Difficulties maintaining prolonged fixation and attention-deficit/hyperactivity symptoms share genetic influences in childhood.

This study investigated the association between the ability to maintain prolonged (2-minute) fixation on a visual target and ADHD traits in a sample consisting of 120 monozygotic and 120 dizygotic twin pairs, aged 9 to 14 years. More intrusive saccades during the task was associated with higher level of parent-reported ADHD traits. Both intrusive saccades and ADHD symptoms had high heritability estimates, and there was a moderate genetic correlation between number of intrusive saccades and ADHD. This study suggests that inability to maintain ocular fixation for longer times is etiologically linked to ADHD traits in the general population.

Zebrafish dscaml1 Deficiency Impairs Retinal Patterning and Oculomotor Function.

Down syndrome cell adhesion molecules (dscam and dscaml1) are essential regulators of neural circuit assembly, but their roles in vertebrate neural circuit function are still mostly unexplored. We investigated the functional consequences of dscaml1 deficiency in the larval zebrafish (sexually undifferentiated) oculomotor system, where behavior, circuit function, and neuronal activity can be precisely quantified. Genetic perturbation of dscaml1 resulted in deficits in retinal patterning and light adaptation, consistent with its known roles in mammals. Oculomotor analyses revealed specific deficits related to the dscaml1 mutation, including severe fatigue during gaze stabilization, reduced saccade amplitude and velocity in the light, greater disconjugacy, and impaired fixation. Two-photon calcium imaging of abducens neurons in control and dscaml1 mutant animals confirmed deficits in saccade-command signals (indicative of an impairment in the saccadic premotor pathway), whereas abducens activation by the pretectum-vestibular pathway was not affected. Together, we show that loss of dscaml1 resulted in impairments in specific oculomotor circuits, providing a new animal model to investigate the development of oculomotor premotor pathways and their associated human ocular disorders.SIGNIFICANCE STATEMENTDscaml1 is a neural developmental gene with unknown behavioral significance. Using the zebrafish model, this study shows that dscaml1 mutants have a host of oculomotor (eye movement) deficits. Notably, the oculomotor phenotypes in dscaml1 mutants are reminiscent of human ocular motor apraxia, a neurodevelopmental disorder characterized by reduced saccade amplitude and gaze stabilization deficits. Population-level recording of neuronal activity further revealed potential subcircuit-specific requirements for dscaml1 during oculomotor behavior. These findings underscore the importance of dscaml1 in the development of visuomotor function and characterize a new model to investigate potential circuit deficits underlying human oculomotor disorders.

Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations.

BACKGROUND: Homozygous sequestomosome-1 gene mutations have been recently linked to neurodegeneration with dystonia, ataxia and gaze palsy. Seven affected families were identified thus far. OBJECTIVE: To describe four new cases with additional phenotypical features. RESULTS: Four affected patients from two unrelated families were identified. Two compound heterozygous variants of the gene (c.257_259delins35 and c.301+1G > T) were found in one family (cases 1 and 2), and homozygous c.823_824delAG variant was identified in cases 3 and 4. In addition to the previously described syndrome characterized by cerebellar ataxia, dystonia, choreoathetosis, cognitive impairment and gaze palsy, two subjects presented with iridoplegia. Furthermore, we report dysautonomic features such as orthostatic hypotension and sudomotor dysfunction, along with other non-motor symptoms. CONCLUSIONS: We expand the phenotype of dystonia caused by Sequestomosome-1 gene by identifying dysautonomic features along with other non-motor symptoms.

Infant neural sensitivity to eye gaze depends on early experience of gaze communication.

