Neural mechanisms of smooth pursuit eye movements in schizotypy

Patients with schizophrenia as well as individuals with high levels of schizotypy are known to have deficits in smooth pursuit eye movements (SPEM). Here, we investigated, for the first time, the neural mechanisms underlying SPEM performance in high schizotypy. Thirty‐one healthy participants [N = 19 low schizotypes, N = 12 high schizotypes (HS)] underwent functional magnetic resonance imaging at 3T with concurrent oculographic recording while performing a SPEM task with sinusoidal stimuli at two velocities (0.2 and 0.4 Hz). Behaviorally, a significant interaction between schizotypy group and velocity was found for frequency of saccades during SPEM, indicating impairments in HS in the slow but not the fast condition. On the neural level, HS demonstrated lower brain activation in different regions of the occipital lobe known to be associated with early sensory and attentional processing and motion perception (V3A, middle occipital gyrus, and fusiform gyrus). This group difference in neural activation was independent of target velocity. Together, these findings replicate the observation of altered pursuit performance in highly schizotypal individuals and, for the first time, identify brain activation patterns accompanying these performance changes. These posterior activation differences are compatible with evidence of motion processing deficits from the schizophrenia literature and, therefore, suggest overlap between schizotypy and schizophrenia both on cognitive‐perceptual and neurophysiological levels. However, deficits in frontal motor areas observed during pursuit in schizophrenia were not seen here, suggesting the operation of additional genetic and/or illness‐related influences in the clinical disorder. Hum Brain Mapp, 36:340–353, 2015. © 2014 Wiley Periodicals, Inc.     

Effects of ketamine on brain function during smooth pursuit eye movements

The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter‐balanced, placebo‐controlled, double‐blind, within‐subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other. Participants performed a block‐design SPEM task during functional magnetic resonance imaging (fMRI) at 3 Tesla field strength. Self‐ratings of psychosis‐like experiences were obtained using the Psychotomimetic States Inventory (PSI). Ketamine administration induced psychosis‐like symptoms, during ketamine infusion, participants showed increased ratings on the PSI dimensions cognitive disorganization, delusional thinking, perceptual distortion and mania. Ketamine led to robust deficits in SPEM performance, which were accompanied by reduced blood oxygen level dependent (BOLD) signal in the SPEM network including primary visual cortex, area V5 and the right frontal eye field (FEF), compared to placebo. A measure of connectivity with V5 and FEF as seed regions, however, was not significantly affected by ketamine. These results are similar to the deviations found in schizophrenia patients. Our findings support the role of glutamate dysfunction in impaired smooth pursuit performance and the use of ketamine as a pharmacological model of psychosis, especially when combined with oculomotor biomarkers. Hum Brain Mapp 37:4047–4060, 2016. © 2016 Wiley Periodicals, Inc .     

Smooth pursuit eye movements of patients with schizophrenia and affective disorder during clinical treatment

Background Smooth pursuit eye movement dysfunctions are considered a biological indicator for vulnerability to schizophrenia. This study examines test-retest stability of specific eye movement variables such as velocity gain and different saccadic categories. Methods Smooth pursuit eye movements of 27 schizophrenic patients and 30 patients with major depression were examined three times during clinical treatment using high-resolution infrared oculography. Forty-one normal controls were retested after four weeks. Results Intraclass correlation coefficients as a measure for retest-stability were highly significant in each group for all time-points, except for anticipatory saccades in schizophrenics. No significant correlations were found between psychopathological status, neuroleptic medication and eye movement variables. Conclusions Our results indicate that the most important measures of eye tracking performance in psychiatric patients are not significantly influenced by neuroleptic medication or clinical state and are stable across time. Received: 15 May 2001 / Accepted: 17 December 2001     

Specific motion processing pathway deficit during eye tracking in schizophrenia: a performance-matched functional magnetic resonance imaging study.

BACKGROUND: The neural mechanisms underlying smooth pursuit eye movement (SPEM) abnormalities in schizophrenia are not well understood. Previous evidence suggests that a deficit in the processing of internal representations of object motion (extraretinal motion) contributes to SPEM deficits in patients. Functional magnetic resonance imaging (fMRI) activation was compared between patients and control subjects to determine whether schizophrenia patients exhibit abnormal cerebral activation in regions associated with extraretinal motion processing during SPEM. METHODS: Patients and control subjects were selected based on matched performance in the closed-loop gain. Despite similar performance on closed-loop pursuit gain, patients showed consistent deficits in extraretinal motion based on predictive pursuit. In the magnet, subjects were tested using a traditional smooth-pursuit task that elicits closed-loop response. RESULTS: Patients had reduced pursuit-related activation in several known extraretinal motion processing areas including frontal and supplemental eye fields, medial superior temporal cortex, and anterior cingulate. Patients also showed increased activation in medial occipitotemporal cortex. CONCLUSIONS: These results provide functional anatomic evidence supporting reduced function in the extraretinal motion processing pathway in schizophrenia. Increased activation in medial occipitotemporal cortex suggests an increased dependence on immediate retinal motion information, which may be used to compensate for reduced extraretinal signaling during sustained visual tracking.     

