Angelina Paolozza

Altered Accuracy of Saccadic Eye Movements in Children with Fetal Alcohol Spectrum Disorder

BACKGROUND Prenatal exposure to alcohol is a major, preventable cause of neurobehavioral dysfunction in children worldwide. The measurement and quantification of saccadic eye movements is a powerful tool for assessing sensory, motor, and cognitive function. The quality of the motor process of an eye movement is known as saccade metrics. Saccade accuracy is 1 component of metrics, which to function optimally requires several cortical brain structures as well as an intact cerebellum and brain-stem. The cerebellum has frequently been reported to be damaged by prenatal alcohol exposure. This study, therefore, tested the hypothesis that children with fetal alcohol spectrum disorder (FASD) will exhibit deficits in the accuracy of saccades. METHODS A group of children with FASD (n = 27) between the ages of 8 and 16 and typically developing control children (n = 27) matched for age and sex, completed 3 saccadic eye movement tasks of increasing difficulty. Eye movement performance during the tasks was captured using an infrared eye tracker. Saccade metrics (e.g., velocity, amplitude, accuracy) were quantified and compared between the 2 groups for the 3 different tasks. RESULTS Children with FASD were more variable in saccade endpoint accuracy, which was reflected by statistically significant increases in the error of the initial saccade endpoint and the frequency of additional, corrective saccades required to achieve final fixation. This increased variability in accuracy was amplified when the cognitive demand of the tasks increased. Children with FASD also displayed a statistically significant increase in response inhibition errors. CONCLUSIONS These data suggest that children with FASD may have deficits in eye movement control and sensory-motor integration including cerebellar circuits, thereby impairing saccade accuracy.

Working memory and visuospatial deficits correlate with oculomotor control in children with fetal alcohol spectrum disorder.

Previous studies have demonstrated that children with Fetal Alcohol Spectrum Disorder (FASD) exhibit deficits in measures of eye movement control that probe aspects of visuospatial processing and working memory. The goal of the present study was to examine, in a large cohort of children with FASD, prenatal alcohol exposure (PAE) but not FASD, and typically developing control children, the relationship between performance in eye movement tasks and standardized psychometric tests that assess visuospatial processing and working memory. Participants for this dataset were drawn from a large, multi-site investigation, and included children and adolescents aged 5-17 years diagnosed with an FASD (n=71), those with PAE but no clinical FASD diagnosis (n=20), and typically developing controls (n=111). Participants completed a neurobehavioral test battery and a series of saccadic eye movement tasks. The FASD group performed worse than controls on the psychometric and eye movement measures of working memory and visuospatial skills. Within the FASD group, digit recall, block recall, and animal sorting were negatively correlated with sequence errors on the memory-guided task, and arrows was negatively correlated with prosaccade endpoint error. There were no significant correlations in the control group. These data suggest that psychometric tests and eye movement control tasks may assess similar domains of cognitive function, and these assessment tools may be measuring overlapping brain regions damaged due to prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests and are able to assess multiple domains of cognition simultaneously, thereby allowing for an efficient and accurate assessment.

Response inhibition deficits in children with Fetal Alcohol Spectrum Disorder: relationship between diffusion tensor imaging of the corpus callosum and eye movement control.

Response inhibition is the ability to suppress irrelevant impulses to enable goal-directed behavior. The underlying neural mechanisms of inhibition deficits are not clearly understood, but may be related to white matter connectivity, which can be assessed using diffusion tensor imaging (DTI). The goal of this study was to investigate the relationship between response inhibition during the performance of saccadic eye movement tasks and DTI measures of the corpus callosum in children with or without Fetal Alcohol Spectrum Disorder (FASD). Participants included 43 children with an FASD diagnosis (12.3 ± 3.1 years old) and 35 typically developing children (12.5 ± 3.0 years old) both aged 7–18, assessed at three sites across Canada. Response inhibition was measured by direction errors in an antisaccade task and timing errors in a delayed memory-guided saccade task. Manual deterministic tractography was used to delineate six regions of the corpus callosum and calculate fractional anisotropy (FA), mean diffusivity (MD), parallel diffusivity, and perpendicular diffusivity. Group differences in saccade measures were assessed using t-tests, followed by partial correlations between eye movement inhibition scores and corpus callosum FA and MD, controlling for age. Children with FASD made more saccade direction errors and more timing errors, which indicates a deficit in response inhibition. The only group difference in DTI metrics was significantly higher MD of the splenium in FASD compared to controls. Notably, direction errors in the antisaccade task were correlated negatively to FA and positively to MD of the splenium in the control, but not the FASD group, which suggests that alterations in connectivity between the two hemispheres of the brain may contribute to inhibition deficits in children with FASD.

Deficits in response inhibition correlate with oculomotor control in children with fetal alcohol spectrum disorder and prenatal alcohol exposure.

