Eye Movement Dysfunction Research Articles

Auxiliary diagnostic method of Parkinson’s disease based on eye movement analysis in a virtual reality environment

Eye movement dysfunction is one of the non-motor symptoms of Parkinson’s disease (PD). An accurate analysis method for eye movement is an effective way to gain a deeper understanding of the nervous system function of PD patients. However, currently, there are only a few assistive methods available to help physicians conveniently and consistently assess patients suspected of having PD. To solve this problem, we proposed a novel visual behavioral analysis method using eye tracking to evaluate eye movement dysfunction in PD patients automatically. This method first provided a physician task simulation to induce PD-related eye movements in Virtual Reality (VR). Subsequently, we extracted eye movement features from recorded eye videos and applied a machine learning algorithm to establish a PD diagnostic model. Then, we collected eye movement data from 66 participants (including 22 healthy controls and 44 PD patients) in a VR environment for training and testing during visual tasks. Finally, on this relatively small dataset, the results reveal that the Support Vector Machine (SVM) algorithm has better classification potential.

Eye movement dysfunction for screening mild cognitive impairment

AbstractBackgroundEarly screening of cognitive impairment is crucial to delay cognitive deterioration and daily living disability in the elderly. However, the complexity and high cost of existing strategies appear to be great limits to the early screening on a large scale. Eye movement test shows a huge advantage in the early identification of mild cognitive impairment (MCI) because of quick, non‐invasive and cost‐effective features.MethodThe study involved a total of 151 participants: 90 MCI patients and 50 cognitive normal controls (CN) . All participants underwent eye movement signals under four visual tasks, including direct gaze towards target, smooth pursuit tasks, saccading toward a jumping target and looking away a jumping target. Five features were extracted from eye movement signals by linear and nonlinear analysis, including saccade number in resting state, saccade number in smooth persuit tasks, saccade lantency, antisaccade lantency, antisaccade error rate. Discriminant features selection was performed using the logistic regression (LR) analysis. Receiver operator characteristic (ROC) analyses and the area under the curve (AUC) were employed to investigate classification ability.ResultAfter the penalization of LR analysis, there were two top features that exhibited significant differences between MCI and CN, which included saccade number in smooth pursuit tasks and antisaccade error rate (p<0.05). ROC curves showed a favorable diagnostic accuracy of the two features in the discrimination between controls and MCI (AUC: 0.823, P<0.01).ConclusionThese results suggest that eye movement test has the potential to screen patients with MCI from the elderly with cognitive normality. Therefore, eye movement test is a powerful tool for broad screening in community‐dwelling older adults.

Eye tracking as a tool for assessing social cognition: A case-control study comparing patients with psychosis and healthy controls

Background: Eye movement dysfunction is a common abnormality in Schizophrenia and other psychotic disorders. Various eye movement paradigms can be used to measure predefined parameters using eye trackers. The current study intends to understand the eye movement characteristics in individuals suffering from psychosis using newer eye-tracking instruments with better precision. Methodology: In this study, we included 29 individuals meeting the diagnostic criteria for schizophrenia spectrum and other psychotic disorders based on the clinical assessment as per Diagnostic and Statistical Manual of Mental Disorders, 5th Edition along with 29 age- and gender-matched healthy controls and measured various eye tracking parameters using a Tobii Pro Spectrum. We compared the eye-tracking parameters between both groups. Results: There were significant differences between the groups in the free-viewing task. The average duration of fixations was higher, whereas the number of fixations and total amplitude of saccades was found to be reduced in the patient group. The peak velocity of the first saccade was also seen to be reduced in the patient group. However, there were no abnormalities in the anti-saccade, predictive saccade, memory saccade, and smooth pursuit tasks. Eye movement parameters were also found to be significantly correlated with the cognitive task measurements. Conclusion: These findings confirm the presence of eye movement abnormalities in psychosis spectrum disorders and their role in cognitive deficits in psychosis. Altered free viewing may be linked to deficits in social cognition found in patients with schizophrenia.

The effect of ketamine on eye movement characteristics during free-viewing of natural images in common marmosets.