What is deviant about deviant smooth pursuit eye movements in schizophrenia?

Smooth pursuit eye movements of schizophrenic, hospitalized nonpsychotic, and normal control subjects (18 per group) were measured in low and high target information conditions. A computer method for measuring saccade frequency and velocity was used. The results indicated that the frequency of saccades was significantly greater in both tracking conditions for schizophrenic than for hospitalized nonpsychotic or normal subjects. Consistent with our earlier finding, the reduction in saccade frequency with high information was greatest for schizophrenic subjects. The results also yielded a unique finding: the velocity of saccades within smooth pursuit records was significantly greater for schizophrenic than for hospitalized nonpsychotic or normal subjects. Greater saccade velocity was not a result of increased saccade size; there was no significant difference in the size of saccades for normal and schizophrenic subjects. Yet, the duration of saccades was significantly less for schizophrenics than for other subjects. Target information affected the frequency, duration and size, yet not the velocity of saccades emitted by all subjects. In contrast to earlier interpretations of deviant smooth pursuit eye movements in schizophrenia, the results may provide the first evidence of differences in the functioning of the saccadic eye movement systems of schizophrenic and normal subjects.     

The effects of nicotine on specific eye tracking measures in schizophrenia.

BACKGROUND: The role of neuronal nicotinic receptors in the etiology and pathophysiology of schizophrenia has been suggested by postmortem findings as well as by linkage analysis implicating chromosome 15q14, the region where the alpha-7 nicotinic receptor gene is located. In addition, drug probe studies show that acute nicotine administration reverses sensory gating and eye-tracking deficits associated with the genetic liability for schizophrenia. The purpose of the current study was to examine the effects of acute administration of nicotine on specific measures of smooth pursuit eye movements and visual attention.METHODS: Twenty nine subjects with schizophrenia (15 smokers and 14 nonsmokers), and 26 healthy comparison subjects (15 smokers and 11 nonsmokers) completed testing. The effects of 1 mg of nicotine, administered by nasal spray, on smooth pursuit initiation, pursuit maintenance, and predictive pursuit were examined.RESULTS: Nicotine significantly improved eye acceleration during smooth pursuit initiation in both smoker and nonsmoker patients but had no effects in healthy subjects. The fact that patient initiation eye acceleration in response to nicotine was significantly higher than in healthy subjects suggests that the lack of effect in healthy subjects was not due to ceiling effects. Nicotine significantly improved pursuit gain during maintenance at a target velocity of 18.7 deg/sec. There were no effects of nicotine on visually guided and memory saccades, or visual attention (d' from a continuous performance task).CONCLUSIONS: Nicotine showed differential effects in schizophrenic patients compared to healthy subjects. These effects of nicotine were unlikely the result of differences in vigilance or sustained attention, because saccadic peak velocity, a sensitive measure of vigilance, and continuous performance task measures were not affected by nicotine. These findings are not thought to be an artifact of nicotine withdrawal effects at baseline, because the abstinence period was very short, and there were similar effects of nicotine on initiation in nonsmoker patients. These findings suggest an abnormality in neuronal nicotinic system functioning in schizophrenic patients.     

抗精神病药对精神分裂症患者探索性眼球活动的影响

目的：探讨抗精神病药对精神分裂症患者探索性眼球活动障碍的疗效及与精神症状变化的关系。方法：对62例精神分裂症患者分别于治疗前和治疗8周做探索性眼球活动检测和阳性与阴性症状量表（PANSS）评分，主要观察指标为凝视点数（number of eye fixation，NEF）、反应性探索评分（responsive search score，RSS）及PANSS总分。结果：精神分裂症患者治疗前NEF和RSS评分均显著低于对照组（P〈0．001），治疗8周后的NEF和RSS与治疗前相比差异均无显著性（P均〉0.05）；PANSS总分显著下降，与NEF和RSS变化无显著相关性（P〉0．05）。结论：抗精神病药对精神分裂症患者探索性眼球活动障碍无明显改善作用。     

