Canadian Practice and Recommendations on Functional MRI to Lateralize Language in Epilepsy.

BACKGROUND/OBJECTIVE: Identifying a patient's dominant language hemisphere is an important evaluation performed prior to epilepsy surgery and is commonly assessed using functional magnetic resonance imaging (fMRI). However, the lack of standardization and resultant heterogeneity of fMRI paradigms used in clinical practice limits the ability of cross-center comparisons to be made regarding language laterality results. METHODS: Through surveying Canadian Epilepsy Centres in combination with reviewing supporting literature, current fMRI language lateralization practices for the clinical evaluation of patients with epilepsy were assessed. To encourage standardization of this practice, we outlined a two-part paradigm series that demonstrates widespread acceptance, reliability and accessibility in lateralizing various aspects of language functioning in individuals with average or near-average IQ and normal literacy skills. RESULTS: The collected data confirm a lack of standardization in fMRI laterality assessments leading to clinical heterogeneity in stimulation and control tasks, paradigm design and timing, laterality index calculations, thresholding values and analysis software and technique. We suggest a Sentence Completion (SC) and Word Generation (WG) paradigm series as it was most commonly employed across Canada, demonstrated reliability in lateralizing both receptive and expressive language areas in supporting literature, and could be readily intelligible to an inclusive population. CONCLUSION: Through providing recommendations for a two-part paradigm series, we hope to contribute to the standardization of this practice across Canada to reduce clinical heterogeneity, encourage communicability between institutions, and enhance methodologies for the surgical treatment of epilepsy for the benefit of all individuals living with epilepsy in Canada.

Maturation of Temporal Saccade Prediction from Childhood to Adulthood: Predictive Saccades, Reduced Pupil Size, and Blink Synchronization.

When presented with a periodic stimulus, humans spontaneously adjust their movements from reacting to predicting the timing of its arrival, but little is known about how this sensorimotor adaptation changes across development. To investigate this, we analyzed saccade behavior in 114 healthy humans (ages 6-24 years) performing the visual metronome task, who were instructed to move their eyes in time with a visual target that alternated between two known locations at a fixed rate, and we compared their behavior to performance in a random task, where target onsets were randomized across five interstimulus intervals (ISIs) and thus the timing of appearance was unknown. Saccades initiated before registration of the visual target, thus in anticipation of its appearance, were labeled predictive [saccade reaction time (SRT) < 90 ms] and saccades that were made in reaction to its appearance were labeled reactive (SRT > 90 ms). Eye-tracking behavior including saccadic metrics (e.g., peak velocity, amplitude), pupil size following saccade to target, and blink behavior all varied as a function of predicting or reacting to periodic targets. Compared with reactive saccades, predictive saccades had a lower peak velocity, a hypometric amplitude, smaller pupil size, and a reduced probability of blink occurrence before target appearance. The percentage of predictive and reactive saccades changed inversely from ages 8-16, at which they reached adult-levels of behavior. Differences in predictive saccades for fast and slow target rates are interpreted by differential maturation of cerebellar-thalamic-striatal pathways.SIGNIFICANCE STATEMENT From the first moments of life, humans are exposed to rhythm (i.e., mother's heartbeat in utero), but the timeline of brain development to promote the identification and anticipation of a rhythmic stimulus, known as temporal prediction, remains unknown. Here, we used saccade reaction time (SRT) in the visual metronome task to differentiate between temporally predictive and reactive responses to a target that alternated at a fixed rate in humans aged 6-24. Periods of age-related change varied little by target rate, with matured predictive performance evident by mid-adolescence for fast and slow rates. A strong correlation among saccade, pupil, and blink responses during target prediction provides evidence of oculomotor coordination and dampened noradrenergic neuronal activity when generating rhythmic motor responses.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Saccade, Pupil, and Blink Responses in Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Parkinson's disease (PD) patients exhibit deficits in saccade performance, pupil function, and blink rate. Isolated REM (rapid eye movement) Sleep Behavior Disorder (RBD) is a harbinger to PD making them candidates to investigate for early oculomotor abnormalities as PD biomarkers. OBJECTIVES: We tested whether saccade, pupillary, and blink responses in RBD were similar to PD. METHODS: RBD (n = 22), PD (n = 22) patients, and healthy controls (CTRL) (n = 74) were studied with video-based eye-tracking. RESULTS: RBD patients did not have significantly different saccadic behavior compared to CTRL, but PD patients differed from CTRL and RBD. Both patient groups had significantly lower blink rates, dampened pupil constriction, and dilation responses compared to CTRL. CONCLUSION: RBD and PD patients had altered pupil and blink behavior compared to CTRL. Because RBD saccade parameters were comparable to CTRL, pupil and blink brain areas may be impacted before saccadic control areas, making them potential prodromal PD biomarkers. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Examining the neural and cognitive processes that underlie reading through naming speed tasks.