Various eye movement abnormalities and impairments in visual information processing have been reported in patients with schizophrenia. Therefore, dysfunction of saccadic eye movements is a potential biological marker for schizophrenia. In the present study, we used a pharmacological model of schizophrenia symptoms in marmosets and compared the eye movement characteristics of marmosets during free-viewing, using an image set identical to those used for human studies. It contains natural and complex images that were randomly presented for 8 s. As a pharmacological model of schizophrenia symptoms, a subanesthetic dose of ketamine was injected intramuscularly for transient and reversible manipulation. Eye movements were recorded and compared under a ketamine condition and a saline condition as a control. The results showed that ketamine affected eye movement characteristics during free-viewing. Saccades amplitude and scanpath length were significantly reduced in the ketamine condition. In addition, the duration of saccades was longer under the ketamine condition than under the saline condition. A similar tendency was observed for the duration of fixations. The number of saccades and fixations tended to decrease in the ketamine condition. The peak saccades velocity also decreased after ketamine injection whereas there was no difference in the main sequence relationship between saccades amplitude and peak velocity. These results suggest that ketamine affected visual exploration but did not affect the oculomotor aspect of saccades in marmosets, consistent with studies in patients with schizophrenia. Therefore, we conclude that the subanesthetic dose of ketamine is a promising pharmacological model of schizophrenia symptoms in common marmosets and can be used in combination with free-viewing paradigms to establish “translatable markers” for schizophrenia in primates.

A window into eye movement dysfunction following mTBI: A scoping review of magnetic resonance imaging and eye tracking findings.

Mild traumatic brain injury (mTBI), commonly known as concussion, is a complex neurobehavioral phenomenon affecting six in 1000 people globally each year. Symptoms last between days and years as microstructural damage to axons and neurometabolic changes result in brain network disruption. There is no clinically available objective biomarker to diagnose the severity of injury or monitor recovery. However, emerging evidence suggests eye movement dysfunction (e.g., saccades and smooth pursuits) in patients with mTBI. Patients with a higher symptom burden and prolonged recovery time following injury may show higher degrees of eye movement dysfunction. Likewise, recent advances in magnetic resonance imaging (MRI) have revealed both white matter tract damage and functional network alterations in mTBI patients, which involve areas responsible for the ocular motor control. This scoping review is presented in three sections: Section 1 explores the anatomical control of eye movements to aid the reader with interpreting the discussion in subsequent sections. Section 2 examines the relationship between abnormal MRI findings and eye tracking after mTBI based on the available evidence. Finally, Section 3 communicates gaps in our knowledge about MRI and eye tracking, which should be addressed in order to substantiate this emerging field.

The similar eye movement dysfunction between major depressive disorder, bipolar depression and bipolar mania

Objective To find eye movement characteristics in patients with affective disorders. Method The demographic and clinical evaluation data of patients with major depressive disorder (MDD), bipolar disorder (BPD), and healthy control (HC) were collected. EyeLink 1000 eye tracker was used to collect eye movement data. Chi-squared test and independent sample t-test were used for demographics and clinical characteristics. The Mann–Whitney U-test was used to compare the eye movement variables among four groups, and the FDR method was used for multiple comparison correction. Pearson correlation analysis was used to analyse the relationship between clinical symptoms and eye movement variables. Results Patients with affective disorders showed smaller saccade amplitude under free-viewing task, more fixations and saccades, shorter fixation duration, longer saccade duration under fixation stability and smooth pursuit tasks (all, p < 0.05) when compared to HC, but there was no significant difference in all eye movement variables among patients in the three groups. Also, all eye movement variables under the three paradigms had no significant correlation with clinical scale scores. Conclusion Patients with major depression, bipolar depression and bipolar mania share similar eye movement dysfunction under free-viewing, fixation stability and smooth pursuit tasks.

Central Ocular Motor Disorders: Clinical and Topographic Anatomical Diagnosis, Syndromes and Underlying Diseases.

