Heidi C. Riek

Background: Functional motor disorder (FMD) is a common and disabling condition with incompletely understood pathophysiology. Eye‐tracking offers a method to objectively examine cognitive and motor control processes and their underlying neural pathways. We aimed to quantify saccade, blink, and pupil responses in FMD and healthy controls performing an interleaved pro‐/anti‐saccade task, and to investigate the relationships between oculomotor measures and motor and non‐motor symptom severity. Methods: We conducted video‐based eye‐tracking in 104 patients with clinically definite FMD and 115 age‐ and sex‐matched healthy controls performing the saccade task. Patients completed questionnaires on depressive, pain‐related, dissociative, and non‐motor somatic symptoms. Clinician‐rated motor severity and centrally acting medication were recorded in FMD patients. Results: Compared to controls, FMD patients showed increased anti‐saccade error rates ( p < 0.001), anticipatory saccades ( p ≤ 0.003), altered blink distribution ( p < 0.001), and reduced pupil dilation velocity ( p < 0.001). However, reduced pupil dilation velocity was not significant in the subsample of unmedicated patients. Higher anti‐saccade error rates were significantly associated with depressive symptoms, pain severity, dissociative symptoms, non‐motor somatic symptom burden, and motor severity (all p < 0.05). Conclusions: We hypothesize that the altered saccade and blink responses result from altered processing in the frontal cortex and basal ganglia, which provide critical input to brainstem oculomotor control areas in FMD. These results support neurobiological models proposing altered predictive and attentional processing underlying FMD. Association between oculomotor measures and symptom severity suggests that specific cognitive abnormalities may play a role in the pathophysiology of these symptoms in FMD.

Humans blink their eyes 16–20 times each minute to spread tear film on the cornea, representing a substantial amount of waking time when one's eyes are closed. These spontaneous blinks are strategically timed to prioritize the processing of important visual input, balancing both stimulus characteristics and personal goals. Until now, the learning process underlying blink timing has not been investigated in detail. Here, we present video-based eye-tracking data from 703 healthy participants (aged 5–91 years, 470 female) performing a structured interleaved prosaccade/antisaccade task, in which we previously found that blinks are suppressed in anticipation of visual stimulus appearance. Our goals are to understand (1) how participants modify their blink timing according to the temporal contingencies of the task, (2) whether the capacity to do so impacts performance, and (3) whether this pattern varies with age. We found evidence that participants quickly adapted their blink timing to minimize co-occurrence with task-relevant stimuli. Blink probability decreased in periods that would compromise antisaccade execution and increased when visual input was less critical. We also found significant differences in blink timing and in the rate of blink adaptation across the task for participants with low versus high error rates. Furthermore, the rate of blink adaptation increased gradually from childhood to early adulthood and then decreased with advanced age. This work supports a possible link between the regulation of blink behavior and lifespan changes in learning capacity and inhibitory control.