A fundamental question in functional brain development is how the brain acquires specialised processing optimised for its individual environment. The current study is the first to demonstrate that distinct experience of eye gaze communication, due to the visual impairment of a parent, affects the specificity of brain responses to dynamic gaze shifts in infants. Event-related potentials (ERPs) from 6 to 10 months old sighted infants with blind parents (SIBP group) and control infants with sighted parents (CTRL group) were recorded while they observed a face with gaze shifting Toward or Away from them. Unlike the CTRL group, ERPs of the SIBP group did not differentiate between the two directions of gaze shift. Thus, selective brain responses to perceived gaze shifts in infants may depend on their eye gaze communication experience with the primary caregiver. This finding highlights the critical role of early communicative experience in the emerging functional specialisation of the human brain.

Genetic Influence on Eye Movements to Complex Scenes at Short Timescales.

Where one looks within their environment constrains one's visual experiences, directly affects cognitive, emotional, and social processing [1-4], influences learning opportunities [5], and ultimately shapes one's developmental path. While there is a high degree of similarity across individuals with regard to which features of a scene are fixated [6-8], large individual differences are also present, especially in disorders of development [9-13], and clarifying the origins of these differences is essential to understand the processes by which individuals develop within the complex environments in which they exist and interact. Toward this end, a recent paper [14] found that "social visual engagement"-namely, gaze to eyes and mouths of faces-is strongly influenced by genetic factors. However, whether genetic factors influence gaze to complex visual scenes more broadly, impacting how both social and non-social scene content are fixated, as well as general visual exploration strategies, has yet to be determined. Using a behavioral genetic approach and eye tracking data from a large sample of 11-year-old human twins (233 same-sex twin pairs; 51% monozygotic, 49% dizygotic), we demonstrate that genetic factors do indeed contribute strongly to eye movement patterns, influencing both one's general tendency for visual exploration of scene content, as well as the precise moment-to-moment spatiotemporal pattern of fixations during viewing of complex social and non-social scenes alike. This study adds to a now growing set of results that together illustrate how genetics may broadly influence the process by which individuals actively shape and create their own visual experiences.

Infant viewing of social scenes is under genetic control and is atypical in autism.

Long before infants reach, crawl or walk, they explore the world by looking: they look to learn and to engage, giving preferential attention to social stimuli, including faces, face-like stimuli and biological motion. This capacity-social visual engagement-shapes typical infant development from birth and is pathognomonically impaired in children affected by autism. Here we show that variation in viewing of social scenes, including levels of preferential attention and the timing, direction and targeting of individual eye movements, is strongly influenced by genetic factors, with effects directly traceable to the active seeking of social information. In a series of eye-tracking experiments conducted with 338 toddlers, including 166 epidemiologically ascertained twins (enrolled by representative sampling from the general population), 88 non-twins with autism and 84 singleton controls, we find high monozygotic twin-twin concordance (0.91) and relatively low dizygotic concordance (0.35). Moreover, the characteristics that are the most highly heritable, preferential attention to eye and mouth regions of the face, are also those that are differentially decreased in children with autism (χ2 = 64.03, P < 0.0001). These results implicate social visual engagement as a neurodevelopmental endophenotype not only for autism, but also for population-wide variation in social-information seeking. In addition, these results reveal a means of human biological niche construction, with phenotypic differences emerging from the interaction of individual genotypes with early life experience.

Imposed Optical Defocus Induces Isoform-Specific Up-Regulation of TGFß Gene Expression in Chick Retinal Pigment Epithelium and Choroid but Not Neural Retina.