The key to the diagnosis of ocular motor disorders is a systematic clinical examination of the different types of eye movements, including eye position, spontaneous nystagmus, range of eye movements, smooth pursuit, saccades, gaze-holding function, vergence, optokinetic nystagmus, as well as testing of the function of the vestibulo-ocular reflex (VOR) and visual fixation suppression of the VOR. This is like a window which allows you to look into the brain stem and cerebellum even if imaging is normal. Relevant anatomical structures are the midbrain, pons, medulla, cerebellum and rarely the cortex. There is a simple clinical rule: vertical and torsional eye movements are generated in the midbrain, horizontal eye movements in the pons. For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), with impaired vertical saccades only or vertical gaze-evoked nystagmus due to dysfunction of the Interstitial nucleus of Cajal (INC). Lesions of the lateral medulla oblongata (Wallenberg syndrome) lead to typical findings: ocular tilt reaction, central fixation nystagmus and dysmetric saccades. The cerebellum is relevant for almost all types of eye movements; typical pathological findings are saccadic smooth pursuit, gaze-evoked nystagmus or dysmetric saccades. The time course of the development of symptoms and signs is important for the diagnosis of underlying diseases: acute: most likely stroke; subacute: inflammatory diseases, metabolic diseases like thiamine deficiencies; chronic progressive: inherited diseases like Niemann-Pick type C with typically initially vertical and then horizontal saccade palsy or degenerative diseases like progressive supranuclear palsy. Treatment depends on the underlying disease. In this article, we deal with central ocular motor disorders. In a second article, we focus on clinically relevant types of nystagmus such as downbeat, upbeat, fixation pendular, gaze-evoked, infantile or periodic alternating nystagmus. Therefore, these types of nystagmus will not be described here in detail.

Alternations of interhemispheric functional connectivity in children with strabismus and amblyopia: a resting-state fMRI study

Previous neuroimaging studies demonstrated that patients with strabismus or amblyopia can show significant functional and anatomical changes in the brain, but alterations of interhemispheric functional connectivity (FC) have not been well studied in this population. The current study analyzed whole-brain changes of interhemispheric FC in children with strabismus and amblyopia (CSA) using voxel-mirrored homotopic connectivity (VMHC).A total of 24 CSA (16 males and 8 females) and 24 normal controls (NCs) consisting of 16 and 8 age-, sex, and education-matched males and females, respectively, underwent functional magnetic resonance imaging (fMRI) scans in the resting state. According to Gaussian random field theory, changes in the resting state FC (rsFC) between hemispheres were evaluated using the VMHC method. The relationships between mean VMHC values in multiple brain regions and behavioral performance were evaluated by Pearson correlation analysis. In contrast to NCs, the CSA group showed significantly decreased VMHC values in the bilateral cerebellum, bilateral frontal superior orbital (frontal sup orb), bilateral temporal inferior(temporal inf),and bilateral frontal superior(frontal sup). CSA have abnormal interhemispheric FC in many brain regions, which may reflect dysfunction of eye movements and visual fusion. These findings might provide insight into the underlying pathogenetic mechanisms of CSA.

MRI topography of lesions related to internuclear ophthalmoplegia in patients with multiple sclerosis or ischemic stroke.

Internuclear ophthalmoplegia is a dysfunction of conjugate eye movements, caused by lesions affecting the medial longitudinal fasciculus (MLF). Multiple sclerosis (MS) and ischemic stroke represent the most common pathophysiologies. While magnetic resonance imaging (MRI) allows for localizing lesions affecting the MLF, comprehensive comparative studies exploring potential different spatial characteristics of lesions affecting the MLF are missing until now. We retrospectively investigated MRI examinations of 82 patients (40 patients with MS and 42 patients with ischemic stroke). For lesion localization, the brainstem was segmented into (1) ponto-medullary junction, (2) mid pons, (3) upper pons, and (4) mesencephalon. Corresponding lesions affecting the MLF were observed in 29/40 (72.5%) MS and 38/42 (90.5%) stroke patients. Compared to stroke patients, MS patients had significantly more lesions in multiple locations (P < .001). Stroke patients showed more lesions at the level of the mesencephalon (P < .001), while lesions at the level of the ponto-medullary junction, mid, and upper pons did not statistically differ between the groups. Our results demonstrate that multiple lesions affecting the MLF make inflammatory-demyelination due to MS more likely, while lesion localization at the level of the mesencephalon favors ischemia.