We combined fMRI with eye tracking and speech recording to examine the neural and cognitive mechanisms that underlie reading. To simplify the study of the complex processes involved during reading, we used naming speed (NS) tasks (also known as rapid automatized naming or RAN) as a focus for this study, in which average reading right-handed adults named sets of stimuli (letters or objects) as quickly and accurately as possible. Due to the possibility of spoken output during fMRI studies creating motion artifacts, we employed both an overt session and a covert session. When comparing the two sessions, there were no significant differences in behavioral performance, sensorimotor activation (except for regions involved in the motor aspects of speech production) or activation in regions within the left-hemisphere-dominant neural reading network. This established that differences found between the tasks within the reading network were not attributed to speech production motion artifacts or sensorimotor processes. Both behavioral and neuroimaging measures showed that letter naming was a more automatic and efficient task than object naming. Furthermore, specific manipulations to the NS tasks to make the stimuli more visually and/or phonologically similar differentially activated the reading network in the left hemisphere associated with phonological, orthographic and orthographic-to-phonological processing, but not articulatory/motor processing related to speech production. These findings further our understanding of the underlying neural processes that support reading by examining how activation within the reading network differs with both task performance and task characteristics.

Mapping neural dynamics underlying saccade preparation and execution and their relation to reaction time and direction errors.

Our ability to control and inhibit automatic behaviors is crucial for negotiating complex environments, all of which require rapid communication between sensory, motor, and cognitive networks. Here, we measured neuromagnetic brain activity to investigate the neural timing of cortical areas needed for inhibitory control, while 14 healthy young adults performed an interleaved prosaccade (look at a peripheral visual stimulus) and antisaccade (look away from stimulus) task. Analysis of how neural activity relates to saccade reaction time (SRT) and occurrence of direction errors (look at stimulus on antisaccade trials) provides insight into inhibitory control. Neuromagnetic source activity was used to extract stimulus-aligned and saccade-aligned activity to examine temporal differences between prosaccade and antisaccade trials in brain regions associated with saccade control. For stimulus-aligned antisaccade trials, a longer SRT was associated with delayed onset of neural activity within the ipsilateral parietal eye field (PEF) and bilateral frontal eye field (FEF). Saccade-aligned activity demonstrated peak activation 10ms before saccade-onset within the contralateral PEF for prosaccade trials and within the bilateral FEF for antisaccade trials. In addition, failure to inhibit prosaccades on anti-saccade trials was associated with increased activity prior to saccade onset within the FEF contralateral to the peripheral stimulus. This work on dynamic activity adds to our knowledge that direction errors were due, at least in part, to a failure to inhibit automatic prosaccades. These findings provide novel evidence in humans regarding the temporal dynamics within oculomotor areas needed for saccade programming and the role frontal brain regions have on top-down inhibitory control.

Age related prefrontal compensatory mechanisms for inhibitory control in the antisaccade task.

