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Abstract Objective This study measured eye movements in children with a history of opsoclonus‐myoclonus ataxia syndrome in order to identify abnormalities in saccade and pupil behavior that map onto specific alterations in brainstem pathways. Methods We used video‐based eye tracking while participants freely viewed 10 min of short (2–4 s) video clips without instructions. Clip transitions represented a large visual perturbation and we quantified multiple characteristics of saccade and pupil responses following these transitions in 13 children recovering from opsoclonus‐myoclonus and 13 healthy, age‐matched control participants. Results The frequency of saccades and distribution of fixation durations differed between the groups. Following the clip transitions, children recovering from opsoclonus‐myoclonus ataxia syndrome exhibited longer time to initiate saccades, leading to a delay in harvesting visual information. Clip transitions to lighter clips produced similar pupil constriction responses in the two groups. However, clip transitions to darker clips produced dilation responses that were initiated earlier and of greater magnitude in opsoclonus‐myoclonus ataxia syndrome, suggesting removal or suppression of a signal that delays dilation. Interpretation Children with a history of opsoclonus‐myoclonus ataxia syndrome demonstrated key abnormalities in saccade and pupil metrics. We propose a novel hypothesis in which dysfunction in the pathway from the superior colliculus to the mesencephalic and pontine reticular formation that houses the saccade and pupil premotor circuits could produce these results.

Abstract Background The oculomotor circuit spans many cortical and subcortical areas that have been implicated in psychiatric disease. This, combined with previous findings, suggests that eye tracking may be a useful method to investigate eating disorders. Therefore, this study aimed to assess oculomotor behaviors in youth with and without an eating disorder. Methods Female youth with and without an eating disorder completed a structured task involving randomly interleaved pro-saccade (toward at a stimulus) and anti-saccade (away from stimulus) trials with video-based eye tracking. Differences in saccades (rapid eye movements between two points), eye blinks and pupil were examined. Results Youth with an eating disorder (n = 65, M age = 17.16 ± 3.5 years) were compared to healthy controls (HC; n = 65, M age = 17.88 ± 4.3 years). The eating disorder group was composed of individuals with anorexia nervosa (n = 49), bulimia nervosa (n = 7) and other specified feeding or eating disorder (n = 9). The eating disorder group was further divided into two subgroups: individuals with a restrictive spectrum eating disorder (ED-R; n = 43) or a bulimic spectrum eating disorder (ED-BP; n = 22). In pro-saccade trials, the eating disorder group made significantly more fixation breaks than HCs (F(1,128) = 5.33, p = 0.023). The ED-BP group made the most anticipatory pro-saccades, followed by ED-R, then HCs (F(2,127) = 3.38, p = 0.037). Groups did not differ on rate of correct express or regular latency pro-saccades. In anti-saccade trials, groups only significantly differed on percentage of direction errors corrected (F(2, 127) = 4.554, p = 0.012). The eating disorder group had a significantly smaller baseline pupil size (F(2,127) = 3.60, p = 0.030) and slower pro-saccade dilation velocity (F(2,127) = 3.30, p = 0.040) compared to HCs. The ED-R group had the lowest blink probability during the intertrial interval (ITI), followed by ED-BP, with HCs having the highest ITI blink probability (F(2,125) = 3.63, p = 0.029). Conclusions These results suggest that youth with an eating disorder may have different oculomotor behaviors during a structured eye tracking task. The oculomotor behavioral differences observed in this study presents an important step towards identifying neurobiological and cognitive contributions towards eating disorders.