探索性眼球轨迹运动对精神分裂症的诊断作用

目的：探讨探索性眼球轨迹运动检查在精神分裂症诊断中的作用。方法：应用眼球轨迹运动标记记录仪对81例精神分裂症患者,81名正常对照人群进行测试,比较眼球轨迹运动的组间差异。结果：81例精神分裂症患者的判别分析值结果获正分67例,负分14例,D分值敏感性82．7％;81名正常对照人群获正分7例,负分74例,D分值的特异性91．4％;眼球轨迹运动的各项指标在精神分裂症组与正常对照人群比较其差异有非常显著性（P〈0．01）,且不受患者发病年龄、性别、受教育年限、不同病程及精神分裂症不同临床症状的影响（P〉0．05）。结论：精神分裂症患者眼球轨迹运动的敏感性较高,对精神分裂症辅助诊断有重要的价值,探究性眼球轨迹运动可能是精神分裂症的生物学指标。     

A clinically oriented approach to smooth pursuit eye movement quantitative evaluation

The electrooculographic technique was used to record smooth pursuit eye movements in 71 healthy subjects homogeneously distributed within an age range between the 2nd and the 6th decades. The target moved at constant velocity (triangular ramps) and 9 different target velocities (V), from 10 deg/s to 50 deg/s were considered and presented according to pseudorandom sequence. Ad hoc software suppressed catch-up saccades so that a pursuit index (PI) value was computed for each ramp taking into account only the smooth pursuit tracking modality. It was demonstrated that the relationship between V and PI could be described by the linear model PI = a + b * V. Pursuit index was proved to be influenced by the age of subject (decade factor in the analysis of variance), since an almost linear increase in b values yields a reduction of pursuit index values. The method was tested in 22 multiple sclerosis patients and an association was found between the occurrence of cerebellar signs and the reduction of a value.     

精神分裂症患者探索性眼球运动的研究

目的:探讨精神分裂症患者探索性眼球运动(EEM)特点及与精神病性症状关系。方法:根据阳性与阴性症状量表(PANSS)评分将精神分裂症患者分为Ⅰ型组(33例)、Ⅱ型组(36例)和混合组(30例),分别进行EEM检查,比较各组眼球运动注视点(NEF)、眼球注视总距离(TESL)、眼球注视平均距离(MESL)、反应性探索分(RSS)、判别分析(D)值等;分析各指标与PANSS的关系。结果:3组间PANSS总分差异有统计学意义(F=3.429,P0.05),I型组PANSS总分明显低于Ⅱ型组及混合组(t=2.023,P0.05;t=5.962,P0.01);3组间EEM的D值差异有统计学意义(F=18.376,P0.01);I型组NEF明显高于混合组(t=2.026,P0.05),RSS明显高于Ⅱ型组(t=2.438,P0.05),D值明显低于Ⅱ型组(t=2.615,P0.01)。RSS与PANSS阴性症状分和阴性因子分呈负相关(r=-0.219,P0.05;r=-0.262,P0.01);D值与PANSS阳性因子分呈负相关(r=-0.203,P0.05),与PANSS阴性因子、认知因子以及阴性症状分呈正相关(r=0.223,P0.05;r=0.198,P0.05;r=0.265,P0.01)。结论:Ⅰ型及Ⅱ型精神分裂症患者有不同的EEM特征,其中RSS与精神分裂症阴性症状相关。     

探索性眼球活动和精神分裂症的诊断

目的:用DEM-2000型眼动监测仪再次验证探索性眼球活动检查在精神分裂症诊断中的价值。方法:给231例精神分裂症(患者组)和274名正常对照者(对照组)进行探索性眼球活动检查。测定凝视点数(NEF)和反应性探索分(RSS),计算敏感度和特异度,进行判别分析,利用判别公式计算判别D值。结果:患者组较对照组的NEF、RSS和D值均显著为低(P均<0.001)。判别公式能区分精神分裂症患者和正常对照者。结论:探索性眼球活动可以作为精神分裂症的辅助诊断指标。     

FMRI of response to nicotine during a smooth pursuit eye movement task in schizophrenia

OBJECTIVE: Nicotine temporarily normalizes smooth pursuit eye movement deficits in schizophrenia. This study used functional magnetic resonance imaging (fMRI) to examine changes in brain hemodynamic response associated with nicotine administration during a smooth pursuit eye movement task in subjects with schizophrenia. METHOD: Nine subjects with schizophrenia performed the eye movement task while undergoing fMRI. Subjects then were given nicotine or placebo and repeated the task while being scanned. Subjects repeated the procedure the following week, receiving the counterbalanced condition. RESULTS: Compared with placebo, nicotine was associated with greater activity in the anterior and posterior cingulate gyri, precuneus, and area MT/MST and less activity in the hippocampus and parietal eye fields. CONCLUSIONS: Changes in area MT/MST and the cingulate gyrus are consistent with an improvement in perception and attention to moving stimuli. The most important observed difference between nicotine and placebo--less activation of the hippocampus after nicotine than after placebo administration--is consistent with nicotinic receptor mediation of inhibitory neuronal dysfunction in schizophrenia.     

