Saccades, pupil response and blink abnormalities in Huntington's disease patients during free viewing.

OBJECTIVE: Video-based eye tracking was used to investigate saccade, pupil, and blink abnormalities among patients with Huntington's disease (HD) who watched sequences of short videos. HD, an autosomal dominant neurodegenerative disorder resulting from a CAG mutation on chromosome 4, produces motor and cognitive impairments including slow or irregular eye movements, which have been studied using structured tasks. METHODS: To explore how HD affects eye movements under instruction free conditions, we assessed 22 HD patients and their age matched controls in a 10-minute video-based free viewing task. RESULTS: Patients with HD experienced a significant reduction in saccade exploration rate following video clip transitions, an increase in pupil reactions to luminance changes after clip transitions, and a significant higher blink rate throughout the task compared to the control group. CONCLUSIONS: These results show that HD has a significant impact on how patients visually explore and respond to their environment under unconstrained and ecologically natural conditions. SIGNIFICANCE: Eye tracking in HD patients revealed saccadic, pupil, and blink abnormalities in early HD patients, suggestive of brain circuitry abnormalities that probably involve brain stem deficits. Further research should explore the impact of these changes on the quality of life of the patients affected by the disease.

Vascular calcification in chronic kidney disease associated with pathogenic variants in ABCC6.

Vascular calcification is prevalent in chronic kidney disease (CKD). Genetic causes of CKD account for 10-20% of adult-onset disease. Vascular calcification is thought to be one of the most important risk factors for increased cardiovascular morbidity and mortality in CKD patients and is detectable in 80% of patients with end stage kidney disease (ESKD). Despite the high prevalence of vascular calcification in CKD, no single gene cause has been described. We hypothesized that variants in vascular calcification genes may contribute to disease pathogenesis in CKD, particularly in families who exhibit a predominant vascular calcification phenotype. We developed a list of eight genes that are hypothesized to play a role in vascular calcification due to their involvement in the ectopic calcification pathway: ABCC6, ALPL, ANK1, ENPP1, NT5E, SLC29A1, SLC20A2, and S100A12. With this, we assessed exome data from 77 CKD patients, who remained unsolved following evaluation for all known monogenic causes of CKD. We also analyzed an independent cohort (Ontario Neurodegenerative Disease Research Initiative (ONDRI), n = 520) who were screened for variants in ABCC6 and compared this to a control cohort of healthy adults (n = 52). We identified two CKD families with heterozygous pathogenic variants (R1141X and A667fs) in ABCC6. We identified 10 participants from the ONDRI cohort with heterozygous pathogenic or likely pathogenic variant in ABCC6. Replication in a healthy control cohort did not reveal any variants. Our study provides preliminary data supporting the hypothesis that ABCC6 may play a role in vascular calcification in CKD. By screening CKD patients for genetic causes early in the diagnostic pathway, patients with genetic causes associated with vascular calcification can potentially be preventatively treated with new therapeutics with aims to decrease mortality.

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.

Non-suicidal self-injury among individuals with an eating disorder: A systematic review and prevalence meta-analysis.

OBJECTIVE: This study aimed to quantify the prevalence of non-suicidal self-injury across eating disorders (EDs) and within diagnostic categories through systematic review and proportional, or so-called prevalence, meta-analysis. METHOD: Included studies had to contain individuals with a verified diagnosis of an ED. The last literature search was conducted on September 11, 2023, for studies published on or before September 2023 without a restriction on earliest publication year. Results were synthesized and analyzed using the "metaprop" package in R and presented using forest plots. Bias was assessed by a Peters' regression test and funnel plot. RESULTS: 79 studies published between 1985 and 2023 were included encompassing 32,334 individuals with an ED. Importantly, 42 studies were not included in any other meta-analyses on self-injury in EDs to date. Overall prevalence of non-suicidal self-injury was 34.59% (95%CI = 30.49-38.81). Prevalence in anorexia nervosa restrictive type, binge/purge type, bulimia nervosa, binge eating disorder and other specified feeding/eating disorder were 23.19% (95%CI = 16.96-30.03%), 41.98% (95%CI = 32.35-51.91%), 36.97% (95%CI = 30.69-43.46%), 21.21% (95%CI = 14.93-28.12%) and 37.65% (95%CI = 28.59-47.09%), respectively. Prevalence estimations could not be estimated for other ED categories due to lack of a sufficient number of studies. DISCUSSION: Non-suicidal self-injury is prevalent across both binge/purge and restrictive EDs. Considering the transdiagnostic nature of self-injurious behaviors in ED, the results highlight the importance of assessment and monitoring of self-injury in people with ED, irrespective of specific diagnoses. The method of determining self-injury varied across studies and may limit this study. PUBLIC SIGNIFICANCE: This study highlights the prevalence of self-injury across eating disorders irrespective of diagnosis and within specific EDs. While diagnoses known to exhibit self-injurious behaviors (e.g., bulimia nervosa, anorexia nervosa binge/purge subtype) demonstrated the highest prevalence of self-injury, all diagnoses were found to have a prevalence greater than 20%. These findings suggest the importance of assessing and monitoring all individuals with an eating disorder for the presence of self-injury.