Cognitive decline during aging includes impairments in frontal executive functions like reduced inhibitory control. However, decline is not uniform across the population, suggesting individual brain response variability to the aging process. Here we tested the hypothesis, within the oculomotor system, that older adults compensate for age-related neural alterations by changing neural activation levels of the oculomotor areas, or even by recruiting additional areas to assist with cognitive performance. We established that the observed changes had to be related to better cognitive performance to be considered as compensatory. To probe this hypothesis we used the antisaccade paradigm and analyzed the effect of aging on brain activations during the inhibition of prepotent responses to visual stimuli. While undergoing a fMRI scan with concurrent eye tracking, 25 young adults (21.7 y/o ± 1.9 SDM) and 25 cognitively normal older adults (66.2 y/o ± 9.8 SDM) performed an interleaved pro/antisaccade task consisting of a preparatory stage and an execution stage. Compared to young adults, older participants showed a larger increase in antisaccade reaction times, while also generating more antisaccade direction errors. BOLD signal analyses during the preparatory stage, when response inhibition processes are established to prevent an automatic response, showed decreased activations in the anterior cingulate and the supplementary eye fields in the older group. Moreover, older adults also showed additional recruitment of the frontal pole not seen in the younger group, and larger activations in the dorsolateral prefrontal cortex during antisaccade preparation. Additional analyses to address the performance variability in the older group showed distinct behavioral-BOLD signal correlations. Larger activations in the saccade network, including the frontal pole, positively correlated with faster antisaccade reaction times, suggesting a functional recruitment of this area. However, only the activation in the dorsolateral prefrontal cortex during the antisaccade events showed a negative correlation with the number of errors across older adults. These findings support the presence of two dissociable age-related plastic mechanisms that result in different behavioral outcomes. One related to the additional recruitment of neural resources within anterior pole to facilitate modulation of cognitive responses like faster antisaccade reaction times, and another related to increased activation of the dorsolateral prefrontal cortex resulting in a better inhibitory control in aging.

Using an emotional saccade task to characterize executive functioning and emotion processing in attention-deficit hyperactivity disorder and bipolar disorder.

Despite distinct diagnostic criteria, attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) share cognitive and emotion processing deficits that complicate diagnoses. The goal of this study was to use an emotional saccade task to characterize executive functioning and emotion processing in adult ADHD and BD. Participants (21 control, 20 ADHD, 20 BD) performed an interleaved pro/antisaccade task (look toward vs. look away from a visual target, respectively) in which the sex of emotional face stimuli acted as the cue to perform either the pro- or antisaccade. Both patient groups made more direction (erroneous prosaccades on antisaccade trials) and anticipatory (saccades made before cue processing) errors than controls. Controls exhibited lower microsaccade rates preceding correct anti- vs. prosaccade initiation, but this task-related modulation was absent in both patient groups. Regarding emotion processing, the ADHD group performed worse than controls on neutral face trials, while the BD group performed worse than controls on trials presenting faces of all valence. These findings support the role of fronto-striatal circuitry in mediating response inhibition deficits in both ADHD and BD, and suggest that such deficits are exacerbated in BD during emotion processing, presumably via dysregulated limbic system circuitry involving the anterior cingulate and orbitofrontal cortex.

Neural Correlates of Predictive Saccades.

Every day we generate motor responses that are timed with external cues. This phenomenon of sensorimotor synchronization has been simplified and studied extensively using finger tapping sequences that are executed in synchrony with auditory stimuli. The predictive saccade paradigm closely resembles the finger tapping task. In this paradigm, participants follow a visual target that "steps" between two fixed locations on a visual screen at predictable ISIs. Eventually, the time from target appearance to saccade initiation (i.e., saccadic RT) becomes predictive with values nearing 0 msec. Unlike the finger tapping literature, neural control of predictive behavior described within the eye movement literature has not been well established and is inconsistent, especially between neuroimaging and patient lesion studies. To resolve these discrepancies, we used fMRI to investigate the neural correlates of predictive saccades by contrasting brain areas involved with behavior generated from the predictive saccade task with behavior generated from a reactive saccade task (saccades are generated toward targets that are unpredictably timed). We observed striking differences in neural recruitment between reactive and predictive conditions: Reactive saccades recruited oculomotor structures, as predicted, whereas predictive saccades recruited brain structures that support timing in motor responses, such as the crus I of the cerebellum, and structures commonly associated with the default mode network. Therefore, our results were more consistent with those found in the finger tapping literature.

Immediate Neural Plasticity Involving Reaction Time in a Saccadic Eye Movement Task is Intact in Children With Fetal Alcohol Spectrum Disorder.