PURPOSE: This study investigated the gene expression of TGFß isoforms and their receptors in chick retina, retinal pigment epithelium (RPE), and choroid and the effects of short-term imposed optical defocus. METHODS: The expression of TGFß isoforms (TGF-ß1, 2, 3) and TGFß receptors (TGFBR1, 2, 3) was examined in the retina, RPE, and choroid of young White-Leghorn untreated chicks (19 days-old). The effects on the expression of the same genes of monocular +10 and -10 D defocusing lenses, worn for either 2 or 48 h by age-matched chicks, were also examined by comparing expression in treated and untreated fellow eyes. RNA was purified, characterized and then reverse transcribed to cDNA. Differential gene expression was quantified using real-time PCR. RESULTS: All 3 isoforms of TGFß and all 3 receptor subtypes were found to be expressed in all 3 ocular tissues, with apparent tissue-dependent differences in expression profiles. Data are reported as mean normalized expression relative to GAPDH. Sign-dependent optical defocus effects were also observed. Optical defocus did not affect retinal gene expression but in the RPE, TGF-ß2 expression was significantly up-regulated with +10 D lenses, worn for either 2 h (349% increase ± 88%, p < 0.01) or 48 h (752% increase ± 166%, p < 0.001), and in the choroid, the expression of TGF-ß3 was up-regulated with -10 D lenses, worn for 48 h (147% increase ± 9%, p < 0.01). CONCLUSIONS: The effects of short term exposure to optical defocus on TGFß gene expression in the RPE and choroid, which were sign-dependent and isoform specific, provide further supporting evidence for important roles of members of the TGFß family and these two tissues in local signal cascades regulating ocular growth.

Human-directed social behaviour in dogs shows significant heritability.

Through domestication and co-evolution with humans, dogs have developed abilities to attract human attention, e.g. in a manner of seeking assistance when faced with a problem solving task. The aims of this study were to investigate within breed variation in human-directed contact seeking in dogs and to estimate its genetic basis. To do this, 498 research beagles, bred and kept under standardized conditions, were tested in an unsolvable problem task. Contact seeking behaviours recorded included both eye contact and physical interactions. Behavioural data was summarized through a principal component analysis, resulting in four components: test interactions, social interactions, eye contact and physical contact. Females scored significantly higher on social interactions and physical contact and age had an effect on eye contact scores. Narrow sense heritabilities (h(2) ) of the two largest components were estimated at 0.32 and 0.23 but were not significant for the last two components. These results show that within the studied dog population, behavioural variation in human-directed social behaviours was sex dependent and that the utilization of eye contact seeking increased with age and experience. Hence, heritability estimates indicate a significant genetic contribution to the variation found in human-directed social interactions, suggesting that social skills in dogs have a genetic basis, but can also be shaped and enhanced through individual experiences. This research gives the opportunity to further investigate the genetics behind dogs' social skills, which could also play a significant part into research on human social disorders such as autism.

5-HTTLPR, HTR1A, and HTR2A cumulative genetic score interacts with mood reactivity to predict mood-congruent gaze bias.

Genetic variation within the serotonin system has been associated with biased attention for affective stimuli and, less consistently, with vulnerability for major depressive disorder. In particular, 5-HTTLPR, HTR1A (rs6295), and HTR2A (rs6311) polymorphisms have been linked with biased cognition. The present study developed a serotonergic cumulative genetic score (CGS) that quantified the number of risk alleles associated with these candidate polymorphisms to yield a single CGS. The CGS was then used to model genetic influence on the relationship between reactivity to a negative mood induction and negatively biased cognition. A passive-viewing eye-tracking task was administered to 170 healthy volunteers to assess sustained attention for positive, dysphoric, neutral, and threatening scenes. Participants were then induced into a sad mood and readministered the passive-viewing task. Change in gaze bias, as a function of reactivity to mood induction, was the primary measure of cognitive vulnerability. Results suggest that, although none of the individual genes interacted with mood reactivity to predict change in gaze bias, individuals with higher serotonin CGS were significantly more likely to look toward dysphoric images and away from positive images as mood reactivity increased. These findings suggest that a CGS approach may better capture genetic influences on cognitive vulnerability and reaffirm the need to examine multilocus approaches in genomic research.

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

Diversified clinical presentations associated with a novel sal-like 4 gene mutation in a Chinese pedigree with Duane retraction syndrome.