OBJETIVO: Este estudio tuvo como objetivo cuantificar la prevalencia de la autolesión no suicida en los trastornos de la conducta alimentaria (TCA) y dentro de las categorías diagnósticas mediante una revisión sistemática y un metaanálisis proporcional, también llamado metaanálisis de prevalencia. MÉTODO: Los estudios incluidos debían contener individuos con un diagnóstico verificado de un TCA. La última búsqueda bibliográfica se realizó el 11 de septiembre de 2023, para estudios publicados en o antes de septiembre de 2023 sin restricción en el año de publicación más temprano. Los resultados fueron sintetizados y analizados utilizando el paquete "metaprop" en R y presentados mediante gráficos de bosque. El sesgo se evaluó mediante una prueba de regresión de Peters y un gráfico de embudo. RESULTADOS: Se incluyeron 79 estudios publicados entre 1985 y 2023 que abarcaron a 32,334 individuos que padecían un TCA. Es importante destacar que 42 estudios no se incluyeron en ningún otro metaanálisis sobre autolesión en TCA hasta la fecha. La prevalencia general de la autolesión no suicida fue del 34.59% (IC del 95% = 30.49-38.81). La prevalencia en la anorexia nerviosa subtipo restrictivo, subtipo atracones/purga, bulimia nerviosa, trastorno de atracones y otros trastornos especificados de la conducta alimentaria y de la alimentación fue del 23.19% (IC del 95% = 16.96-30.03%), 41.98% (IC del 95% = 32.35-51.91%), 36.97% (IC del 95% = 30.69-43.46%), 21.21% (IC del 95% = 14.93-28.12%) y 37.65% (IC del 95% = 28.59-47.09%), respectivamente. No se pudieron estimar las estimaciones de prevalencia para otras categorías de TCA debido a la falta de un número suficiente de estudios. DISCUSIÓN: La autolesión no suicida es prevalente tanto en los TCA subtipo de atracón/purgación como en los restrictivos. Dada la naturaleza transdiagnóstica de los comportamientos autolesivos en los TCA, los resultados resaltan la importancia de la evaluación y el monitoreo de la autolesión en personas que padecen TCA, independientemente de los diagnósticos específicos. El método para determinar la autolesión varió entre los estudios y puede limitar este estudio.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

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.

Rasch analyses of the Quick Inventory of Depressive Symptomatology Self-Report in neurodegenerative and major depressive disorders.

Background: Symptoms 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. Aim: To 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). Methods: De-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. Results: The 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. Conclusion: The 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.

Human microsaccade cueing modulation in visual- and memory-delay saccade tasks after theta burst transcranial magnetic stimulation over the frontal eye field.

Microsaccades that occur during periods of fixation are modulated by various cognitive processes and have an impact on visual processing. A network of brain areas is involved in microsaccade generation, including the superior colliculus and frontal eye field (FEF) which are involved in modulating microsaccade rate and direction after the appearance of a visual cue (referred to as microsaccade cueing modulation). Although the neural mechanisms underlying microsaccade cueing modulations have been demonstrated in monkeys, limited research has investigated a causal role of these areas in humans. By applying continuous theta-burst transcranial magnetic stimulation (cTBS) over the right FEF and vertex, we investigated the role of human FEF in modulating microsaccade responses after the appearance of a visual target in a visual- and memory-delay saccade task. After target appearance, microsaccade rate was initially suppressed but then increased in both cTBS conditions. More importantly, in the visual-delay task, microsaccades after target appearance were directed to the ipsilateral side more often with FEF, compared to vertex stimulation. Moreover, microsaccades were directed towards the target location, then to the opposite location of the target in both tasks, with larger effects in the visual-, compared to, memory-delay task. This microsaccade direction modulation was delayed after FEF stimulation in the memory-delay task. Overall, some microsaccade cueing modulations were moderately disrupted after FEF cTBS, suggesting a causal role for involvement of the human FEF in microsaccade generation after presentation of salient stimuli.