The tremendous increase in the use of video-based eye tracking has made it possible to collect eye tracking data from thousands of participants. The traditional procedures for the manual detection and classification of saccades and for trial categorization (e.g., correct vs. incorrect) are not viable for the large datasets being collected. Additionally, video-based eye trackers allow for the analysis of pupil responses and blink behaviors. Here, we present a detailed description of our pipeline for collecting, storing, and cleaning data, as well as for organizing participant codes, which are fairly lab-specific but nonetheless, are important precursory steps in establishing standardized pipelines. More importantly, we also include descriptions of the automated detection and classification of saccades, blinks, “blincades” (blinks occurring during saccades), and boomerang saccades (two nearly simultaneous saccades in opposite directions where speed-based algorithms fail to split them), This is almost entirely task-agnostic and can be used on a wide variety of data. We additionally describe novel findings regarding post-saccadic oscillations and provide a method to achieve more accurate estimates for saccade end points. Lastly, we describe the automated behavior classification for the interleaved pro/anti-saccade task (IPAST), a task that probes voluntary and inhibitory control. This pipeline was evaluated using data collected from 592 human participants between 5 and 93 years of age, making it robust enough to handle large clinical patient datasets. In summary, this pipeline has been optimized to consistently handle large datasets obtained from diverse study cohorts (i.e., developmental, aging, clinical) and collected across multiple laboratory sites.

Shifting motor actions from reflexively reacting to an environmental stimulus to predicting it allows for smooth synchronization of behavior with the outside world. This shift relies on the identification of patterns within the stimulus – knowing when a stimulus is predictable and when it is not – and launching motor actions accordingly. Failure to identify predictable stimuli results in movement delays whereas failure to recognize unpredictable stimuli results in early movements with incomplete information that can result in errors. Here we used a metronome task, combined with video-based eye-tracking, to quantify temporal predictive learning and performance to regularly paced visual targets at 5 different interstimulus intervals (ISIs). We compared these results to the random task where the timing of the target was randomized at each target step. We completed these tasks in female pediatric psychiatry patients (age range: 11–18 years) with borderline personality disorder (BPD) symptoms, with (n = 22) and without (n = 23) a comorbid attention-deficit hyperactivity disorder (ADHD) diagnosis, against controls (n = 35). Compared to controls, BPD and ADHD/BPD cohorts showed no differences in their predictive saccade performance to metronome targets, however, when targets were random ADHD/BPD participants made significantly more anticipatory saccades (i.e., guesses of target arrival). The ADHD/BPD group also significantly increased their blink rate and pupil size when initiating movements to predictable versus unpredictable targets, likely a reflection of increased neural effort for motor synchronization. BPD and ADHD/BPD groups showed increased sympathetic tone evidenced by larger pupil sizes than controls. Together, these results support normal temporal motor prediction in BPD with and without ADHD, reduced response inhibition in BPD with comorbid ADHD, and increased pupil sizes in BPD patients. Further these results emphasize the importance of controlling for comorbid ADHD when querying BPD pathology.

BackgroundSymptoms of depression are present in neurodegenerative disorders (ND). It is important that depression-related symptoms be adequately screened and monitored in persons living with ND. The Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) is a widely-used self-report measure to assess and monitor depressive severity across different patient populations. However, the measurement properties of the QIDS-SR have not been assessed in ND.AimTo use Rasch Measurement Theory to assess the measurement properties of the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) in ND and in comparison to major depressive disorder (MDD).MethodsDe-identified data from the Ontario Neurodegenerative Disease Research Initiative (NCT04104373) and Canadian Biomarker Integration Network in Depression (NCT01655706) were used in the analyses. Five hundred and twenty participants with ND (Alzheimer’s disease or mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia and Parkinson’s disease) and 117 participants with major depressive disorder (MDD) were administered the QIDS-SR. Rasch Measurement Theory was used to assess measurement properties of the QIDS-SR, including unidimensionality and item-level fit, category ordering, item targeting, person separation index and reliability and differential item functioning.ResultsThe QIDS-SR fit well to the Rasch model in ND and MDD, including unidimensionality, satisfactory category ordering and goodness-of-fit. Item-person measures (Wright maps) showed gaps in item difficulties, suggesting poor precision for persons falling between those severity levels. Differences between mean person and item measures in the ND cohort logits suggest that QIDS-SR items target more severe depression than experienced by the ND cohort. Some items showed differential item functioning between cohorts.ConclusionThe present study supports the use of the QIDS-SR in MDD and suggest that the QIDS-SR can be also used to screen for depressive symptoms in persons with ND. However, gaps in item targeting were noted that suggests that the QIDS-SR cannot differentiate participants falling within certain severity levels. Future studies would benefit from examination in a more severely depressed ND cohort, including those with diagnosed clinical depression.

