Refining the Predictive Pursuit Endophenotype in Schizophrenia

doi:10.1016/j.biopsych.2007.06.004

Biological Psychiatry

Volume 63, Issue 5, 1 March 2008, Pages 458-464

https://doi.org/10.1016/j.biopsych.2007.06.004 Get rights and content

Background

To utilize fully a schizophrenia endophenotype in gene search and subsequent neurobiological studies, it is critical that the precise underlying physiologic deficit is identified. Abnormality in smooth pursuit eye movements is one of the endophenotypes of schizophrenia. The precise nature of the abnormality is unknown. Previous work has shown a reduced predictive pursuit response to a briefly masked (i.e., invisible) moving object in schizophrenia. However, the overt awareness of target removal can confound the measurement.

Methods

This study employed a novel method that covertly stabilized the moving target image onto the fovea. The foveal stabilization was implemented after the target on a monitor had oscillated at least for one cycle and near the change of direction when the eye velocity momentarily reached zero. Thus, the subsequent pursuit eye movements were completely predictive and internally driven. Eye velocity during this foveally stabilized smooth pursuit was compared among schizophrenia patients (n = 45), their unaffected first-degree relatives (n = 42), and healthy comparison subjects (n = 22).

Results

Schizophrenia patients and their unaffected relatives performed similarly and both had substantially reduced predictive pursuit acceleration and velocity under the foveally stabilized condition.

Conclusions

These findings show that inability to maintain internal representation of the target motion or integration of such information into a predictive response may be the specific brain deficit indexed by the smooth pursuit endophenotype in schizophrenia. Similar performance between patients and unaffected relatives suggests that the refined predictive pursuit measure may index a less complex genetic origin of the eye-tracking deficits in schizophrenia families.

Section snippets

Subjects

Forty-five schizophrenia patient probands (a proband is defined as the first patient from a family that entered the study), 42 first-degree relatives without schizophrenia, 7 first-degree relatives with schizophrenia, and 22 unrelated normal control subjects were included. Inclusion criteria limited ages between 16 and 58 years because of age effects on eye movements outside of this range (12, 13, 14). Medical conditions likely to affect eye movements were excluded, including neurologic

Results

There were no statistical differences in gender (female/male: 17/28, 25/17, and 10/12 in patients, relatives, and control subjects, respectively; χ² = 4.2, p = .12), ethnicity (Caucasian:African American:others: 24:20:1, 18:21:3, and 15:5:2, respectively; χ² = 6.0, p = .20), and years of education (mean ± SD: 11.5 ± 2.0, 15.3 ± 13.6, and 14.5 ± 1.9, respectively, F_(2,108) = 2.23, p = .11). Differences in age were marginally nonsignificant (38.7 ± 12.6, 43.0 ± 11.0, and 35.8 ± 13.3,

Discussion

This study used a covert foveal stabilization procedure to demonstrate that predictive pursuit acceleration in the absence of corresponding retinal motion was abnormally low in schizophrenia. The patients and unaffected relatives also maintained predictive pursuit at a lower eye velocity than the control subjects. The findings provided confirmatory evidence of impaired predictive pursuit in schizophrenia, which was first observed using a target masking procedure (2, 11), now in different

References (43)

J.A. Sweeney et al.
Eye tracking abnormalities in schizophrenia: Evidence for dysfunction in the frontal eye fields
Biol Psychiatry
(1998)
G.K. Thaker et al.
Smooth pursuit eye movements to extraretinal motion signals: Deficits in patients with schizophrenia
Psychiatry Res
(1999)
J.T. Hutton et al.
Variables affecting eye tracking performance
Electroencephalogr Clin Neurophysiol
(1983)
R.G. Ross et al.
The effects of age on a smooth pursuit tracking task in adults with schizophrenia and normal subjects
Biol Psychiatry
(1999)
S.M. Heidenreich et al.
Speed discrimination under stabilized and normal viewing conditions
Vision Res
(1996)
C.B. Jarrett et al.
The volitional inhibition of anticipatory ocular pursuit using a stop signal
Brain Res Cogn Brain Res
(2003)
L.E. Hong et al.
Specific motion processing pathway deficit during eye tracking in schizophrenia: A performance-matched functional magnetic resonance imaging study
Biol Psychiatry
(2005)
K.A. Turano et al.
Nonlinear contribution of eye velocity to motion perception
Vision Res
(2001)
M. Nagel et al.
Different extraretinal neuronal mechanisms of smooth pursuit eye movements in schizophrenia: An fMRI study
NeuroImage
(2007)
W.B. Cushman et al.
Characteristics of smooth eye movements with stabilized targets
Vision Res
(1984)