BACKGROUND: Saccades are rapid eye movements that bring an image of interest onto the retina. Previous research has found that in healthy individuals performing eye movement tasks, the location of a previous visual target can influence performance of the saccade on the next trial. This rapid behavioral adaptation represents a form of immediate neural plasticity within the saccadic circuitry. Our studies have shown that children with fetal alcohol spectrum disorder (FASD) are impaired on multiple saccade measures. We therefore investigated these previous trial effects in typically developing children and children with FASD to measure sensory neural plasticity and how these effects vary with age and pathology. METHODS: Both typically developing control children (n = 102; mean age = 10.54 ± 3.25; 48 males) and children with FASD (n = 66; mean age = 11.85 ± 3.42; 35 males) were recruited from 5 sites across Canada. Each child performed a visually guided saccade task. Reaction time and saccade amplitude were analyzed and then assessed based on the previous trial. RESULTS: There was a robust previous trial effect for both reaction time and amplitude, with both the control and FASD groups displaying faster reaction times and smaller saccades during alternation trials (visual target presented on the opposite side to the previous trial). Children with FASD exhibited smaller overall mean amplitude and smaller amplitude selectively on alternation trials compared with controls. The effect of the previous trial on reaction time and amplitude did not differ across childhood and adolescent development. CONCLUSIONS: Children with FASD did not display any significant reaction time differences, despite exhibiting numerous deficits in motor and higher level cognitive control over saccades in other studies. These results suggest that this form of immediate neural plasticity in response to sensory information before saccade initiation remains intact in children with FASD. In contrast, the previous trial effect on amplitude suggests that the motor component of saccades may be affected, signifying differential vulnerability to prenatal alcohol exposure.

Pupil size reveals preparatory processes in the generation of pro-saccades and anti-saccades.

The ability to generate flexible behaviors to accommodate changing goals in response to identical sensory stimuli is a signature that is inherited in humans and higher-level animals. In the oculomotor system, this function has often been examined with the anti-saccade task, in which subjects are instructed, prior to stimulus appearance, to either automatically look at the peripheral stimulus (pro-saccade) or to suppress the automatic response and voluntarily look in the opposite direction from the stimulus (anti-saccade). Distinct neural preparatory activity between the pro-saccade and anti-saccade conditions has been well documented, particularly in the superior colliculus (SC) and the frontal eye field (FEF), and this has shown higher inhibition-related fixation activity in preparation for anti-saccades than in preparation for pro-saccades. Moreover, the level of preparatory activity related to motor preparation is negatively correlated with reaction times. We hypothesised that preparatory signals may be reflected in pupil size through a link between the SC and the pupil control circuitry. Here, we examined human pupil dynamics during saccade preparation prior to the execution of pro-saccades and anti-saccades. Pupil size was larger in preparation for correct anti-saccades than in preparation for correct pro-saccades and erroneous pro-saccades made in the anti-saccade condition. Furthermore, larger pupil dilation prior to stimulus appearance accompanied saccades with faster reaction times, with a trial-by-trial correlation between dilation size and anti-saccade reaction times. Overall, our results demonstrate that pupil size is modulated by saccade preparation, and neural activity in the SC, together with the FEF, supports these findings, providing unique insights into the neural substrate coordinating cognitive processing and pupil diameter.

Developmental improvements in voluntary control of behavior: effect of preparation in the fronto-parietal network?

The ability to prepare for an action improves the speed and accuracy of its performance. While many studies indicate that behavior performance continues to improve throughout childhood and adolescence, it remains unclear whether or how preparatory processes change with development. Here, we used a rapid event-related fMRI design in three age groups (8-12, 13-17, 18-25years) who were instructed to execute either a prosaccade (look toward peripheral target) or an antisaccade (look away from target) task. We compared brain activity within the core fronto-parietal network involved in saccade control at two epochs of saccade generation: saccade preparation related to task instruction versus saccade execution related to target appearance. The inclusion of catch trials containing only task instruction and no target or saccade response allowed us to isolate saccade preparation from saccade execution. Five regions of interest were selected: the frontal, supplementary, parietal eye fields which are consistently recruited during saccade generation, and two regions involved in top down executive control: the dorsolateral prefrontal and anterior cingulate cortices. Our results showed strong evidence that developmental improvements in saccade performance were related to better saccade preparation rather than saccade execution. These developmental differences were mostly attributable to children who showed reduced fronto-parietal activity during prosaccade and antisaccade preparation, along with longer saccade reaction times and more incorrect responses, compared to adolescents and adults. The dorsolateral prefrontal cortex was engaged similarly across age groups, suggesting a general role in maintaining task instructions through the whole experiment. Overall, these findings suggest that developmental improvements in behavioral control are supported by improvements in effectively presetting goal-appropriate brain systems.