Abstract Background The lack of effective treatments for Alzheimer’s disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. Methods We exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1 −/− ) mice received an i.c.v. infusion of AβOs. Results We report that anakinra prevented AβO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1 −/− mice. Conclusion These findings indicate that IL-1β mediates the impact of AβOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

The capacity for inhibitory control is an important cognitive process that undergoes dynamic changes over the course of the lifespan. Robust characterization of this trajectory, considering age continuously and using flexible modeling techniques, is critical to advance our understanding of the neural mechanisms that differ in healthy aging and neurological disease. The interleaved pro/anti-saccade task (IPAST), in which pro- and anti-saccade trials are randomly interleaved within a block, provides a simple and sensitive means of assessing the neural circuitry underlying inhibitory control. We utilized IPAST data collected from a large cross-sectional cohort of normative participants (n = 604, 5–93 years of age), standardized pre-processing protocols, generalized additive modeling, and change point analysis to investigate the effect of age on saccade behavior and identify significant periods of change throughout the lifespan. Maturation of IPAST measures occurred throughout adolescence, while subsequent decline began as early as the mid-20s and continued into old age. Considering pro-saccade correct responses and anti-saccade direction errors made at express (short) and regular (long) latencies was crucial in differentiating developmental and aging processes. We additionally characterized the effect of age on voluntary override time, a novel measure describing the time at which voluntary processes begin to overcome automated processes on anti-saccade trials. Drawing on converging animal neurophysiology, human neuroimaging, and computational modeling literature, we propose potential frontal-parietal and frontal-striatal mechanisms that may mediate the behavioral changes revealed in our analysis. We liken the models presented here to “cognitive growth curves” which have important implications for improved detection of neurological disease states that emerge during vulnerable windows of developing and aging.

The Ontario Brain Institute's “Brain-CODE” is a large-scale informatics platform designed to support the collection, storage and integration of diverse types of data across several brain disorders as a means to understand underlying causes of brain dysfunction and developing novel approaches to treatment. By providing access to aggregated datasets on participants with and without different brain disorders, Brain-CODE will facilitate analyses both within and across diseases and cover multiple brain disorders and a wide array of data, including clinical, neuroimaging, and molecular. To help achieve these goals, consensus methodology was used to identify a set of core demographic and clinical variables that should be routinely collected across all participating programs. Establishment of Common Data Elements within Brain-CODE is critical to enable a high degree of consistency in data collection across studies and thus optimize the ability of investigators to analyze pooled participant-level data within and across brain disorders. Results are also presented using selected common data elements pooled across three studies to better understand psychiatric comorbidity in neurological disease (Alzheimer's disease/amnesic mild cognitive impairment, amyotrophic lateral sclerosis, cerebrovascular disease, frontotemporal dementia, and Parkinson's disease).

Impulsivity and emotional dysregulation are two core features of borderline personality disorder (BPD), and the neural mechanisms recruited during mixed-strategy interactions overlap with frontolimbic networks that have been implicated in BPD. We investigated strategic choice patterns during the classic two-player game, Matching Pennies, where the most efficient strategy is to choose each option randomly from trial-to-trial to avoid exploitation by one’s opponent. Twenty-seven female adolescents with BPD (mean age: 16 years) and twenty-seven age-matched female controls (mean age: 16 years) participated in an experiment that explored the relationship between strategic choice behavior and impulsivity in both groups and emotional dysregulation in BPD. Relative to controls, BPD participants showed marginally fewer reinforcement learning biases, particularly decreased lose-shift biases, increased variability in reaction times (coefficient of variation; CV), and a greater percentage of anticipatory decisions. A subset of BPD participants with high levels of impulsivity showed higher overall reward rates, and greater modulation of reaction times by outcome, particularly following loss trials, relative to control and BPD participants with lower levels of impulsivity. Additionally, BPD participants with higher levels of emotional dysregulation showed marginally increased reward rate and increased entropy in choice patterns. Together, our preliminary results suggest that impulsivity and emotional dysregulation may contribute to variability in mixed-strategy decision-making in female adolescents with BPD.

