Familial aggregation of eye-tracking endophenotypes in families of schizophrenic patients
ABSTRACT Abnormal smooth pursuit eye movements (SPEMs) are some of the most reproducible biological changes associated with the susceptibility for schizophrenia. Recent studies have suggested that deficit in predictive pursuit, a specific component of the SPEMs, marks schizophrenia susceptibility.
To test whether predictive pursuit contains less extraneous noise and may be under more direct genetic control than the traditional measure of overall pursuit performance using maintenance pursuit gain.
Familial aggregation estimation of the predictive pursuit measure and the traditional maintenance pursuit measure in sibling pairs from families of schizophrenic patients.
Patients with schizophrenia and their full siblings were recruited, provided that at least 1 sibling pair could be formed per family. Ninety-two siblings were recruited into the study. They formed 70 sibling pairs. Ninety healthy control subjects were also recruited using targeted local community advertisements based on patients' county of residence, aiming to capture the basic demographics of the regions from which the patients were recruited.
Familial correlations and heritability estimates of 2 SPEM measures: maintenance pursuit gain and predictive pursuit gain.
The sibling intraclass correlation coefficient of the predictive pursuit gain (r = 0.45-0.48) was significantly higher than that of maintenance pursuit gain (r = 0.02-0.20) (P = .005-.007). Variance component analysis suggested a high genetic loading for predictive pursuit (heritability = 0.90, SE = 0.22; P<.001) but relatively low heritability in the traditional maintenance pursuit measure (heritability = 0.27, SE = 0.21; P = .08).
These results suggest that predictive pursuit may index stronger genetic effect and may be better suited for genetic studies than the traditional SPEM measure of maintenance pursuit gain.
- SourceAvailable from: Lee Friedman
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- "While the findings of impaired eye tracking in patients with schizophrenia are rather consistent across the literature, studies are difficult to compare as stimulus presentation parameters and operational definitions vary widely between research groups. For example, studies have used outcome measures such as initiation of smooth pursuit eye tracking (Clementz et al., 1994; Sweeney et al., 2008), predictive pursuit measures (Thaker et al., 1996, 1998, 1999), i.e. anticipatory, catch up saccades, refixation saccades (McDowell et al., 2002), saccadic intrusions (Friedman et al., 1992), pursuit gain (Ross et al., 2002; Kathmann et al., 2003; Hong et al., 2006), quality of tracking performance (Shagass et al., 1974; Siever et al., 1994; Keefe et al., 2008), as well as low (i.e. 5°/s—Friedman et al., 1991) and high velocity target speeds (i.e. "
ABSTRACT: In order to investigate the nature of the eye tracking impairment in schizophrenia spectrum we measured pursuit gain with a constant velocity target using a quantitative (RMS error in pursuit gain) and, on an exploratory basis, a qualitative (quality of tracking) measure. We utilized a sample consisting of three clinically characterized groups: patients with schizophrenia (SZ), their first degree non-psychotic relatives, subjects with schizotypal personality disorder (SPD), and healthy volunteers (HV). Thirty three SZ patients, 19 SPD subjects, 66 non-psychotic relatives (all clinically assessed for schizophrenia spectrum psychopathology--DSM-IIIR) and 18 HV were evaluated using an infrared eye tracking system. Targets were constant velocity trapezoids at 5°/s (slow) and 16°/s (fast). The quality of the eye tracking was independently evaluated by at least two raters (ICC: 0.92). The RMS measures at the two velocities (quantitative measure) and the quality of the tracking obtained for each velocity were entered separately into a two factor repeated measures ANOVA, with velocity and diagnosis as the independent measures. For the quantitative ratings (RMS error), a significant effect for velocity was found, with all subjects performing worse at the higher velocity, but there was no significant velocity by diagnosis interaction. In addition, an overall significant effect for diagnosis was found in the four-group ANOVA. In post hoc multiple comparison tests, SZ subjects performed significantly worse from the HV and