Smooth pursuit eye tracking and neuro-psychological performance in healthy volunteers. Exploring a possible genetic marker for vulnerability to schizophrenia

Eye movement dysfunction (EMD) has been repeatedly found in schizophrenics and their first-degree relatives. In the present study, smooth pursuit eye tracking was measured in healthy subjects and related to performance on computerized neuropsychological tasks assumed to involve frontal or frontoparietal functions: monitoring perspective fluctuations (Necker cube), finger tapping, trail making, reaction time (RT) and a perceptual maze test. Poor trackers performed worse on tasks requiring parallel processing (trail making with letters and digits and RT with random auditory signals for response inhibition) and made more errors and cancellations on the mazes. Results are in line with our earlier EMD results on schizophrenics, showing poor performance on frontal tasks. However, their deficiency was more pervasive, whereas the present healthy EMD subjects only had difficulties with more complex tasks. The results are of interest in view of the recent evidence that EMD may be a genetic marker for vulnerability to schizophrenia.     

The relationship between antisaccades, smooth pursuit, and executive dysfunction in first-episode schizophrenia.

BACKGROUND: Both oculomotor and neuropsychologic deficits have been used to support the hypothesis that schizophrenia is associated with prefrontal cortex dysfunction, but studies that have specifically investigated the relationships between these deficits have produced inconsistent findings. METHODS: We measured both smooth pursuit and antisaccade performance in a large group (n = 109) of patients with first-episode schizophrenia and a group of matched control subjects (n = 59) and investigated the relationship between performance on these tasks and performance on a range of executive tasks. We additionally explored the relationship between these variables and measures of psychopathology at presentation and duration of untreated psychosis. RESULTS: Antisaccade errors were significantly correlated with spatial working memory performance. Smooth pursuit gain did not correlate with any neuropsychologic measure. There were no reliable correlations between either oculomotor variables and measures of psychopathology and duration of untreated psychosis. CONCLUSIONS: These findings suggest that in schizophrenia working memory and antisaccade performance reflect the same abnormal prefrontal substrates and that smooth pursuit is mediated by a separate neural abnormality.     

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia

Aim: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non‐schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). Methods: The data for the 251 schizophrenia subjects used in the previous discriminant‐analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. Results: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. Conclusion: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.     

Impairment of exploratory eye movement in schizophrenia patients and their siblings

Aims: Previous family, adoption and twin studies of schizophrenia have shown that genetic factors contribute significantly to the risk of schizophrenia. The aim of the present study was therefore to investigate whether exploratory eye movement (EEM) abnormalities are related to the genetic markers linked to schizophrenia. Methods: Twenty‐three probands with schizophrenia, 23 of their healthy siblings (23 proband–sibling pairs), and 43 unrelated normal controls performed EEM tasks. Two parameters were measured: (i) number of eye fixations in responsive search (NEFRS) and (ii) responsive search score (RSS). Results: Abnormalities in NEFRS and RSS were more frequent in schizophrenia probands than in their unaffected siblings and in normal controls, and were also more frequent in the healthy siblings than in normal controls. Thus, the EEM test performances of the healthy siblings were intermediate between those of the probands with schizophrenia and those of normal controls. Conclusion: Abnormalities of the EEM test parameters may be related to the genetic etiology of schizophrenia. The use of EEM parameters as an endophenotype for schizophrenia may facilitate linkage and association studies in schizophrenia.     