Abstract Monkeys are becoming important translational models of neurodegenerative disease. To facilitate model development, we measured cerebrospinal fluid (CSF) concentrations of key biomarkers in healthy male and female cynomolgus and rhesus macaques. Amyloid beta (Aβ40, Aβ42), tau (total tau [t‐tau], phosphorylated tau [pThr181]), and neurofilament light (NfL) concentrations were measured in CSF of 82 laboratory‐housed, experimentally naïve cynomolgus (n = 33) and rhesus (n = 49) macaques. Aβ40 and Aβ42 were significantly higher in rhesus, and female rhesus were higher than males. NfL and t‐tau were higher in males, and NfL was higher in rhesus macaques. p‐tau was not affected by species or sex. We also examined whether sample location (lumbar or cisterna puncture) affected concentrations. Sample acquisition site only affected NfL, which was higher in CSF from lumbar puncture compared to cisterna magna puncture. Establishing normative biomarker values for laboratory‐housed macaque monkeys provides an important resource by which to compare to monkey models of neurodegenerative diseases.

Despite the wide application of the magnetic resonance imaging (MRI) technique, there are no widely used standards on naming and describing MRI sequences. The absence of consistent naming conventions presents a major challenge in automating image processing since most MRI software require a priori knowledge of the type of the MRI sequences to be processed. This issue becomes increasingly critical with the current efforts toward open-sharing of MRI data in the neuroscience community. This manuscript reports an MRI sequence detection method using imaging metadata and a supervised machine learning technique. Three datasets from the Brain Center for Ontario Data Exploration (Brain-CODE) data platform, each involving MRI data from multiple research institutes, are used to build and test our model. The preliminary results show that a random forest model can be trained to accurately identify MRI sequence types, and to recognize MRI scans that do not belong to any of the known sequence types. Therefore the proposed approach can be used to automate processing of MRI data that involves a large number of variations in sequence names, and to help standardize sequence naming in ongoing data collections. This study highlights the potential of the machine learning approaches in helping manage health data.

Studying the typical development of reading is key to understanding the precise deficits that underlie reading disabilities. An important correlate of efficient reading is the speed of naming arrays of simple stimuli such as letters and pictures. In this cross-sectional study, we examined developmental changes in visual processing that occurs during letter and object naming from childhood to early adulthood in terms of behavioral task efficiency, associated articulation and eye movement parameters, and the coordination between them, as measured by eye-voice span in both the spatial and temporal domains. We used naming speed (NS) tasks, in which participants were required to name sets of letters or simple objects as quickly and as accurately as possible. Single stimulus manipulations were made to these tasks to make the stimuli either more visually and/or phonologically similar to one another in order to examine how these manipulations affected task performance and the coordination between speech and eye movements. Across development there was an increased efficiency in speech and eye movement performance and their coordination in both the spatial and temporal domains. Furthermore, manipulations to the phonological and visual similarity of specific letter and object stimuli revealed that orthographic processing played a greater role than phonological processing in performance, with the contribution of phonological processing diminishing across development. This comprehensive typical developmental trajectory provides a benchmark for clinical populations to elucidate the nature of the cognitive dysfunction underlying reading difficulties.

The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online.

Abstract Introduction Neurofilament light (NFL) in cerebrospinal fluid (CSF) is elevated in neurodegenerative disease patients, and may track disease progression and treatment. Macaque monkeys are emerging as important translational models of neurodegeneration, and NFL may be a useful biomarker. Methods To determine the influence of a previous lumbar puncture (LP) on NFL, we collected CSF at multiple time points in macaque monkeys via LP or cisterna magna puncture. NFL, amyloid beta (Aβ40, Aβ42), and tau (tTau, pTau) in CSF were measured by standard enzyme‐linked immunosorbent assay and multiplex. Results NFL was significantly elevated at 14 to 23 days after an LP (median increase: 162%). Aβ and tau biomarkers remained stable. NFL peaked and decayed over 1 to 2 months after LP. NFL was not elevated after cisterna magna puncture. Discussion Results suggest damage of the cauda equina during LP may increase NFL. Caution should be taken in interpreting NFL concentration in studies in which repeat LPs are performed.