Eye movement alterations in presymptomatic C9orf72 expansion gene carriers

ObjectiveThe clinical manifestation of amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration, whereas frontotemporal dementia (FTD) patients show alterations of behavior and cognition. Both share repeat expansions in C9orf72 as the most prevalent genetic cause. Before disease-defining symptoms onset, structural and functional changes at cortical level may emerge in C9orf72 carriers. Here, we characterized oculomotor parameters and their association to neuropsychological domains in apparently asymptomatic individuals with mutations in ALS/FTD genes.Patients and methodsForty-eight carriers of ALS genes, without any clinical symptoms underwent video-oculographic examination, including 22 subjects with C9orf72 mutation, 17 with SOD1, and 9 with other ALS associated gene mutations (n = 3 KIF5A; n = 3 FUS/FUS + TBK1; n = 1 NEK1; n = 1 SETX; n = 1 TDP43). A total of 17 subjects underwent a follow-up measurement. Data were compared to 54 age- and gender-matched healthy controls. Additionally, mutation carriers performed a neuropsychological assessment.ResultsIn comparison to controls, the presymptomatic subjects performed significantly worse in executive oculomotor tasks such as the ability to perform correct anti-saccades. A gene mutation subgroup analysis showed that dysfunctions in C9orf72 carriers were much more pronounced than in SOD1 carriers. The anti-saccade error rate of ALS mutation carriers was associated with cognitive deficits: this correlation was increased in subjects with C9orf72 mutation, whereas SOD1 carriers showed no associations.ConclusionIn C9orf72 carriers, executive eye movement dysfunctions, especially the increased anti-saccade error rate, were associated with cognitive impairment and unrelated to time. These oculomotor impairments are in support of developmental deficits in these mutations, especially in prefrontal areas.

Eye Movement and Cognitive Dysfunction

Eye Movement and Cognitive Dysfunction

Subclinical Saccadic Eye Movement Dysfunction in Pediatric Multiple Sclerosis.

Efferent visual dysfunction in children could lead to impaired quality of life at home and school. Eye-tracking can detect subtle efferent dysfunction missed on bedside examination but has not been validated in the pediatric multiple sclerosis population. We sought to determine the feasibility of eye-tracking in children and associations with multiple sclerosis. Participants meeting criteria for pediatric multiple sclerosis without acute efferent vision abnormalities and healthy controls were recruited. Multiple sclerosis participants underwent a clinical assessment and saccade and antisaccade testing paradigms. Intraclass correlation coefficients were generated for intertest repeatability. Adjusting for age and intereye correlations, generalized estimating equations compared latencies with case status, Expanded Disability Status Scale and Symbol Digit Modalities Test (SDMT) scores. We eye-tracked 15 children with multiple sclerosis (n = 30 eyes, mean age 15.6 ± 2.1, mean disease duration 3.9 years, median Expanded Disability Status Scale 1.5) compared to 6 healthy controls (n = 12 eyes, age 14.3 ± .95). The intraclass correlation coefficient for repeated trials was 0.85. Adjusting for age, saccadic latency was 60 milliseconds (ms) longer for cases than controls (95% confidence interval = 26.4, 93.8; P = .0005). For antisaccadic latency, we observed a similar trend of 60 ms longer for cases than controls ( P = .06). Eye-tracking is a short noninvasive examination, and high intertest repeatability supports use of eye-tracking technology in pediatric multiple sclerosis. Longer saccadic latencies were seen in children with multiple sclerosis despite short disease duration and low Expanded Disability Status Scale scores.