R. Lencer et al.

Eye-tracking dysfunction (ETD) in families with sporadic and familial schizophrenia

Biol Psychiatry

(2000)

I.I. Gottesman et al.

The endophenotype concept in psychiatry: Etymology and strategic intentions

Am J Psychiatry

(2003)

G.K. Thaker et al.

Smooth pursuit eye movements to extraretinal motion signals: deficits in relatives of patients with schizophrenia

Arch Gen Psychiatry

(1998)

Y. Chen et al.

Psychophysical isolation of a motion-processing deficit in schizophrenics and their relatives and its association with impaired smooth pursuit

Proc Natl Acad Sci U S A

(1999)

L.E. Hong et al.

Familial aggregation of eye tracking endophenotypes in families of schizophrenic patients

Arch Gen Psychiatry

(2006)

D. Tadin et al.

Weakened center-surround interactions in visual motion processing in schizophrenia

J Neurosci

(2006)

S.G. Lisberger et al.

Properties of visual inputs that initiate horizontal smooth pursuit eye movements in monkeys

J Neurosci

(1985)

W.T. Newsome et al.

Relation of cortical areas MT and MST to pursuit eye movementsII. Differentiation of retinal from extraretinal inputs

J Neurophysiol

(1988)

A.V. van den Berg

Human smooth pursuit during transient perturbations of predictable and unpredictable target movement

Exp Brain Res

(1988)

G.R. Barnes et al.

Pursuit of intermittently illuminated moving targets in the human

J Physiol

(1992)

J. Katsanis et al.

Development of oculomotor functioning in preadolescence, adolescence, and adulthood

Psychophysiology

(1998)

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Original ArticleRefining the Predictive Pursuit Endophenotype in Schizophrenia

Background

Methods

Results

Conclusions

Section snippets

Subjects

Results

Discussion

Biol Psychiatry

Psychiatry Res

Electroencephalogr Clin Neurophysiol

Biol Psychiatry

Vision Res

Brain Res Cogn Brain Res

Biol Psychiatry

Vision Res

NeuroImage

Vision Res

Biol Psychiatry

The endophenotype concept in psychiatry: Etymology and strategic intentions

Am J Psychiatry

Smooth pursuit eye movements to extraretinal motion signals: deficits in relatives of patients with schizophrenia

Arch Gen Psychiatry

Psychophysical isolation of a motion-processing deficit in schizophrenics and their relatives and its association with impaired smooth pursuit

Proc Natl Acad Sci U S A

Familial aggregation of eye tracking endophenotypes in families of schizophrenic patients

Arch Gen Psychiatry

Weakened center-surround interactions in visual motion processing in schizophrenia

J Neurosci

Properties of visual inputs that initiate horizontal smooth pursuit eye movements in monkeys

J Neurosci

Relation of cortical areas MT and MST to pursuit eye movementsII. Differentiation of retinal from extraretinal inputs

J Neurophysiol

Human smooth pursuit during transient perturbations of predictable and unpredictable target movement

Exp Brain Res

Pursuit of intermittently illuminated moving targets in the human

J Physiol

Development of oculomotor functioning in preadolescence, adolescence, and adulthood

Psychophysiology

Original Article
Refining the Predictive Pursuit Endophenotype in Schizophrenia