Automated Analysis Pipeline for Extracting Saccade, Pupil, and Blink Parameters Using Video-Based Eye Tracking.

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.

Attentional modulation of eye blinking is altered by sex, age, and task structure.

Spontaneous eye blinking is gaining popularity as a proxy for higher cognitive functions, as it is readily modulated by both environmental demands and internal processes. Prior studies were impoverished in sample size, sex representation and age distribution, making it difficult to establish a complete picture of the behavior. Here we present eye-tracking data from a large cohort of normative participants (n=604, 393 F, aged 5-93 years) performing two tasks: one with structured, discrete trials (interleaved pro/anti-saccade task; IPAST) and one with a less structured, continuous organization in which participants watch movies (free-viewing; FV). Sex- and age-based analyses revealed that females had higher blink rates between the ages of 22 and 58 years in the IPAST, and 22 and 34 years in FV. We derived a continuous measure of blink probability to reveal behavioral changes driven by stimulus appearance in both paradigms. In the IPAST, blinks were suppressed near stimulus appearance, particularly on correct anti-saccade trials, which we attribute to the stronger inhibitory control required for anti-saccades compared to pro-saccades. In FV, blink suppression occurred immediately after scene changes, and the effect was sustained on scenes where gaze clustered among participants (indicating engagement of attention). Females were more likely than males to blink during appearance of novel stimuli in both tasks, but only within the age bin of 18-44 years. The consistency of blink patterns in each paradigm endorses blinking as a sensitive index for changes in visual processing and attention, while sex and age differences drive interindividual variability.Significance Statement Eye-tracking is becoming useful as a non-invasive tool for detecting preclinical markers of neurological and psychiatric disease. Blinks are understudied despite being an important supplement to saccade and pupil eye-tracking metrics. The present study is a crucial step in developing a healthy baseline for blink behavior to compare to clinical groups. While many prior blink studies suffered from small sample sizes with relatively low age- and sex-diversity (review by Jongkees & Colzato, 2016), our large cohort of healthy participants has permitted a more detailed analysis of sex and age effects in blink behavior. Furthermore, our analysis techniques are robust to temporal changes in blink probability, greatly clarifying the relationship between blinking, visual processing, and inhibitory control mechanisms on visual tasks.

Literature review and protocol for a prospective multicentre cohort study on multimodal prediction of seizure recurrence after unprovoked first seizure.

INTRODUCTION: Epilepsy is a common neurological disorder characterised by recurrent seizures. Almost half of patients who have an unprovoked first seizure (UFS) have additional seizures and develop epilepsy. No current predictive models exist to determine who has a higher risk of recurrence to guide treatment. Emerging evidence suggests alterations in cognition, mood and brain connectivity exist in the population with UFS. Baseline evaluations of these factors following a UFS will enable the development of the first multimodal biomarker-based predictive model of seizure recurrence in adults with UFS. METHODS AND ANALYSIS: 200 patients and 75 matched healthy controls (aged 18-65) from the Kingston and Halifax First Seizure Clinics will undergo neuropsychological assessments, structural and functional MRI, and electroencephalography. Seizure recurrence will be assessed prospectively. Regular follow-ups will occur at 3, 6, 9 and 12 months to monitor recurrence. Comparisons will be made between patients with UFS and healthy control groups, as well as between patients with and without seizure recurrence at follow-up. A multimodal machine-learning model will be trained to predict seizure recurrence at 12 months. ETHICS AND DISSEMINATION: This study was approved by the Health Sciences and Affiliated Teaching Hospitals Research Ethics Board at Queen's University (DMED-2681-22) and the Nova Scotia Research Ethics Board (1028519). It is supported by the Canadian Institutes of Health Research (PJT-183906). Findings will be presented at national and international conferences, published in peer-reviewed journals and presented to the public via patient support organisation newsletters and talks. TRIAL REGISTRATION NUMBER: NCT05724719.

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.

Delayed oculomotor response associates with optic neuritis in youth with demyelinating disorders.