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.

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.

Role of Rostral Superior Colliculus in Gaze Stabilization during Visual Fixation.

Visual fixation (i.e., holding gaze on a specific visual object or location of interest) has been shown to be influenced by activity in the rostral pole of the intermediate layers of the superior colliculus (SCi)-a sensory-motor integration nucleus in the midbrain involved in visual fixation and saccadic eye movement generation. Neurons in the rostral SCi discharge tonically during visual fixation and pause during saccades to locations beyond their foveal visual-sensory or saccadic-motor response fields. Injection of muscimol to deactivate rostral SCi neurons also leads to an increase in fixation instability. However, the precise role of rostral SCi activity for controlling visual fixation has not been established and is actively debated. Here, we address whether this activity reflects signals related to task demands (i.e., maintaining visual fixation) or foveal visual stimulus properties. Two non-human primates performed an oculomotor task that required fixation of a central fixation point (FP) of varying luminance at the start of each trial. During this fixation period, we measured fixational saccades (≤ 2° of the FP, including microsaccades) and fixation-error saccades (> 2° from the FP) in combination with activity from the rostral SCi. Fixation of the lowest FP luminance increased the latency (onset time relative to initial FP foveation) for both fixational and fixation-error saccades. Fifty percent of the rostral SCi neurons exhibited activity that opposed the change in FP luminance and correlated with delayed fixational saccades and increased fixation-error saccades. Twenty-two percent of rostral SCi neurons exhibited activity that followed the change in FP luminance and correlated with earlier fixational saccades and decreased fixation-error saccades. This suggests the rostral SCi contains both sensory-driven and task-related motor signals related to foveal sensory stimuli and visual fixation. This evidence supports a role for the rostral SCi in gaze stabilization and can help inform artificial computational models of vision.

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.

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.

Caregiving concerns and clinical characteristics across neurodegenerative and cerebrovascular disorders in the Ontario neurodegenerative disease research initiative.

OBJECTIVES: Caregiving burdens are a substantial concern in the clinical care of persons with neurodegenerative disorders. In the Ontario Neurodegenerative Disease Research Initiative, we used the Zarit's Burden Interview (ZBI) to examine: (1) the types of burdens captured by the ZBI in a cross-disorder sample of neurodegenerative conditions (2) whether there are categorical or disorder-specific effects on caregiving burdens, and (3) which demographic, clinical, and cognitive measures are related to burden(s) in neurodegenerative disorders? METHODS/DESIGN: N = 504 participants and their study partners (e.g., family, friends) across: Alzheimer's disease/mild cognitive impairment (AD/MCI; n = 120), Parkinson's disease (PD; n = 136), amyotrophic lateral sclerosis (ALS; n = 38), frontotemporal dementia (FTD; n = 53), and cerebrovascular disease (CVD; n = 157). Study partners provided information about themselves, and information about the clinical participants (e.g., activities of daily living (ADL)). We used Correspondence Analysis to identify types of caregiving concerns in the ZBI. We then identified relationships between those concerns and demographic and clinical measures, and a cognitive battery. RESULTS: We found three components in the ZBI. The first was "overall burden" and was (1) strongly related to increased neuropsychiatric symptoms (NPI severity r = 0.586, NPI distress r = 0.587) and decreased independence in ADL (instrumental ADLs r = -0.566, basic ADLs r = -0.43), (2) moderately related to cognition (MoCA r = -0.268), and (3) showed little-to-no differences between disorders. The second and third components together showed four types of caregiving concerns: current care of the person with the neurodegenerative disease, future care of the person with the neurodegenerative disease, personal concerns of study partners, and social concerns of study partners. CONCLUSIONS: Our results suggest that the experience of caregiving in neurodegenerative and cerebrovascular diseases is individualized and is not defined by diagnostic categories. Our findings highlight the importance of targeting ADL and neuropsychiatric symptoms with caregiver-personalized solutions.

