 241 Bethesda, MD 20892-1377; Fax: 301-480-7795, E-maiL [email protected], gov
Patients with schizophrenia have impairments in executive function, memory, language, psychomotor speed, and general intelligence. Impairments in some of these domains have also been observed in unaffected sibs, suggesting they could be heritable. To assess the suitability of impaired cognition for use as phenotypes in genetic studies, we estimated relative risk (2) in a large cohort of sibs. Subjects with significant medical problems, history of head trauma, or drug abuse were excluded. One hundred and forty seven patients, 193 sibs, and 47 controls were given a test battery including IQ, WRAT reading, Wisconsin Card Sort (WCST), Wechsler Memory Scale (WMS), CVLT, CPT, Trails A and B, and Verbal Fluency. Relative risk was estimated using cutoff scores of 1 and 2 standard deviations below the control mean to define 'affected' probands and siblings. Patients performed markedly worse than controls on all tests except WRAT reading. At risk siblings had significantly worse scores relative to controls on WCST, WMS, CVLT, letter fluency, CPT, and Trails A and B. Using ISD as the criterion for 'affected status', sibs had rates of impairment ranging from 25% to 35%, compared to 10% to 20% in controls. Relative
VI. Genetics A. Intermediate Phenotypes A . 129. P R E F R O N T A L CORTEX INEFFICIENCY: POTENTIAL INTERMEDIATE PHENOTYPE IN SCHIZOPHRENICS AND THEIR SIBLINGS J.H. Callicott, M.F. Egan, V.S. M a t t a y , A. Bertolino, A. Bone, D.R. Weinberger CBDB N1MH. NIH. Bethesda. MD 20892
Intermediate phenotypes are a potentially powerful tool in the search for susceptibility genes in illnesses like schizophrenia by identifying fundamental, heritable physiological components of schizophrenia. Potentially intermediate phenotypes are those physiological characteristics present to a greater extent in the siblings of schizophrenics than a control population (i.e., increased relative risk). Previously, we found an increased relative risk for reduced hippocampal area neuronal integrity as reflected in IHMRSI measures of n-acetylaspartate (Callicott et al., 1998). We used echo-planar functional MRI and a parametric n-back working memory task to search for shared physiological characteristics in this same cohort of schizophrenic patients (n = 13), their siblings (n =23), and healthy controls (n = 18). Previously, we have found that schizophrenic patients showed a profound prefrontal cortical inefficiency - - requiring greater fMRI activation to achieve lower working memory accuracy - - which was predicted by the extent of DLPFC neuronal pathology (Callicott et al., in submission). fMRI data (zero, one, and two back) were analyzed as ordinal averages using SPM97. Unaffected siblings and healthy controls performed with similar accuracy. However, siblings showed a prefrontal activation pattern similar to schizophrenic patients - significantly hyperfrontal in spite of equal working memory accuracy. We have recently repeated this finding using a separate cohort of siblings (n = 29) and comrols (n = 24) and a spiral fMRI protocol. Though preliminary, these data suggest that prefrontal cortical inefficiency may represent the subtle effects of a shared susceptibility factor evident with functional neuroimaging, but leading to clinically manifest dysfunction when combined with other genetic and environmental factors in schizophrenia.
A . 130. E Y E T R A C K I N G TESTS IN FAMILIES OF SCHIZOPHRENIC PATIENTS C. Boudet, P. Denise, M.L. Bocca, P. Brazo, P. Abadie, C. R o u l l a n d , B. C h a b o t , P. Delamillieure, K. Benali, S. Dollfus Groupe de recherche sur les schizophrknies (UPRES JE 2014), Centre Esquirol, Centre Hospitalier Universitaire de Caen, Crte de Nacre. 14033 Caen, France
Most of the schizophrenic patients have eye disorders and their biological relatives demonstrate an increased
prevalence of eye tracking impairments. The aim of the study was to research if eye tracking disorders could be a vulnerability marker of schizophrenia. Methods: Fifteen DSM IV schizophrenic patients, nineteen parents of the probands without a schizophrenic spectrum diagnosis and two groups of healthy subjects matched in age and sex with the probands and with the parents were included in the study. Four eye movements tasks (smooth pursuit, pursuit of a pseudo-random stimulus, saccade and antisaccade) were used for the eye tracking evaluation. Results: Schizophrenic patients had significantly less successful antisaccades (p < 0.0001 ), more errors of antisaccades (p = 0.011 ), and their gain of pursuit for the pseudo-random stimulus was lower for the 0.4, 0.6 and 0.8 Hz frequencies (p =0.032, p = 0.032 and p = 0.046 respectively) than the healthy subjects, The relatives of probands had significantly more catch-up saccades during smooth pursuit than the healthy subjects (p =0.006) Conclusion: Patients with schizophrenia had eye tracking impairments for the antisaccade and for the pursuit of a pseudo-random task, their parents only had impairments for the smooth pursuit task but without defect of gain. These results did not allow us to sustain that eye tracking disorders are a marker of vulnerability of schizophrenia.
A . 131. H E R I T A B I L I T Y ESTIMATES FOR INDEPENDENT DOMAINS OF COGNITIVE DYSFUNCTION IN SCHIZOPHRENIA Michael F. Egan*, M D , Terry E. Goldberg, P h D , T o n y a Gscheidle, BA, Llewellyn Bigelow, M D , Daniel R. Weinberger, M D Clinical Brain Disorders Branch, N I M H Bldg 10, Rm4S 241 Bethesda, MD 20892-1377; Fax: 301-480-7795, E-maiL [email protected], gov
Patients with schizophrenia have impairments in executive function, memory, language, psychomotor speed, and general intelligence. Impairments in some of these domains have also been observed in unaffected sibs, suggesting they could be heritable. To assess the suitability of impaired cognition for use as phenotypes in genetic studies, we estimated relative risk (2) in a large cohort of sibs. Subjects with significant medical problems, history of head trauma, or drug abuse were excluded. One hundred and forty seven patients, 193 sibs, and 47 controls were given a test battery including IQ, WRAT reading, Wisconsin Card Sort (WCST), Wechsler Memory Scale (WMS), CVLT, CPT, Trails A and B, and Verbal Fluency. Relative risk was estimated using cutoff scores of 1 and 2 standard deviations below the control mean to define 'affected' probands and siblings. Patients performed markedly worse than controls on all tests except WRAT reading. At risk siblings had significantly worse scores relative to controls on WCST, WMS, CVLT, letter fluency, CPT, and Trails A and B. Using ISD as the criterion for 'affected status', sibs had rates of impairment ranging from 25% to 35%, compared to 10% to 20% in controls. Relative