Genome-wide Association Analysis of Eye Movement Dysfunction in Schizophrenia

Eye movements are considered endophenotypes of schizophrenia. However, the genetic factors underlying eye movement are largely unknown. In this study, we explored the susceptibility loci for four eye movement scores: the scanpath length during the free viewing test (SPL), the horizontal position gain during the fast Lissajous paradigm of the smooth pursuit test (HPG), the duration of fixations during the far distractor paradigm of the fixation stability test (DF) and the integrated eye movement score of those three scores (EMS). We found 16 SNPs relevant to the HPG that were located in 3 genomic regions (1q21.3, 7p12.1 and 20q13.12) in the patient group; however, these SNPs were intronic or intergenic SNPs. To determine whether these SNPs occur in functional non-coding regions (i.e., enhancer or promoter regions), we examined the chromatin status on the basis of publicly available epigenomic data from 127 tissues or cell lines. This analysis suggested that the SNPs on 1q21.3 and 20q13.12 are in enhancer or promoter regions. Moreover, we performed an analysis of expression quantitative trait loci (eQTL) in human brain tissues using a public database. Finally, we identified significant eQTL effects for all of the SNPs at 1q21.3 and 20q13.12 in particular brain regions.

Visual Dysfunction and Associated Co-morbidities as Predictors of Mild Traumatic Brain Injury Seen Among Veterans in Non-VA Facilities: Implications for Clinical Practice.

Traumatic brain injury (TBI) and post-traumatic stress disorder are considered the signature injuries of the Iraq and Afghanistan conflicts. With the extensive use of improvised explosive devices by the enemy, the concussive effects from blast have a greater potential to cause mild TBI (mTBI) in military Service Members. These mTBI can be associated with other physical and psychological health problems, including mTBI-induced visual processing and eye movement dysfunctions. Our study assessed if any visual dysfunctions existed in those surveyed in non-Veterans Administration (VA) facilities who had suffered mTBI (concussive effect), in addition to the presence of concussion-related co-morbidities. As part of a larger study involving veterans from different service eras, we surveyed 235 Veterans who had served during the Iraq and/or Afghanistan conflict era. Data for the study were collected using diagnostic telephone interviews of these veterans who were outpatients of the Geisinger Health System. We assess visual dysfunction in this sample and compare visual dysfunctions of those who had suffered a mTBI (concussive effect), as well as co-morbidities, with those in the cohort who had not suffered concussion effects. Of those veterans who experienced visual dysfunctions, our results reflected that the visual symptoms were significant for concussion with the subjects surveyed, even though all had experienced a mTBI event greater than five years ago. Although we did find an association with concussion and visual symptoms, the association for concussion was strongest with the finding of greater than or equal to three current TBI symptoms, therefore we found this to be the best predictor of previous concussion among the veterans. Veterans from the Iraq/Afghanistan era who had suffered concussive blast effects (mTBI) can present with covert visual dysfunction as well as additional physical and psychological health problems. The primary eye care providers, especially those in a non-military/VA facility, who encounter these veterans need to be aware of the predictors of mTBI, with the aim of uncovering visual dysfunctions and other associated co-morbidities.

Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment.

Multiple sclerosis (MS) commonly causes eye movement abnormalities that may have a significant impact on patients’ disability. Inflammatory demyelinating lesions, especially occurring in the posterior fossa, result in a wide range of disorders, spanning from acquired pendular nystagmus (APN) to internuclear ophthalmoplegia (INO), among the most common. As the control of eye movements is well understood in terms of anatomical substrate and underlying physiological network, studying ocular motor abnormalities in MS provides a unique opportunity to gain insights into mechanisms of disease. Quantitative measurement and modeling of eye movement disorders, such as INO, may lead to a better understanding of common symptoms encountered in MS, such as Uhthoff’s phenomenon and fatigue. In turn, the pathophysiology of a range of eye movement abnormalities, such as APN, has been clarified based on correlation of experimental model with lesion localization by neuroimaging in MS. Eye movement disorders have the potential of being utilized as structural and functional biomarkers of early cognitive deficit, and possibly help in assessing disease status and progression, and to serve as platform and functional outcome to test novel therapeutic agents for MS. Knowledge of neuropharmacology applied to eye movement dysfunction has guided testing and use of a number of pharmacological agents to treat some eye movement disorders found in MS, such as APN and other forms of central nystagmus.

Evidence that eye-movement profiles do not explain slow binocular rivalry rate in bipolar disorder: support for a perceptual endophenotype.