Pupil-linked Arousal Signals in the Midbrain Superior Colliculus.

The orienting response evoked by the appearance of a salient stimulus is modulated by arousal; however, neural underpinnings for the interplay between orienting and arousal are not well understood. The superior colliculus (SC), causally involved in multiple components of the orienting response including gaze and attention shifts, receives not only multisensory and cognitive inputs but also arousal-regulated inputs from various cortical and subcortical structures. To investigate the impact of moment-by-moment fluctuations in arousal on orienting saccade responses, we used microstimulation of the monkey SC to trigger saccade responses, and we used pupil size and velocity to index the level of arousal at stimulation onset because these measures correlate with changes in brain states and locus coeruleus activity. Saccades induced by SC microstimulation correlated with prestimulation pupil velocity, with higher pupil velocities on trials without evoked saccades than with evoked saccades. In contrast, prestimulation absolute pupil size did not correlate with saccade behavior. Moreover, pupil velocity correlated with evoked saccade latency and metrics. Together, our results demonstrated that small fluctuations in arousal, indexed by pupil velocity, can modulate the saccade response evoked by SC microstimulation in awake behaving monkeys.

Eye tracking identifies biomarkers in α-synucleinopathies versus progressive supranuclear palsy.

OBJECTIVES: This study (1) describes and compares saccade and pupil abnormalities in patients with manifest alpha-synucleinopathies (αSYN: Parkinson's disease (PD), Multiple System Atrophy (MSA)) and a tauopathy (progressive supranuclear palsy (PSP)); (2) determines whether patients with rapid-eye-movement sleep behaviour disorder (RBD), a prodromal stage of αSYN, already have abnormal responses that may indicate a risk for developing PD or MSA. METHODS: Ninety (46 RBD, 27 PD, 17 MSA) patients with an αSYN, 10 PSP patients, and 132 healthy age-matched controls (CTRL) were examined with a 10-min video-based eye-tracking task (Free Viewing). Participants were free to look anywhere on the screen while saccade and pupil behaviours were measured. RESULTS: PD, MSA, and PSP spent more time fixating the centre of the screen than CTRL. All patient groups made fewer macro-saccades (> 2◦ amplitude) with smaller amplitude than CTRL. Saccade frequency was greater in RBD than in other patients. Following clip change, saccades were temporarily suppressed, then rebounded at a slower pace than CTRL in all patient groups. RBD had distinct, although discrete saccade abnormalities that were more marked in PD, MSA, and even more in PSP. The vertical saccade rate was reduced in all patients and decreased most in PSP. Clip changes produced large increases or decreases in screen luminance requiring pupil constriction or dilation, respectively. PSP elicited smaller pupil constriction/dilation responses than CTRL, while MSA elicited the opposite. CONCLUSION: RBD patients already have discrete but less pronounced saccade abnormalities than PD and MSA patients. Vertical gaze palsy and altered pupil control differentiate PSP from αSYN.

Pupillary responses to differences in luminance, color and set size.

The pupil responds to a salient stimulus appearing in the environment, in addition to its modulation by global luminance. These pupillary responses can be evoked by visual or auditory stimuli, scaled with stimulus salience, and enhanced by multisensory presentation. In addition, pupil size is modulated by various visual stimulus attributes, such as color, area, and motion. However, research that concurrently examines the influence of different factors on pupillary responses is limited. To explore how presentation of multiple visual stimuli influences human pupillary responses, we presented arrays of visual stimuli and systematically varied their luminance, color, and set size. Saliency level, computed by the saliency model, systematically changed with set size across all conditions, with higher saliency levels in larger set sizes. Pupillary constriction responses were evoked by the appearance of visual stimuli, with larger pupillary responses observed in larger set size. These effects were pronounced even though the global luminance level was unchanged using isoluminant chromatic stimuli. Furthermore, larger pupillary constriction responses were obtained in the blue, compared to other color conditions. Together, we argue that both cortical and subcortical areas contribute to the observed pupillary constriction modulated by set size and color.