PURPOSE: To determine the underlying genetic cause of Duane retraction syndrome (DRS) in a non-consanguineous Chinese Han family. METHODS: Detailed ophthalmic and physical examinations were performed on all members from a pedigree with DRS. All exons and their adjacent splicing junctions of the sal-like 4 (SALL4) gene were amplified with polymerase chain reaction and analyzed with direct sequencing in all the recruited family members and 200 unrelated control subjects. RESULTS: Clinical examination revealed a broad spectrum of phenotypes in the DRS family. Mutation analysis of SALL4 identified a novel heterozygous duplication mutation, c.1919dupT, which was completely cosegregated with the disease in the family and absent in controls. This mutation was predicted to cause a frameshift, introducing a premature stop codon, when translated, resulting in a truncated SALL4 protein, i.e., p.Met640IlefsX25. Bioinformatics analysis showed that the affected region of SALL4 shared a highly conserved sequence across different species. Diversified clinical manifestations were observed in the c.1919dupT carriers of the family. CONCLUSIONS: We identified a novel truncating mutation in the SALL4 gene that leads to diversified clinical features of DRS in a Chinese family. This mutation is predicted to result in a truncated SALL4 protein affecting two functional domains and cause disease development due to haploinsufficiency through nonsense-mediated mRNA decay.

Schizophrenia-related RGS4 gene variations specifically disrupt prefrontal control of saccadic eye movements.

BACKGROUND: The gene encoding the regulator of G-protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia and has been specifically linked to prefrontal cortical structural and functional integrity. METHOD: The effects of four core single nucleotide polymorphisms (SNPs) within the RGS4 gene on oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. RESULTS: The risk allele of RGS4SNP18 was found to be associated with two variables of antisaccade performance, increased error rate and variation in the correct antisaccade latency. By contrast, the same allele and also the risk allele of RGS4SNP4 led to an improvement in smooth eye pursuit performance (increased gain). Structural equation modeling confirmed that the combined gene variation of RGS4SNP4 and RGS4SNP18 was a significant predictor of antisaccade but not smooth eye pursuit performance. CONCLUSIONS: These results provide evidence for a specific effect of schizophrenia-related RGS4 genotype variations to prefrontal dysfunction measured by oculomotor indices of performance in normal individuals, further validating the hypothesis that RGS4 is related to prefrontal dysfunction in schizophrenia.

Revisiting the suitability of antisaccade performance as an endophenotype in schizophrenia.

Poor performance on the antisaccade task has been proposed as a candidate endophenotype in schizophrenia. Caveats to this proposal, however, include inconsistent findings in first-degree relatives of individuals with schizophrenia, and substantial heterogeneity in individuals with the disorder. In this study, we examined antisaccade performance in patients and relatives, and sought to establish whether antisaccade measures could differentiate between two patients clusters identified in the Western Australian Family Study of Schizophrenia with either pervasive cognitive deficits (CD) or cognitively spared (CS). Ninety-three patients (CD=47, CS=46), 99 relatives and 62 healthy controls carried out a standard antisaccade task. Results showed: (i) significantly greater error rate, and prolonged latencies to correct responses and self-correction saccades in patients compared with controls; (ii) high error rates in relatives of poorly performing patients; (iii) longer latencies of self-correction saccades in relatives compared to controls; and (iv) higher error rate and longer latencies of self-correction saccades in the CD subgroup compared with CS. Unaffected relatives as a group were unimpaired in error rate as compared to healthy controls. These findings suggest that the antisaccade error rate and latency of self-correction saccades are useful measures in specific applications of genetic research in schizophrenia, without fully meeting endophenotype co-familiality requirements.

Serotonin and early cognitive development: variation in the tryptophan hydroxylase 2 gene is associated with visual attention in 7-month-old infants.

