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Relationships among cognitive and electrophysiological schizophrenia phenotypes
17. Eye Movement Physiology
269
of leadfng and large anticipatory saccades compared to both the relatives and the typically developing children; however, only the frequency of leading saccades differentiated relatives from typically developing childi'en. Admixture analysis suggested that 94% of schizophrenic children, 50% of the I st-degree relatives, and 19% of controls had an abnormal elevation in the frequency of leading saccades. There was no effect of age on the frequency of leading saccades and rates were similar in typically developing children to that seen in normal young adults. Thus, brain functions modulating leading saccade frequency seem fully developed by 6 years of age. The abnormal leading saccade phenotype is also already fully expressed in the childhood-onset subjects and in the unaffected but vulnerable family members. Treatment and prevention strategies for schizophrenia will need to consider early developmental alterations in brain function.
THE RELATIONSHIP BETWEEN EYETRACKING AND MORPHOMETRY IN PATIENTS WITH SCHIZOPHRENIA AND THEIR
UNAFFECTED RELATIVES K. Schulze,* C. M c D o n a l d , J. M a c C a b e , S. R a b e - H e s k e t h , R. M. M u r r a y
Division of Psychological Medicine, Institute of Psychiatry, London, United Kingdom Schizophrenia is associated with subtle eyetracking and brain structural abnormalities and similar deviations are over-represented in groups of unaffected relatives of patients who are likely to share susceptibility genes for the illness. Our group has previously found increased lateral and third ventricular volumes in patients and their unaffected relatives [1] and reduced hippocampal volume [3] and antisaccade [2] and smooth pursuit abnormalites in patients. However, the relationship between these potential morphometric and neurophysiological vulnerability markers remains unclear. We examined associations between regional brain volumes (whole brain, prefrontal region, lateral and third ventricles, hippocampus and cerebellum) and antisaccade and smooth pursuit performance in patients with schizophrenia or schizo-affective disorder (n=71), their unaffected first-degree relatives (n=105) and controls (n=68) using clustered regression analyses. Interaction terms between subject group (patients, relatives) and volume were entered into the regression to explore potential between-group differences in the relationship between eyetracking and morphometry. In the total sample, smaller frontal lobe volume was significantly associated with longer mean latency of correct antisaccades (partial correlation r=-0.22, p=0.01) and larger third ventricular volume was significantly associated with larger mean amplitude of saccades during smooth pursuit (1"=0.28, p=0.01). There were no significant between-group differences in the relationship between eyetracking and morphometry. Our findings confirm the importance of prefrontal integrity in normal antisaccade generation, in keeping with evidence from other sources [4]. The results also suggest that structures surrounding the third ventricle, one possibility being the thalamus, are involved in maintaining normal smooth pursuit function. The association of third ventricular enlargement with smooth pursuit deficits in this sample indicates that
a potential endophenotype for schizophrenia that combines these measures may warrant further investigation. [ 1] McDonald C, Grech A, Toulopoulou T, Schulze K et al Am J Med Genet, 1t4 616-25 2002 [2] Crawford TJ, Sharma T, Puri BK, Murray RM et al Am J Psychiatry, 155:1703-10, 1998 [3] Stefanis N, Frangou S, Yakeley J, Sharma T et al Biol Psychiatry, 46:697-702, 1999
RELATIONSHIPS AMONG COGNITIVE AND ELECTROPHYSIOLOGICAL SCHIZOPHRENIA PHENOTYPES G. K. Thaker,* M. T. Avila, J. T. Gold, T. A. Blaxton, H. M. A d a m i
Maryland Psychiatric Research Center, Dept. of Psychiatry, University of Maryland School c~fMedicine, Baltimore, MD, USA The syndrome of schizophrenia likely encompasses several phenotypes, each caused by multiple genes contributing small effects. Investigators have identified several heritable electrophysiological and cognitive abnormalities in schizophrenia, which help to demarcate the phenotypic boundary and may identify biological subtypes. Few studies have examined relationships or the concordance rates among these putative phenotypic markers in ill or at-risk subjects. In an ongoing study, eye movement measures were obtained from 117 first-degree relatives of schizophrenic patients, and 139 healthy subjects with no family history of psychoses. Predictive and initiation smooth pursuit and saccadic disinhibition (i.e., antisaccade error rate) measures were collected. Data on cognitive measures are being collected and are available in 48 relatives and 67 healthy controls. Prevalence rates of abnormalities based on 2 SD cutoff points were calculated for each measure in relatives and controls, which were used to calculate risk ratios (i.e, prevalence rates in relatives/rates in control subjects). Conditional odds ratios were calculated for pairs of measures with risk ratios higher than 2.5. Conditional odds ratios indicate the increase in the odds of having an abnormality in Measure B, given an abnormality in Measure A. Predictive pursuit, antisaccade error rate, CPT d' (identical paired version), Trails B time, and several cognitive measures were associated with modest risk ratios (ranging from 2.7 to 12.7). Conditional odds ratios identified clusters of measures, which were abnormal in the same individuals. Conditional odds ratios were high for pairs of eye tracking measures (ranging from 3.4 to 39); thus in the presence of one eye tracking abnormality there were likely to be others. Similarly, abnormalities in attention as measured by CPT d', Trails B, comprehension, vocabulary, and WRAT- reading clustered together (conditional odds ratios ranging from 7.5 to 32). On the other hand, conditional odds ratios were small for predictive pursuit abnormality, trails B abnormality, and CPT measures (ranging from 1.3 to 2.7). Several phenotypic markers were examined in a sample of subjects at-risk for schizophrenia and healthy controls. Several measures clustered together being abnormal in the same subjects suggesting that these mark the same phenotype. On the other hand, there was minimal overlap among these clusters suggesting multiple phenotypic expressions.