INTRODUCTION: Impairment in visual and cognitive functions occur in youth with demyelinating disorders such as multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. Quantitative behavioral assessment using eye-tracking and pupillometry can provide functional metrics for important prognostic and clinically relevant information at the bedside. METHODS: Children and adolescents diagnosed with demyelinating disorders and healthy, age-matched controls completed an interleaved pro- and anti-saccade task using video-based eye-tracking and underwent spectral-domain optical coherence tomography examination for evaluation of retinal nerve fiber layer and ganglion cell inner plexiform layer thickness. Low-contrast visual acuity and Symbol Digit Modalities Test were performed for visual and cognitive functional assessments. We assessed saccade and pupil parameters including saccade reaction time, direction error rate, pupil response latency, peak constriction time, and peak constriction and dilation velocities. Generalized Estimating Equations were used to examine the association of eye-tracking parameters with optic neuritis history, structural metrics, and visual and cognitive scores. RESULTS: The study included 36 demyelinating disorders patients, aged 8-18 yrs. (75% F; median = 15.22 yrs., SD = 2.8) and 34 age-matched controls (65% F; median = 15.26 yrs., SD = 2.3). Surprisingly, pro- and anti-saccade performance was comparable between patients and controls, whereas pupil control was altered in patients. Oculomotor latency measures were strongly associated with the number of optic neuritis episodes, including saccade reaction time, pupil response latency, and peak constriction time. Peak constriction time was associated with both retinal nerve fiber layer and ganglion cell inner plexiform layer thickness. Pupil response latency and peak constriction time were associated with visual acuity. Pupil velocity for both constriction and dilation was associated with Symbol Digit Modalities Test scores. CONCLUSION: The strong associations between oculomotor measures with history of optic neuritis, structural, visual, and cognitive assessments in these cohorts demonstrates that quantitative eye-tracking can be useful for probing demyelinating injury of the brain and optic nerve. Future studies should evaluate their utility in discriminating between demyelinating disorders and tracking disease progression.

Classification and staging of Parkinson's disease using video-based eye tracking.

INTRODUCTION: 83% of those diagnosed with Parkinson's Disease (PD) eventually progress to PD with mild cognitive impairment (PD-MCI) followed by dementia (PDD) - suggesting a complex spectrum of pathology concomitant with aging. Biomarkers sensitive and specific to this spectrum are required if useful diagnostics are to be developed that may supplement current clinical testing procedures. We used video-based eye tracking and machine learning to develop a simple, non-invasive test sensitive to PD and the stages of cognitive dysfunction. METHODS: From 121 PD (45 Cognitively Normal/45 MCI/20 Dementia/11 Other) and 106 healthy controls, we collected video-based eye tracking data on an interleaved pro/anti-saccade task. Features of saccade, pupil, and blink behavior were used to train a classifier to predict confidence scores for PD/PD-MCI/PDD diagnosis. RESULTS: The Receiver Operator Characteristic Area Under the Curve (ROC-AUC) of the classifier was 0.88, with the cognitive-dysfunction subgroups showing progressively increased AUC, and the AUC of PDD being 0.95. The classifier reached a sensitivity of 83% and a specificity of 78%. The confidence scores predicted PD motor and cognitive performance scores. CONCLUSION: Biomarkers of saccade, pupil, and blink were extracted from video-based eye tracking to create a classifier with high sensitivity to the landscape of PD cognitive and motor dysfunction. A complex landscape of PD is revealed through a quick, non-invasive eye tracking task and our model provides a framework for such a task to be used as a supplementary screening tool in the clinic.

Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls (n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.

Impaired executive function signals in motor brain regions in Parkinson's disease.

Recent evidence has shown that patients with Parkinson's disease (PD) often display deficits in executive functions, such as planning for future behavior, and these deficits may stem from pathologies in prefrontal cortex and basal ganglia circuits that are critical to executive control. Using the antisaccade task (look away from a visual stimulus), we show that when the preparatory 'readiness' to perform a given action is dissociated from the actual execution of that action, PD patients off and on dopamine medication display behavioral impairments and reduced cortical brain activation that cannot be explained by a pathology related to dysfunction in movement execution. Rather, they show that the appropriate task set signals were not in place in motor regions prior to execution, resulting in impairments in the control of subsequent voluntary movement. This is the first fMRI study of antisaccade deficits in Parkinson's disease, and importantly, the findings point to a critical role of the basal ganglia in translating signals related to rule representation (executive) into those governing voluntary motor behavior.