Children with fetal alcohol spectrum disorder (FASD) or prenatal alcohol exposure (PAE) frequently exhibit impairment on tasks measuring inhibition. The objective of this study was to determine if a performance-based relationship exists between psychometric tests and eye movement tasks in children with FASD. Participants for this dataset were aged 5-17 years and included those diagnosed with an FASD (n=72), those with PAE but no clinical FASD diagnosis (n=21), and typically developing controls (n=139). Participants completed a neurobehavioral test battery, which included the NEPSY-II subtests of auditory attention, response set, and inhibition. Each participant completed a series of saccadic eye movement tasks, which included the antisaccade and memory-guided tasks. Both the FASD and the PAE groups performed worse than controls on the subtest measures of attention and inhibition. Compared with controls, the FASD group made more errors on the antisaccade and memory-guided tasks. Among the combined FASD/PAE group, inhibition and switching errors were negatively correlated with direction errors on the antisaccade task but not on the memory-guided task. There were no significant correlations in the control group. These data suggests that response inhibition deficits in children with FASD/PAE are associated with difficulty controlling saccadic eye movements which may point to overlapping brain regions damaged by prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests that are used during FASD diagnosis, and may therefore help with early identification of children who would benefit from a multidisciplinary diagnostic assessment.

Brain Structural and Vascular Anatomy Is Altered in Offspring of Pre-Eclamptic Pregnancies: A Pilot Study

The authors assessed the brain structural and vascular anatomy in 7- to 10-year-old offspring of pre-eclamptic pregnancies compared with matched controls (n=10 per group). TOF-MRA and a high-resolution anatomic T1-weighted MPRAGE sequence were acquired for each participant. Offspring of pre-eclamptic pregnancies exhibited enlarged brain regional volumes of the cerebellum, temporal lobe, brain stem, and right and left amygdalae. These offspring displayed reduced cerebral vessel radii in the occipital and parietal lobes. The authors conclude that these structural and vascular anomalies may underlie the cognitive deficits reported in the pre-eclamptic offspring population. BACKGROUND AND PURPOSE: Pre-eclampsia is a serious clinical gestational disorder occurring in 3%–5% of all human pregnancies and characterized by endothelial dysfunction and vascular complications. Offspring born of pre-eclamptic pregnancies are reported to exhibit deficits in cognitive function, higher incidence of depression, and increased susceptibility to stroke. However, no brain imaging reports exist on these offspring. We aimed to assess brain structural and vascular anatomy in 7- to 10-year-old offspring of pre-eclamptic pregnancies compared with matched controls. MATERIALS AND METHODS: Offspring of pre-eclamptic pregnancies and matched controls (n = 10 per group) were recruited from an established longitudinal cohort examining the effects of pre-eclampsia. Children underwent MR imaging to identify brain structural and vascular anatomic differences. Maternal plasma samples collected at birth were assayed for angiogenic factors by enzyme-linked immunosorbent assay. RESULTS: Offspring of pre-eclamptic pregnancies exhibited enlarged brain regional volumes of the cerebellum, temporal lobe, brain stem, and right and left amygdalae. These offspring displayed reduced cerebral vessel radii in the occipital and parietal lobes. Enzyme-linked immunosorbent assay analysis revealed underexpression of the placental growth factor among the maternal plasma samples from women who experienced pre-eclampsia. CONCLUSIONS: This study is the first to report brain structural and vascular anatomic alterations in the population of offspring of pre-eclamptic pregnancies. Brain structural alterations shared similarities with those seen in autism. Vascular alterations may have preceded these structural alterations. This pilot study requires further validation with a larger population to provide stronger estimates of brain structural and vascular outcomes among the offspring of pre-eclamptic pregnancies.

Eye movements reveal sexually dimorphic deficits in children with fetal alcohol spectrum disorder.

Background: We examined the accuracy and characteristics of saccadic eye movements in children with fetal alcohol spectrum disorder (FASD) compared with typically developing control children. Previous studies have found that children with FASD produce saccades that are quantifiably different from controls. Additionally, animal studies have found sex-based differences for behavioral effects after prenatal alcohol exposure. Therefore, we hypothesized that eye movement measures will show sexually dimorphic results. Methods: Children (aged 5–18 years) with FASD (n = 71) and typically developing controls (n = 113) performed a visually-guided saccade task. Saccade metrics and behavior were analyzed for sex and group differences. Results: Female control participants had greater amplitude saccades than control males or females with FASD. Accuracy was significantly poorer in the FASD group, especially in males, which introduced significantly greater variability in the data. Therefore, we conducted additional analyses including only those trials in which the first saccade successfully reached the target within a ± 1° window. In this restricted amplitude dataset, the females with FASD made saccades with significantly lower velocity and longer duration, whereas the males with FASD did not differ from the control group. Additionally, the mean and peak deceleration were selectively decreased in the females with FASD. Conclusions: These data support the hypothesis that children with FASD exhibit specific deficits in eye movement control and sensory-motor integration associated with cerebellar and/or brain stem circuits. Moreover, prenatal alcohol exposure may have a sexually dimorphic impact on eye movement metrics, with males and females exhibiting differential patterns of deficit.