International Congress on Schizophrenia Research 2003
269
of leadfng and large anticipatory saccades compared to both the relatives and the typically developing children; however, only the frequency of leading saccades differentiated relatives from typically developing childi'en. Admixture analysis suggested that 94% of schizophrenic children, 50% of the I st-degree relatives, and 19% of controls had an abnormal elevation in the frequency of leading saccades. There was no effect of age on the frequency of leading saccades and rates were similar in typically developing children to that seen in normal young adults. Thus, brain functions modulating leading saccade frequency seem fully developed by 6 years of age. The abnormal leading saccade phenotype is also already fully expressed in the childhood-onset subjects and in the unaffected but vulnerable family members. Treatment and prevention strategies for schizophrenia will need to consider early developmental alterations in brain function.
THE RELATIONSHIP BETWEEN EYETRACKING AND MORPHOMETRY IN PATIENTS WITH SCHIZOPHRENIA AND THEIR
UNAFFECTED RELATIVES K. Schulze,* C. M c D o n a l d , J. M a c C a b e , S. R a b e - H e s k e t h , R. M. M u r r a y
Division of Psychological Medicine, Institute of Psychiatry, London, United Kingdom Schizophrenia is associated with subtle eyetracking and brain structural abnormalities and similar deviations are over-represented in groups of unaffected relatives of patients who are likely to share susceptibility genes for the illness. Our group has previously found increased lateral and third ventricular volumes in patients and their unaffected relatives [1] and reduced hippocampal volume [3] and antisaccade [2] and smooth pursuit abnormalites in patients. However, the relationship between these potential morphometric and neurophysiological vulnerability markers remains unclear. We examined associations between regional brain volumes (whole brain, prefrontal region, lateral and third ventricles, hippocampus and cerebellum) and antisaccade and smooth pursuit performance in patients with schizophrenia or schizo-affective disorder (n=71), their unaffected first-degree relatives (n=105) and controls (n=68) using clustered regression analyses. Interaction terms between subject group (patients, relatives) and volume were entered into the regression to explore potential between-group differences in the relationship between eyetracking and morphometry. In the total sample, smaller frontal lobe volume was significantly associated with longer mean latency of correct antisaccades (partial correlation r=-0.22, p=0.01) and larger third ventricular volume was significantly associated with larger mean amplitude of saccades during smooth pursuit (1"=0.28, p=0.01). There were no significant between-group differences in the relationship between eyetracking and morphometry. Our findings confirm the importance of prefrontal integrity in normal antisaccade generation, in keeping with evidence from other sources [4]. The results also suggest that structures surrounding the third ventricle, one possibility being the thalamus, are involved in maintaining normal smooth pursuit function. The association of third ventricular enlargement with smooth pursuit deficits in this sample indicates that
a potential endophenotype for schizophrenia that combines these measures may warrant further investigation. [ 1] McDonald C, Grech A, Toulopoulou T, Schulze K et al Am J Med Genet, 1t4 616-25 2002 [2] Crawford TJ, Sharma T, Puri BK, Murray RM et al Am J Psychiatry, 155:1703-10, 1998 [3] Stefanis N, Frangou S, Yakeley J, Sharma T et al Biol Psychiatry, 46:697-702, 1999
RELATIONSHIPS AMONG COGNITIVE AND ELECTROPHYSIOLOGICAL SCHIZOPHRENIA PHENOTYPES G. K. Thaker,* M. T. Avila, J. T. Gold, T. A. Blaxton, H. M. A d a m i
Maryland Psychiatric Research Center, Dept. of Psychiatry, University of Maryland School c~fMedicine, Baltimore, MD, USA The syndrome of schizophrenia likely encompasses several phenotypes, each caused by multiple genes contributing small effects. Investigators have identified several heritable electrophysiological and cognitive abnormalities in schizophrenia, which help to demarcate the phenotypic boundary and may identify biological subtypes. Few studies have examined relationships or the concordance rates among these putative phenotypic markers in ill or at-risk subjects. In an ongoing study, eye movement measures were obtained from 117 first-degree relatives of schizophrenic patients, and 139 healthy subjects with no family history of psychoses. Predictive and initiation smooth pursuit and saccadic disinhibition (i.e., antisaccade error rate) measures were collected. Data on cognitive measures are being collected and are available in 48 relatives and 67 healthy controls. Prevalence rates of abnormalities based on 2 SD cutoff points were calculated for each measure in relatives and controls, which were used to calculate risk ratios (i.e, prevalence rates in relatives/rates in control subjects). Conditional odds ratios were calculated for pairs of measures with risk ratios higher than 2.5. Conditional odds ratios indicate the increase in the odds of having an abnormality in Measure B, given an abnormality in Measure A. Predictive pursuit, antisaccade error rate, CPT d' (identical paired version), Trails B time, and several cognitive measures were associated with modest risk ratios (ranging from 2.7 to 12.7). Conditional odds ratios identified clusters of measures, which were abnormal in the same individuals. Conditional odds ratios were high for pairs of eye tracking measures (ranging from 3.4 to 39); thus in the presence of one eye tracking abnormality there were likely to be others. Similarly, abnormalities in attention as measured by CPT d', Trails B, comprehension, vocabulary, and WRAT- reading clustered together (conditional odds ratios ranging from 7.5 to 32). On the other hand, conditional odds ratios were small for predictive pursuit abnormality, trails B abnormality, and CPT measures (ranging from 1.3 to 2.7). Several phenotypic markers were examined in a sample of subjects at-risk for schizophrenia and healthy controls. Several measures clustered together being abnormal in the same subjects suggesting that these mark the same phenotype. On the other hand, there was minimal overlap among these clusters suggesting multiple phenotypic expressions.
International Congress on Schizophrenia Research 2003