Presenting conflicting images simultaneously, one to each eye, produces perceptual alternations known as binocular rivalry (BR). Slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) for use in large-scale genome-wide association studies. However, the trait could conceivably reflect eye movement (EM) dysfunction in BD rather than anomalous perceptual processing per se. To address this question, we examined the relationship between EM profiles and BR rate for various stimulus types in BD and healthy subjects. We also examined differences in EM profiles between these groups. Employing a repeated-measures within-subjects design, 20 BD outpatients and 20 age- and sex-matched healthy controls completed EM tasks and separate BR tasks involving a range of stimuli with different drift speeds. The association between each EM measure and BR rate was examined with correlational analyses for all stimulus conditions in both groups. Between-group comparisons were performed to determine any differences in those EM measures. Corresponding Bayesian analyses were also conducted. There were no EM measures that showed a significant relationship with BR rate in either the BD group or the healthy group (P≥7.87×10-3 ), where those EM measures were also significantly different between the BD and healthy groups (P≥1.32×10-2 ). These findings were verified with Bayes factors. The results provide evidence that EM profiles do not explain the slow BR endophenotype for BD, thus indicating that the trait reflects anomalous perceptual processing per se. This perceptual trait can be employed in clinical, genetic, mechanistic and pathophysiological studies.

Functional Organization of Vestibulo-Ocular Responses in Abducens Motoneurons.

Vestibulo-ocular reflexes (VORs) are the dominating contributors to gaze stabilization in all vertebrates. During horizontal head movements, abducens motoneurons form the final element of the reflex arc that integrates visuovestibular inputs into temporally precise motor commands for the lateral rectus eye muscle. Here, we studied a possible differentiation of abducens motoneurons into subtypes by evaluating their morphology, discharge properties, and synaptic pharmacology in semi-intact in vitro preparations of larval Xenopus laevis Extracellular nerve recordings during sinusoidal head motion revealed a continuum of resting rates and activation thresholds during vestibular stimulation. Differences in the sensitivity to changing stimulus frequencies and velocities allowed subdividing abducens motoneurons into two subgroups, one encoding the frequency and velocity of head motion (Group I), and the other precisely encoding angular velocity independent of stimulus frequency (Group II). Computational modeling indicated that Group II motoneurons are the major contributor to actual eye movements over the tested stimulus range. The segregation into two functional subgroups coincides with a differential activation of glutamate receptor subtypes. Vestibular excitatory inputs in Group I motoneurons are mediated predominantly by NMDA receptors and to a lesser extent by AMPA receptors, whereas an AMPA receptor-mediated excitation prevails in Group II motoneurons. Furthermore, glycinergic ipsilateral vestibular inhibitory inputs are activated during the horizontal VOR, whereas the tonic GABAergic inhibition is presumably of extravestibular origin. These findings support the presence of physiologically and pharmacologically distinct functional subgroups of extraocular motoneurons that act in concert to mediate the large dynamic range of extraocular motor commands during gaze stabilization.SIGNIFICANCE STATEMENT Outward-directed gaze-stabilizing eye movements are commanded by abducens motoneurons that combine different sensory inputs including signals from the vestibular system about ongoing head movements (vestibulo-ocular reflex). Using an amphibian model, this study investigates whether different types of abducens motoneurons exist that become active during different types of eye movements. The outcome of this study demonstrates the presence of specific motoneuronal populations with pharmacological profiles that match their response dynamics. The evolutionary conservation of the vestibulo-ocular circuitry makes it likely that a similar motoneuronal organization is also implemented in other vertebrates. Accordingly, the physiological and pharmacological understanding of specific motoneuronal contributions to eye movements might help in designing drug therapies for human eye movement dysfunctions such as abducens nerve palsy.