Impact of preeclampsia on cognitive function in the offspring

Preeclampsia (PE) is a significant clinical disorder occurring in 3-5% of all human pregnancies. Offspring of PE pregnancies (PE-F1s) are reported to exhibit greater cognitive impairment than offspring from uncomplicated pregnancies. Previous studies of PE-F1 cognitive ability used tests with bias that do not assess specific cognitive domains. To improve cognitive impairment classification in PE-F1s we used standardized clinical psychometric testing and eye tracking studies of saccadic eye movements. PE-F1s (n=10) and sex/age matched control participants (n=41 for psychometrics; n=59 for eye-tracking) were recruited from the PE-NET study or extracted from the NeuroDevNet study databases. Participants completed a selected array of psychometric tests which assessed executive function, working memory, attention, inhibition, visuospatial processing, reading, and math skills. Eye-tracking studies included the prosaccade, antisaccade, and memory-guided tasks. Psychometric testing revealed an impairment in working memory among PE-F1s. Eye-tracking studies revealed numerous impairments among PE-F1s including additional saccades required to reach the target, poor endpoint accuracy, and slower reaction time. However, PE-F1s made faster saccades than controls, and fewer sequence errors in the memory-guided task. Our study provides a comprehensive assessment of cognitive function among PE-F1s. The development of PE may be seen as an early predictor of reduced cognitive function in children, specifically in working memory and oculomotor control. Future studies should extended to a larger study populations, and may be valuable for early studies of children born to pregnancies complicated by other disorders, such as gestational diabetes or intrauterine growth restriction.

Diffusion tensor imaging of white matter and correlates to eye movement control and psychometric testing in children with prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) can cause central nervous system dysfunction and widespread structural anomalies as detected by magnetic resonance imaging (MRI). This study focused on diffusion tensor imaging (DTI) of white matter in a large sample of PAE participants that allowed us to examine correlations with behavioral outcomes. Participants were confirmed PAE (n = 69, mean age = 12.5 ± 3.2 years) or typically developing control children (n = 67, mean age = 12.1 ± 3.2 years) who underwent brain MRI, eye movement tasks, and psychometric tests. A semi‐automated tractography method extracted fractional anisotropy (FA) and mean diffusivity (MD) values from 15 white matter tracts. The PAE group displayed decreased FA compared with controls in multiple tracts including 3 corpus callosum regions, right corticospinal tract, and 3 left hemisphere tracts connecting to the frontal lobe (cingulum, uncinate fasciculus, and superior longitudinal fasciculus). Significant group by sex interactions were found for the genu, left superior longitudinal fasciculus, and the left uncinate, with females in the PAE group exhibiting lower FA compared with control females. Correlations were found between DTI and eye movement measures in the control group, but these same relationships were absent in the PAE group. In contrast, no correlations were found between DTI and any of the psychometric tests used in this study. These findings support the hypothesis that measures of eye movement control may be valuable functional biomarkers of the brain injury induced by PAE as these tasks reveal group differences that appear to be linked to deficits in white matter integrity in the brain. Hum Brain Mapp 38:444–456, 2017.

Ethical Challenges in Contemporary FASD Research and Practice.

Fetal alcohol spectrum disorder (FASD) is increasingly recognized as a growing public health issue worldwide. Although more research is needed on both the diagnosis and treatment of FASD, and a broader and more culturally diverse range of services are needed to support those who suffer from FASD and their families, both research and practice for FASD raise significant ethical issues. In response, from the point of view of both research and clinical neuroethics, we provide a framework that emphasizes the need to maximize benefits and minimize harm, promote justice, and foster respect for persons within a global context.

Performance- and questionnaire-based tools for the evaluation of executive function in children and adolescents with fetal alcohol spectrum disorder

Individuals with ASD often demonstrate difficulties with behavioural inhibition (Adams and Jarrold, 2012). This can cause individuals with ASD to exhibit socially inappropriate behaviour that may make them an “easy target” for victimization. The current study investigated the hypothesis that inhibition mediates the relation between diagnosis (ASD, TD) and victimization. Methods: Fifty-one male participants were recruited (Mage = 14.39, range = 11.57–18.59). Thirty-two participants did not have an ASD diagnosis and 19 participants met criteria for ASD. Victimization experiences were evaluated using the WHO bullying and victimization questionnaire. Parent’s indicated the victimization their children experienced in the past 3 months. Inhibition was measured using the Behavioural Rating Inventory for Executive Functioning (Gioia et al., 2000). Results: A mediation analysis was run using Hayes’s (2013) PROCESS macro. Consistent with the hypothesis, inhibition fully mediated the relation between diagnosis (ASD, TD) and victimization. A bias-corrected bootstrap confidence interval for the indirect effect (b = .8452) based on 10,000 bootstrap samples was above zero (.3035 to 1.54) indicating the indirect effect was significant. Consistent with previous research, diagnosis was significantly related to victimization, b = 1.2155, t(49) = 3.67, p < .001; however, diagnosis was no longer significantly related to victimization controlling for inhibition b = .37, t(48) = .95, p = .35. Discussions: Results suggest that diagnostic differences in victimization are fully accounted for by differences in inhibition. Implications for bullying intervention and prevention programs are discussed.