Basal ganglia can both facilitate or inhibit movement through excitatory and inhibitory pathways; however whether these opposing signals are dynamically regulated during behavior is not known. Here the authors use multinucleus LFP recordings and electrical microstimulation in monkeys performing saccade based tasks to show task specific changes in the tonic weighting of these pathways.

Saliency maps have been proposed to guide visual attention, yet the underlying neural correlates remain undetermined. Here, the authors record from monkeys as they watch videos of natural scenes, and find superior colliculus superficial visual-layer neurons exhibit activity patterns consistent with a visual saliency map.

The ability to inhibit automatic versus voluntary saccade commands in demanding situations can be impaired in neurodegenerative diseases such as Huntington's disease (HD). These deficits could result from disruptions in the interaction between basal ganglia and the saccade control system. To investigate voluntary oculomotor control deficits related to the cortico-basal circuitry, we evaluated early HD patients using an interleaved pro- and anti-saccade task that requires flexible executive control to generate either an automatic response (look at a peripheral visual stimulus) or a voluntary response (look away from the stimulus in the opposite direction). The impairments of HD patients in this task are mainly attributed to degeneration in the striatal medium spiny neurons leading to an over-activation of the indirect-pathway thorough the basal ganglia. However, some studies have proposed that damage outside the indirect-pathway also contribute to executive and saccade deficits. We used the interleaved pro- and anti-saccade task to study voluntary saccade inhibition deficits, Voxel-based morphometry and Tract-based spatial statistic to map cortico-basal ganglia circuitry atrophy in HD. HD patients had voluntary saccade inhibition control deficits, including increased regular-latency anti-saccade errors and increased anticipatory saccades. These deficits correlated with white-matter atrophy in the inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior corona radiata and superior longitudinal fasciculus. These findings suggest that cortico-basal ganglia white-matter atrophy in HD, disrupts the normal connectivity in a network controlling voluntary saccade inhibitory behavior beyond the indirect-pathway. This suggests that in vivo measures of white-matter atrophy can be a reliable marker of the progression of cognitive deficits in HD. Keywords: Saccades, Anti-saccade inhibition, Basal ganglia, Frontal cortex, White-matter atrophy, Bio-marker

A number of clinical disorders that are either neurodevelopmental or neurodegenerative exhibit significant cognitive impairments that require some form of intervention. However, the current paucity of pro-cognitive treatments that are available, due to the lack of knowledge of biological targets and symptomologies, impedes the treatment of individuals with cognitive impairments. In this review article, we explore three critical steps that need to be established in order to lead to the development of effective and appropriate treatments for cognitive impairments. The first step specifically involves the ability to efficiently reproduce and standardize current animal models of disease. The second step involves establishing well-controlled and standardized animal models across different species, such as rodents and monkeys, that link to human disease conditions. The third step involves building these animal models from both a translational and a reverse translational perspective in order to gain critical insight into the etiologies of specific cognitive impairments and the development of their early physiological and behavioral biomarkers. This bidirectional translational approach is important to improve the investigation of disease biomarkers, the underlying mechanisms of novel therapeutics on cognition, and to validate preclinical findings of drug discovery. Overall, even though animal models play an important role in investigating the pathophysiological processes and mechanisms associated with typical and atypical behavior, we discuss the ongoing challenges associated with these three critical steps of cross-translational research that has led to the current lack of success of developing effective new compounds for potential treatments and suggest approaches to stimulate advances in the field.