BACKGROUND: Allelic variation in the promoter region of a gene that encodes tryptophan hydroxylase isoform 2 (TPH2), a rate-limiting enzyme of serotonin synthesis in the central nervous system, has been associated with variations in cognitive function and vulnerability to affective spectrum disorders. Little is known about the effects of this gene variant on cognition during development and about possible intermediate developmental steps that lead to the adult phenotype. Here, we examined the hypothesis that the TPH2 -703 may act during early stages of development and bias the acquisition of elementary cognitive processes involved in attention and emotion regulation. METHODS: Seven-month-old infants (n = 66) were genotyped for the TPH2 -703 G/T polymorphism (rs4570625) and tested for the efficiency of attention shifts from a stimulus at fixation to a new stimulus in the visual periphery. RESULTS: Compared to TPH2 G/G homozygotes, infants with the T-carrier genotype exhibited a significantly higher number of missing attention shifts. This genotype effect tended to be particularly pronounced when infants had to disengage from an affectively salient stimulus before shifting attention to the peripheral stimulus. The results also showed that TPH2 genotype was indirectly associated, via its effect on attention disengagement, with temperamental emotion regulation (soothability). CONCLUSIONS: Together, these results implicate serotonin system genes in early cognitive development and suggest variations in the early-emerging cognitive capacities as a potential developmental precursor of individual differences in emotion regulation and vulnerability to affective disorders.

Eye gaze during face processing in children and adolescents with 22q11.2 deletion syndrome.

OBJECTIVE: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic syndrome with high risk for the development of psychiatric disorder. There is interest in identifying reliable markers for measuring and monitoring socio-emotional impairments in 22q11DS during development. The current study investigated eye gaze as a potential marker during a face-processing task in children and young adolescents with 22q11DS. METHOD: Eye gaze and behavioral correlates were investigated in 26 subjects (aged 8 to 15 years) with 22q11DS during the Jane Task, which targets featural and configural face processing. Individuals with 22q11DS were compared with chronologically age-matched healthy controls and individuals with idiopathic developmental delay (DD). RESULTS: Few differences in accuracy were observed between patients with 22q11DS and DD controls; however individuals with 22q11DS spent less time on the eyes and more time on the mouths than both comparison groups. IQ predicted time on the eyes in subjects with 22q11DS, and anxiety predicted time on the eyes in DD and 22q11DS subjects. CONCLUSIONS: These results provide evidence for abnormal exploration of faces in the syndrome and suggest that time spent on the eyes may contribute to face processing difficulties and interact with anxiety levels to exacerbate socio-emotional dysfunction in affected individuals.

Eye movement dysfunction in first-degree relatives of patients with schizophrenia: a meta-analytic evaluation of candidate endophenotypes.

Several forms of eye movement dysfunction (EMD) are regarded as promising candidate endophenotypes of schizophrenia. Discrepancies in individual study results have led to inconsistent conclusions regarding particular aspects of EMD in relatives of schizophrenia patients. To quantitatively evaluate and compare the candidacy of smooth pursuit, saccade and fixation deficits in first-degree biological relatives, we conducted a set of meta-analytic investigations. Among 18 measures of EMD, memory-guided saccade accuracy and error rate, global smooth pursuit dysfunction, intrusive saccades during fixation, antisaccade error rate and smooth pursuit closed-loop gain emerged as best differentiating relatives from controls (standardized mean differences ranged from .46 to .66), with no significant differences among these measures. Anticipatory saccades, but no other smooth pursuit component measures were also increased in relatives. Visually-guided reflexive saccades were largely normal. Moderator analyses examining design characteristics revealed few variables affecting the magnitude of the meta-analytically observed effects. Moderate effect sizes of relatives v. controls in selective aspects of EMD supports their endophenotype potential. Future work should focus on facilitating endophenotype utility through attention to heterogeneity of EMD performance, relationships among forms of EMD, and application in molecular genetics studies.

Defining and quantifying the social phenotype in autism.