the relatives. SPD subjects were not different from patients with schizophrenia (or from any group--and their performance was intermediate between the HV and the SZ). Relatives of the patients with schizophrenia were different from SZ subjects, but not different from SPD or HV subjects. Similar results were obtained in the exploratory qualitative ratings. Clinical symptoms did not correlate significantly with quantitative or qualitative performance in any group. We have found that the performance of SPD subjects is intermediate between that of patients with schizophrenia and the healthy volunteers in both qualitative and quantitative (exploratory) measures. Indeed, SPD subjects comprise the only group not statistically different from schizophrenic patients in quantitative or qualitative ratings.Psychiatry Research 03/2011; 186(1):18-22. DOI:10.1016/j.psychres.2010.08.004 · 2.68 Impact Factor
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- "The findings in Thaker's study suggest that extra-retinal SPEM processes may be more sensitive to differences in prefrontal dopamine levels. A recent study found that predictive pursuit had stronger sibling-pair correlations and larger heritability estimates than the steady-state SPEM task (Hong et al., 2006). Predictive pursuit deficits may therefore represent a more refined endophenotype with a less complicated genetic basis than steady-state pursuit deficits. "
ABSTRACT: The association between the catechol-O-methyltransferase (COMT) val(158)met polymorphism (rs4680) and smooth pursuit eye movements (SPEM) was investigated in 110 schizophrenia patients and 96 controls. Patients had lower steady-state pursuit gain and made more frequent saccades than controls. Genotype was not associated with schizophrenia or SPEM, in either group or the combined sample. SPEM deficits in schizophrenia appear to be determined by genotypes other than rs4680, although the study may have lacked power to detect small effects.Psychiatry Research 08/2009; 169(2):173-5. DOI:10.1016/j.psychres.2008.10.003 · 2.68 Impact Factor
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- "SPEM deficits are also present in unaffected relatives of schizophrenia patients (i.e., relatives without DSM-IV schizophrenia), suggesting that they may reflect underlying genetic liabilities for schizophrenia (Karoumi et al., 2001). The predictive component of the SPEM phenotype has an estimated broad sense heritability of 0.9 in families with schizophrenia vs. 0.27 for the traditional global measure of eyetracking (Hong et al., 2006a). Pursuit eye movements are initiated by the sensory signal of a target's image on the retina. "
ABSTRACT: Smooth pursuit eye movement (SPEM) deficit is an established schizophrenia endophenotype with a similar neurocognitive construct to working memory. Frontal eye field (FEF) neurons controlling SPEM maintain firing when visual sensory information is removed, and their firing rates directly correlate with SPEM velocity. We previously demonstrated a paradoxical association between a functional polymorphism of dopamine signaling (COMT gene) and SPEM. Recent evidence implicates the dopamine transporter gene (DAT1) in modulating cortical dopamine and associated neurocognitive functions. We hypothesized that DAT1 10/10 genotype, which reduces dopamine transporter expression and increases extracellular dopamine, would affect SPEM. We examined the effects of DAT1 genotype on: Clinical diagnosis in the study sample (n = 418; 190 with schizophrenia), SPEM measures in a subgroup with completed oculomotor measures (n = 200; 87 schizophrenia), and DAT1 gene expression in FEF tissue obtained from postmortem brain samples (n = 32; 16 schizophrenia). DAT1 genotype was not associated with schizophrenia. DAT1 10/10 genotype was associated with better SPEM in healthy controls, intermediate SPEM in unaffected first-degree relatives of schizophrenia subjects, and worse SPEM in schizophrenia subjects. In the gene expression study, DAT1 10/10 genotype was associated with significantly reduced DAT1 mRNA transcript in FEF tissue from healthy control donors (P < 0.05), but higher expression in schizophrenia donors. Findings suggest regulatory effects of another gene(s) or etiological factor in schizophrenia, which modulate DAT1 gene function.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 03/2009; 150B(2):282-9. DOI:10.1002/ajmg.b.30811 · 3.27 Impact Factor