The distributed nature of information processing in the brain creates a complex variety of decision making behavior. Likewise, computational models of saccadic decision making behavior are numerous and diverse. Here we present a generative model of saccadic action selection in the context of competitive decision making in the superior colliculus (SC) in order to investigate how independent neural signals may converge to interact and guide saccade selection, and to test if systematic variations can better replicate the variability in responses that are part of normal human behavior. The model was tasked with performing pro- and anti-saccades in order to replicate specific attributes of healthy human saccade behavior. Participants (ages 18–39) were instructed to either look toward (pro-saccade, well-practiced automated response) or away from (anti-saccade, combination of inhibitory and voluntary responses) a peripheral visual stimulus. They generated express and regular latency saccades in the pro-saccade task. In the anti-saccade task, correct reaction times were longer and participants occasionally looked at the stimulus (direction error) at either express or regular latencies. To gain a better understanding of the underlying neural processes that lead to saccadic action selection and response inhibition, we implemented 8 inputs inspired by systems neuroscience. These inputs reflected known sensory, automated, voluntary, and inhibitory components of cortical and basal ganglia activity that coalesces in the intermediate layers of the SC (SCi). The model produced bimodal reaction time distributions, where express and regular latency saccades had distinct modes, for both correct pro-saccades and direction errors in the anti-saccade task. Importantly, express and regular latency direction errors resulted from interactions of different inputs in the model. Express latency direction errors were due to a lack of pre-emptive fixation and inhibitory activity, which aloud sensory and automated inputs to initiate a stimulus-driven saccade. Regular latency errors occurred when the automated motor signals were stronger than the voluntary motor signals. While previous models have emulated fewer aspects of these behavioral findings, the focus of the simulations here is on the interaction of a wide variety of physiologically-based information integration producing a richer set of natural behavioral variability.

Neuropsychiatric disorders and type 2 diabetes (T2D) are major public health concerns proposed to be intimately connected. T2D is associated with increased risk of dementia, neuropsychiatric and mood disorders. Evidences of the involvement of insulin signaling on brain mechanisms related to depression indicate that insulin resistance, a hallmark of type 2 diabetes, could develop in the brains of depressive patients. In this article, we briefly review possible molecular mechanisms associating defective brain insulin signaling with reward system, neurogenesis, synaptic plasticity and hypothalamic-pituitary-adrenal (HPA) stress axis in depression. We further discuss the involvement of tumor necrosis factor α (TNFα) promoting defective insulin signaling and depressive-like behavior in rodent models. Finally, due to the high resistant rate of anti-depressants, novel insights into the link between insulin resistance and depression may advance the development of alternative treatments for this disease.

Background: Fetal alcohol spectrum disorders (FASD) is one of the most common causes of developmental disabilities and neurobehavioral deficits. Despite the high-prevalence of FASD, the current diagnostic process is challenging and time- and money- consuming, with underreported profiles of the neurocognitive and neurobehavioral impairments because of limited clinical capacity. We assessed children/youth with FASD from a multimodal perspective and developed a high-performing, low-cost screening protocol using a machine learning framework.Methods and Findings: Participants with FASD and age-matched typically developing controls completed up to six assessments, including saccadic eye movement tasks (prosaccade, antisaccade, and memory-guided saccade), free viewing of videos, psychometric tests, and neuroimaging of the corpus callosum. We comparatively investigated new machine learning methods applied to these data, toward the acquisition of a quantitative signature of the neurodevelopmental deficits, and the development of an objective, high-throughput screening tool to identify children/youth with FASD. Our method provides a comprehensive profile of distinct measures in domains including sensorimotor and visuospatial control, visual perception, attention, inhibition, working memory, academic functions, and brain structure. We also showed that a combination of four to six assessments yields the best FASD vs. control classification accuracy; however, this protocol is expensive and time consuming. We conducted a cost/benefit analysis of the six assessments and developed a high-performing, low-cost screening protocol based on a subset of eye movement and psychometric tests that approached the best result under a range of constraints (time, cost, participant age, required administration, and access to neuroimaging facility). Using insights from the theory of value of information, we proposed an optimal annual screening procedure for children at risk of FASD.Conclusions: We developed a high-capacity, low-cost screening procedure under constrains, with high expected monetary benefit, substantial impact of the referral and diagnostic process, and expected maximized long-term benefits to the tested individuals and to society. This annual screening procedure for children/youth at risk of FASD can be easily and widely deployed for early identification, potentially leading to earlier intervention and treatment. This is crucial for neurodevelopmental disorders, to mitigate the severity of the disorder and/or frequency of secondary comorbidities.