Abnormal antisaccades and smooth pursuit eye movements in patients with Wilson's disease

Neurological symptoms in Wilson's disease (WD) may include oculomotor abnormalities. However, to date, eye movements in WD patients were rarely investigated and the data concerning this issue are sparse. The purpose of this study was to evaluate reflexive and voluntary eye movements in WD patients. We examined horizontal saccadic and smooth pursuit eye movements using infra‐red oculography in 50 WD patients, including 29 neurologically symptomatic (WDn) and 21 asymptomatic ones (WDa), and in 29 healthy controls. We found statistically significant increase in mean antisaccadic latency (378 ms) and in mean antisaccadic error rate (22.5) in the WDn group, when compared with WDa group (317 ms and 9.1, respectively) and controls (318 ms and 9.7, respectively). In contrast, there were no statistically significant differences in mean latency of prosaccades and in size of the gap effect. Patients with neurological manifestations had also abnormal smooth pursuit—increased number of saccadic intrusions (mean: 8.6) and decreased gain (mean: 0.69) comparing with WDa patients (4.1 and 0.83, respectively) and controls (2.2 and 0.91, respectively). The data suggest that WD is associated both with impairment of voluntary control of saccades and with disturbed smooth pursuit eye movements while reflexive saccades seem to be preserved. © 2008 Movement Disorder Society     

fMRI of optokinetic eye movements with and without a contribution of smooth pursuit.

BACKGROUND AND PURPOSE: Optokinetic eye movements are elicited when tracking a moving pattern. It can be argued that a moving pattern of stripes invokes both the optokinetic and the smooth pursuit eye movement system, which may confound the observed brain activation patterns using functional magnetic resonance imaging (fMRI). A moving pattern of limited-lifetime-dot stimulation does not target the smooth pursuit eye movement system. METHODS: fMRI was used to compare the cortical activity elicited by an optokinetic eye movement response evoked by a moving pattern of stripes and a moving pattern of limited lifetime dots. RESULTS: The eye movement behavior showed that both types of stimuli evoked an adequate and similar optokinetic eye movement response, but stimulation with stripes evoked more activation in the frontal and parietal eye fields, MT/V5, and in the cerebellar area VI than stimulation with limited-lifetime dots. CONCLUSIONS: These brain areas are implicated in smooth pursuit eye movements. Our results suggest that indeed both the optokinetic and the smooth pursuit eye movement system are involved in tracking a moving pattern of stripes.     

Neuronal effects of nicotine during auditory selective attention in schizophrenia

Although nicotine has been shown to improve attention deficits in schizophrenia, the neurobiological mechanisms underlying this effect are poorly understood. We hypothesized that nicotine would modulate attention‐associated neuronal response in schizophrenia patients in the ventral parietal cortex (VPC), hippocampus, and anterior cingulate based on previous findings in control subjects. To test this hypothesis, the present study examined response in these regions in a cohort of nonsmoking patients and healthy control subjects using an auditory selective attention task with environmental noise distractors during placebo and nicotine administration. In agreement with our hypothesis, significant diagnosis (Control vs. Patient) X drug (Placebo vs. Nicotine) interactions were observed in the VPC and hippocampus. The interaction was driven by task‐associated hyperactivity in patients (relative to healthy controls) during placebo administration, and decreased hyperactivity in patients after nicotine administration (relative to placebo). No significant interaction was observed in the anterior cingulate. Task‐associated hyperactivity of the VPC predicted poor task performance in patients during placebo. Poor task performance also predicted symptoms in patients as measured by the Brief Psychiatric Rating Scale. These results are the first to suggest that nicotine may modulate brain activity in a selective attention‐dependent manner in schizophrenia. Hum Brain Mapp 37:410–421, 2016. © 2015 Wiley Periodicals, Inc.     

Relationship between exploratory eye movement, P300, and reaction time in schizophrenia

Aims:  Exploratory eye movement (EEM), P300 and reaction time (RT) tests may relate to the important parts of information processing in the human brain. Therefore the aim of the present study was to compare EEM, P300 and RT test data in schizophrenic and normal control groups to investigate whether schizophrenic patients have information processing abnormalities. In addition, the potential correspondence between the three tests was examined in order to investigate the information processing dysfunctions seen in schizophrenic patients.
Methods:  The EEM, P300 and RT performances were recorded in 34 schizophrenic and 36 normal control subjects. Ten parameters were measured: four from the EEM test (number of eye fixations, total eye scanning length, cognitive search score and responsive search score [RSS]); two from the P300 test (amplitude and latency); and four from the RT test (simple reaction time, index of reaction time crossover [IRT-crossover], set index and coefficient of variation).
Results:  These parameters in the schizophrenic patients differed significantly from those in the control group. Additionally, there was a significant correlation between the RSS and the IRT-crossover in the schizophrenic patients.
Conclusion:  The present group comparisons (schizophrenia vs normal controls) are consistent with previous studies in that the abnormalities in EEM, P300 and RT tests in schizophrenic patients were able to be replicated. Moreover, based on the former psychological theory, it is reasonable to propose that the RSS is associated with the IRT-crossover. The present results may contribute to elucidation of the pathophysiological signature of schizophrenia.