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.

Genetic variation in the dopamine system is associated with mixed-strategy decision-making in patients with Parkinson's disease.

Decision-making during mixed-strategy games requires flexibly adapting choice strategies in response to others' actions and dynamically tracking outcomes. Such decisions involve diverse cognitive processes, including reinforcement learning, which are affected by disruptions to the striatal dopamine system. We therefore investigated how genetic variation in dopamine function affected mixed-strategy decision-making in Parkinson's disease (PD), which involves striatal dopamine pathology. Sixty-six PD patients (ages 49-85, Hoehn and Yahr Stages 1-3) and 22 healthy controls (ages 54-75) competed in a mixed-strategy game where successful performance depended on minimizing choice biases (i.e., flexibly adapting choices trial by trial). Participants also completed a fixed-strategy task that was matched for sensory input, motor outputs and overall reward rate. Factor analyses were used to disentangle cognitive from motor aspects within both tasks. Using a within-subject, multi-centre design, patients were examined on and off dopaminergic therapy, and genetic variation was examined via a multilocus genetic profile score representing the additive effects of three single nucleotide polymorphisms (SNPs) that influence dopamine transmission: rs4680 (COMT Val158 Met), rs6277 (C957T) and rs907094 (encoding DARPP-32). PD and control participants displayed comparable mixed-strategy choice behaviour (overall); however, PD patients with genetic profile scores indicating higher dopamine transmission showed improved performance relative to those with low scores. Exploratory follow-up tests across individual SNPs revealed better performance in individuals with the C957T polymorphism, reflecting higher striatal D2/D3 receptor density. Importantly, genetic variation modulated cognitive aspects of performance, above and beyond motor function, suggesting that genetic variation in dopamine signalling may underlie individual differences in cognitive function in PD.

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.

A novel fMRI paradigm to dissociate the behavioral and neural components of mixed-strategy decision making from non-strategic decisions in humans.

During competitive interactions, such as predator-prey or team sports, the outcome of one's actions is dependent on both their own choices and those of their opponents. Success in these rivalries requires that individuals choose dynamically and unpredictably, often adopting a mixed strategy. Understanding the neural basis of strategic decision making is complicated by the fact that it recruits various cognitive processes that are often shared with non-strategic forms of decision making, such as value estimation, working memory, response inhibition, response selection, and reward processes. Although researchers have explored neural activity within key brain regions during mixed-strategy games, how brain activity differs in the context of strategic interactions versus non-strategic choices is not well understood. We developed a novel behavioral paradigm to dissociate choice behavior during mixed-strategy interactions from non-strategic choices, and we used task-based functional magnetic resonance imaging (fMRI) to contrast brain activation. In a block design, participants competed in the classic mixed-strategy game, "matching pennies," against a dynamic computer opponent designed to exploit predictability in players' response patterns. Results were contrasted with a non-strategic task that had comparable sensory input, motor output, and reward rate; thus, differences in behavior and brain activation reflect strategic processes. The mixed-strategy game was associated with activation of a distributed cortico-striatal network compared to the non-strategic task. We propose that choosing in mixed-strategy contexts requires additional cognitive demands present to a lesser degree during the control task, illustrating the strength of this design in probing function of cognitive systems beyond core sensory, motor, and reward processes.

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.

The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-ß oligomers (AßOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AßOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic, and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. The results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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.

Cognitive deterioration and functional compensation in ALS measured with fMRI using an inhibitory task.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, resulting in progressive weakness and muscle atrophy. Recent studies suggest that nondemented ALS patients can show selective cognitive impairments, predominantly executive dysfunction, but little is known about the neural basis of these impairments. Oculomotor studies in ALS have described deficits in antisaccade execution, which requires the implementation of a task set that includes inhibition of automatic responses followed by generation of a voluntary action. It has been suggested that the dorsolateral prefrontal cortex (DLPFC) contributes in this process. Thus, we investigated whether deterioration of executive functions in ALS patients, such as the ability to implement flexible behavior during the antisaccade task, is related to DLPFC dysfunction. While undergoing an fMRI scan, 12 ALS patients and 12 age-matched controls performed an antisaccade task with concurrent eye tracking. We hypothesized that DLPFC deficits would appear during the antisaccade preparation stage, when the task set is being established. ALS patients made more antisaccade direction errors and showed significant reductions in DLPFC activation. In contrast, regions, such as supplementary eye fields and frontal eye fields, showed increased activation that was anticorrelated with the number of errors. The ALS group also showed reduced saccadic latencies that correlated with increased activation across the oculomotor saccade system. These findings suggest that ALS results in deficits in the inhibition of automatic responses that are related to impaired DLPFC activation. However, they also suggest that ALS patients undergo functional changes that partially compensate the neurological impairment.

Alzheimer's disease-like pathology induced by amyloid-ß oligomers in nonhuman primates.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-ß (Aß) oligomers, AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble Aß oligomers are known to accumulate in the brains of AD patients and correlate with disease-associated cognitive dysfunction. When injected into the lateral ventricle of rats and macaques, Aß oligomers diffused into the brain and accumulated in several regions associated with memory and cognitive functions. Cardinal features of AD pathology, including synapse loss, tau hyperphosphorylation, astrocyte and microglial activation, were observed in regions of the macaque brain where Aß oligomers were abundantly detected. Most importantly, oligomer injections induced AD-type neurofibrillary tangle formation in the macaque brain. These outcomes were specifically associated with Aß oligomers, as fibrillar amyloid deposits were not detected in oligomer-injected brains. Human and macaque brains share significant similarities in terms of overall architecture and functional networks. Thus, generation of a macaque model of AD that links Aß oligomers to tau and synaptic pathology has the potential to greatly advance our understanding of mechanisms centrally implicated in AD pathogenesis. Furthermore, development of disease-modifying therapeutics for AD has been hampered by the difficulty in translating therapies that work in rodents to humans. This new approach may be a highly relevant nonhuman primate model for testing therapeutic interventions for AD.

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.

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.

Motor synchronization and impulsivity in pediatric borderline personality disorder with and without attention-deficit hyperactivity disorder: an eye-tracking study of saccade, blink and pupil behavior.

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.

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.

Interleaved Pro/Anti-saccade Behavior Across the Lifespan.

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.