Arousal level changes constantly and it has a profound influence on performance during everyday activities. Fluctuations in arousal are regulated by the autonomic nervous system, which is mainly controlled by the balanced activity of the parasympathetic and sympathetic systems, commonly indexed by heart rate (HR) and galvanic skin response (GSR), respectively. Although a growing number of studies have used pupil size to indicate the level of arousal, research that directly examines the relationship between pupil size and HR or GSR is limited. The goal of this study was to understand how pupil size is modulated by autonomic arousal. Human participants fixated various emotional face stimuli, of which low-level visual properties were carefully controlled, while their pupil size, HR, GSR, and eye position were recorded simultaneously. We hypothesized that a positive correlation between pupil size and HR or GSR would be observed both before and after face presentation. Trial-by-trial positive correlations between pupil diameter and HR and GSR were found before face presentation, with larger pupil diameter observed on trials with higher HR or GSR. However, task-evoked pupil responses after face presentation only correlated with HR. Overall, these results demonstrated a trial-by-trial relationship between pupil size and HR or GSR, suggesting that pupil size can be used as an index for arousal level involuntarily regulated by the autonomic nervous system.

The signature of spatial attention effects has been demonstrated through saccade planning and working memory. Although saccade planning and working memory have been commonly linked to attention, the comparison of effects resulting from saccade planning and working memory is less explored. It has recently been shown that spatial attention interacts with local luminance at the attended location. When bright and dark patch stimuli are presented simultaneously in the periphery, thereby producing no change in global luminance, pupil size is nonetheless smaller when the locus of attention overlaps with the bright, compared to the dark patch stimulus (referred to as the local luminance modulation). Here, we used the local luminance modulation to directly compare the effects of saccade planning and spatial working memory. Participants were required to make a saccade towards a visual target location (visual-delay) or a remembered target location (memory-delay) after a variable delay, and the bright and dark patch stimuli were presented during the delay period between target onset and go signal. Greater pupil constriction was observed when the bright patch, compared to the dark patch, was spatially aligned with the target location in both tasks. However, the effects were diminished when there was no contingency implemented between the patch and target locations, particularly in the memory-delay task. Together, our results suggest the involvement of similar, but not identical, attentional mechanisms through saccade planning and working memory, and highlight a promising potential of local pupil luminance responses for probing visuospatial processing.

Although reading is an important and generative skill, it remains controversial how reading skills and reading difficulties develop. Currently, the fields of neuroscience, cognition, and education each have complex models to describe reading and elucidate where in the reading process deficits occur. We suggest that integrating the neural, cognitive, and educational accounts of reading offers the promise of transformative change in understanding reading development and reading difficulties. As a starting point for bridging the gaps among these fields, we used naming speed tasks as the basis for this review because they provide a “microcosm” of the processes involved during reading. We use naming speed tasks to investigate how incorporating cognitive psychology with neuroimaging techniques, under the guidance of educational theories, can further the understanding of learning and instruction, and may lead to the identification of the neural signatures of reading difficulties that might be hidden from view earlier in development.

The capture of covert spatial attention by salient visual events influences subsequent gaze behavior. A task irrelevant stimulus (cue) can reduce (Attention capture) or prolong (Inhi-bition of return) saccade reaction time to a subsequent target stimulus depending on the cue-target delay. Here we investigated the mechanisms that underlie the sensory-based account of AC/IOR by manipulating the visual processing stage where the cue and target interact. In Experiment 1, liquid crystal shutter goggles were used to test whether AC/IOR occur at a monocular versus binocular processing stage (before versus after signals from both eyes converge). In Experiment 2, we tested whether visual orientation selective mechanisms are critical for AC/IOR by using oriented “Gabor” stimuli. We found that the magnitude of AC and IOR was not different between monocular and interocular viewing conditions, or between iso- and ortho-oriented cue-target interactions. The results suggest that the visual mechanisms that contribute to AC/IOR arise at an orientation-independent binocular processing stage.

Systematic modulations of microsaccades have been observed in humans during covert orienting. We show here that monkeys are a suitable model for studying the neurophysiology governing these modulations of microsaccades. Using various cue-target saccade tasks, we observed the effects of visual and auditory cues on microsaccades in monkeys. As in human studies, following visual cues there was an early bias in cue-congruent microsaccades followed by a later bias in cue-incongruent microsaccades. Following auditory cues there was a cue-incongruent bias in left cues only. In a separate experiment, we observed that brainstem omnipause neurons, which gate all saccades, also paused during microsaccade generation. Thus, we provide evidence that at least part of the same neurocircuitry governs both large saccades and microsaccades.