OBJECTIVE: Genetic and neurofunctional research in autism has highlighted the need for improved characterization of the core social disorder defining the broad spectrum of syndrome manifestations. METHOD: This article reviews the advantages and limitations of current methods for the refinement and quantification of this highly heterogeneous social phenotype. RESULTS: The study of social visual pursuit by use of eye-tracking technology is offered as a paradigm for novel tools incorporating these requirements and as a research effort that builds on the emerging synergy of different branches of social neuroscience. CONCLUSIONS: Advances in the area will require increased consideration of processes underlying experimental results and a closer approximation of experimental methods to the naturalistic demands inherent in real-life social situations.

Dopamine D3 receptor (DRD3) gene polymorphism is associated with the intensity of eye movement disturbances in schizophrenic patients and healthy subjects.

Altered dopamine neurotransmission and eye movement disturbances have been implicated in the pathogenic process of schizophrenia. So far, molecular genetic studies have shown little association between schizophrenia and polymorphism of any dopamine receptor or transporter genes except for some findings concerning D3 receptor (DRD3) gene. Eye movement disturbances occur in a majority of patients with schizophrenia and in a proportion of their first-degree relatives and they have been suggested as a phenotypic marker in genetic studies of this illness. Here we report an association between the Ser9Gly polymorphism of the DRD3 gene and the intensity of eye movement disturbances (fixation and smooth pursuit) observed in 119 schizophrenic patients and in 94 unrelated healthy control subjects. In schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was highest in individuals with the Ser-Ser genotype, significantly lower in Ser-Gly and lowest in the Gly-Gly genotype. The Ser-Ser genotype was more prevalent in patients with a higher intensity of both fixation (58.1 vs 23.9% P < 0.001) and smooth pursuit disturbances (52.3 vs 25.8%, P < 0.02) and the Ser-Gly genotype frequency was lower in patients with higher fixation disturbances (37.0 vs 60.9%, P < 0.02). In control subjects, the genotype frequency Ser-Ser was higher in subjects with any degree of eye movement disturbances compared to subjects without such disturbances both for fixation and smooth pursuit performance (81.0 vs 50.7%, P < 0.05 and 79.2 vs 50.0%, P < 0.05, respectively). In control subjects the frequency of Ser-Gly was lower in the first group, for either fixation or smooth pursuit, compared to normal performers (9.5 vs 43.8%, P < 0.01 and 8.3 vs 45.7, P < 0.005, respectively). We suggest that the DRD3 Ser9Gly polymorphism may be a contributing factor to the performance of eye movements used as a phenotypic marker of schizophrenia.

Paroxysmal tonic upgaze of childhood with ataxia: a benign transient dystonia with autosomal dominant inheritance.

Paroxysmal tonic upgaze of childhood with ataxia is a rare form of age related dystonia. Out of 12 previously reported cases, three had a clinical history of similar symptoms occurring in at least one first degree relative belonging to the same or two consecutive generations. Autosomal dominant inheritance was therefore hypothesized. We report on a family in which the disorder appeared in three consecutive generations between ages 6 and 11 months, disappearing gradually and spontaneously between ages 18 to 24 months. All affected individuals had normal neurologic development. The pedigree analysis of previously reported cases and of the family reported herein provides strong evidence that the disorder may be inherited as an autosomal dominant trait and represents a form of transient paroxysmal dystonia with benign long-term prognosis.

Visual fixation and smooth pursuit eye movement abnormalities in patients with schizophrenia and their relatives.

Increasing evidence suggests that smooth pursuit eye movement (SPEM) dysfunction may serve as an endophenotype or genetic marker of schizophrenia. The authors tested SPEM and visual fixation (VF) in 31 patients with schizophrenia, 33 of their first-degree relatives, and 24 patients with major depressive disorder. A high rate of abnormal VF was found in schizophrenic patients and their first-degree relatives, but not in affective disorder patients with or without psychotic features. Rate of VF abnormality distinguished schizophrenic patients from acutely depressed mood disorder patients; SPEM did not. VF and SPEM performance correlated only moderately, suggesting that the pathophysiologies of these two eye movement abnormalities may be partially independent. Implications for identifying a schizophrenia endophenotype are discussed.