Genome-Wide Association Studies Of Smooth Pursuit Eye Movements Across Psychotic Disorders: Preliminary Findings From The B-Snip Sample

Background Smooth pursuit eye movement dysfunctions are regarded as intermediate phenotypes for psychotic disorders. They include first, impairments of sensorimotor processing during pursuit initiation and second, deficits of sustained pursuit maintenance implicating different functional brain systems. Here we were interested in genetic alterations specifically related to these pursuit deficits. Methods Pursuit performance was assessed in 849 participants (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206, and healthy controls N=258) of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Participants were 18-65 years of age and without significant neurological disorder, recent substance abuse or dependence. A mixed modeling GWAS approach (EMMAX) was performed using genotyping assessed with the PsychChip (287,637 SNPs with MAF>0.01 passing standard GWAS QC criteria). Eye acceleration (measure of sensorimotor processing) and sustained maintenance gain (measure of cognitive control) were modeled as quantitative trait phenotypes in relation to genetic data while controlling for genetically-derived ancestry measures, age, and sex. Probands and controls were grouped together for primary analyses stratified by the top two genetically-derived ancestry groups with follow-up studies in proband or control categories. Results Genome-wide associations (p Discussion Protocadherin 12 (PCDH12) encodes a member of the cadherin family of proteins previously identified for involvement in neurodevelopment and brain morphology in both schizophrenia and bipolar disorder. By disturbing fast axonal guidance and synaptic specificity, variation in this gene may impact neuronal signaling needed for sensorimotor processing. CABLES1 encodes a protein involved in cell cycle regulation and has been identified as an important component of neural development and interhemispheric connections needed for predictive control of sustained pursuit. Relationships between neurodevelopment related genes and smooth pursuit genotypes represent novel findings that may give insights into the behavioral/neurophysiological consequences of genetic variation in these systems and its alterations in severe mental illness. Other genes implicated in our association studies represent novel relationships requiring further study.

Association of DISC1, BDNF, and COMT polymorphisms with exploratory eye movement of schizophrenia in a Chinese Han population.

Previous studies suggested that exploratory eye movement (EEM) dysfunction appears to be a biological marker specific to schizophrenia, with an unknown molecular mechanism. Genetic studies indicate that disrupted-in-schizophrenia-1 (DISC1), brain-derived neurotrophic factor (BDNF), and catechol-O-methyl transferase (COMT) genes might be implicated in the etiology of schizophrenia, but not in all populations. The present study aimed to explore associations between these candidate genes and EEM endophenotypes for schizophrenia in a Chinese Han population. EEM recordings were examined in 139 patients with schizophrenia and 143 healthy control participants. All five EEM parameters, responsive search score, cognitive search score, number of eye fixations, total eye scanning length, and mean eye scanning length, of schizophrenic patients differed significantly from those of healthy controls (P<0.001). The DISC1 SerCys, BDNF ValMet, and COMT ValMet were genotyped in a total sample of 818 schizophrenic patients and 827 healthy control participants, including the above EEM samples. We found that DISC1 Cys and BDNF Met were associated with an increased risk of developing schizophrenia (P<0.001). Furthermore, responsive search score scores of BDNF Met/Met carriers were significantly lower than those of Val allele carriers (P=0.022), which remained modest after Bonferroni correction. The BDNF MetMet polymorphism might be associated with the EEM dysfunction of schizophrenia.

Does COMT val158met polymorphism influence P50 sensory gating, eye tracking or saccadic inhibition dysfunctions in schizophrenia?

Three electrophysiological endophenotypes are routinely studied in schizophrenia (SCZ): smooth pursuit eye movement (SPEM) dysfunction, deficits in P50 auditory-evoked potential inhibition, and saccadic inhibition deficits. The current study aimed to investigate the relationship between the COMT val158met polymorphism and these three endophenotypes. One hundred four SCZ patients (DSM-IV-R criteria) and 89 healthy controls were included in this study. P50 auditory-evoked potential inhibition, antisaccade paradigm and SPEM were analyzed. All individuals were genotyped for the COMT val158met. SCZ patients showed a higher rate of deficits measured by the SPEM, antisaccade and P50 inhibition paradigms without association with COMT val158met. However, in our control group, we have found an association between the Val polymorphism and the smoking status. More importantly, we have found a higher accuracy of saccades during the predictive pursuit task associated to the Met polymorphism in controls but not in SCZ patients who were receiving antidopaminergic medications. This result is in line with the hypothesis of the relationship between the Met polymorphism of the COMT gene, a higher level of dopamine in the prefrontal cortex and the role of the fronto-cerebellar loop in smooth predictive pursuit.