Background: Functional motor disorder (FMD) is a common and disabling condition with incompletely understood pathophysiology. Eye-tracking offers a method to objectively examine cognitive and motor control processes and their underlying neural pathways. We aimed to quantify saccade, blink and pupil responses in FMD and healthy controls performing an interleaved pro-/anti-saccade task, and to investigate the relationships between oculomotor measures and motor and non-motor symptom severity. Methods: We conducted video-based eye-tracking in 104 patients with clinically definite FMD and 115 age- and sex-matched healthy controls performing the saccade task. Patients completed questionnaires on depressive, pain-related, dissociative, non-motor somatic symptoms. Clinician-rated motor severity and centrally acting medication was recorded in FMD patients. Results: Compared to controls, FMD patients showed increased anti-saccade error rates (p < 0.001), anticipatory saccades (p ≤ 0.003), altered blink distribution (p < 0.001), and reduced pupil dilation velocity (p < 0.001). However, reduced pupil dilation velocity was not significant in subsample of unmedicated patients. Higher anti-saccade error rates were significantly associated with depressive symptoms, pain severity, dissociative symptoms, non-motor somatic symptom burden, and motor severity (all p < 0.05). Conclusions: We hypothesize that the altered saccade and blink responses result from altered processing in the frontal cortex and basal ganglia which provide critical input to brainstem oculomotor control areas in FMD. These results support neurobiological models proposing altered predictive and attentional processing underlying FMD. Association between oculomotor measures and symptom severity suggests that specific cognitive abnormalities may play a role in the pathophysiology of these symptoms in FMD. WHAT IS ALREADY KNOWN ON THIS TOPIC: FMD is increasingly interpreted through predictive coding models suggesting abnormalities in predictions about motor and sensory states driven by abnormally focused attention. Yet the underlying neurobiology remains poorly defined. Empirical studies directly probing basic predictive processes in FMD are scarce, and implicit cognitive–motor interactions, particularly those involving motor learning and adaptation, have been insufficiently explored. WHAT THIS STUDY ADDS: Only two previous studies have used eye-tracking in FMD, focusing mainly on diagnostic saccadic markers. Using time-series analyses of saccadic, blink, and pupillary data, we show abnormalities in inhibitory control, predictive processing, and implicit learning. Due to strong homology between human and primate neurophysiology and neuroimaging findings in oculomotor control, the findings can be linked to dysfunction within cortico–basal ganglia circuits. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY: Oculomotor abnormalities correlated with motor and non-motor symptom severity, indicating mechanistic relevance. The findings provide empirical support for predictive coding accounts and point to involvement of subcortical structures including projections from the frontal cortex to the basal ganglia. This highlights the value of studying cortico–basal ganglia circuits with implications for treatment and of developing oculomotor measures as potential biomarkers in FMD.

Freezing of gait is a debilitating motor symptom in Parkinson's disease that significantly increases fall risk and impairs quality of life. The poorly understood pathophysiology of freezing of gait presents challenges for early prediction and therapeutic intervention. This prospective study investigated whether eye movement abnormalities, specifically in the anti-saccade paradigm, could predict freezing of gait onset in Parkinson's disease patients over a two-year follow-up period. We analysed longitudinal data from the Ontario Neurodegenerative Disease Research Initiative, focusing on Parkinson's disease patients without freezing of gait at baseline who underwent comprehensive clinical evaluations and eye movement recordings. Anti-saccade reaction time and error ratio, combined with clinical measures including right upper extremity rigidity, demonstrated significant predictive value for freezing of gait development within two years. These findings suggest that eye movement deficits and upper limb rigidity emerge years before freezing of gait onset, indicating a prodromal phase in freezing of gait pathogenesis. The predictive relationship between these measures supports the hypothesis of shared neural substrates, potentially involving the mesencephalic locomotor region, in the development of both oculomotor dysfunction and gait freezing episodes.

Humans blink their eyes 16-20 times each minute to spread tear film on the cornea, representing a substantial amount of waking time when one’s eyes are closed. These spontaneous blinks are strategically timed to prioritize the processing of important visual input, balancing both stimulus characteristics and personal goals. Until now, the learning process underlying optimal blink timing has not been investigated in detail. Here, we present video-based eye-tracking data from 703 healthy participants (aged 5-91 years, 470 female) performing a structured interleaved pro-/anti-saccade task, in which we previously found that blink suppression occurs in anticipation of visual stimulus appearance (Pitigoi et al., 2024). Our goals are to understand (1) how participants modify their blink timing according to the temporal contingencies of the task; (2) whether the capacity to optimize blink timing impacts performance; and (3) whether this pattern varies with age. We found that participants quickly and strategically modified their blink distribution to optimize task performance. Blink probability decreased in periods that would compromise anti-saccade execution and increased when visual input was less critical. We also found significant differences in blink patterns and adaptive ability based on cognitive control capacity (indicated by participants’ anti-saccade error rates). Furthermore, we demonstrated that blink optimization improves gradually from childhood to early adulthood, before declining with advanced age. This supports a possible link between regulation of blink behavior and age-related changes in learning capacity and inhibitory control across the lifespan.

Background: Saccade, pupil, and blink control are impaired in patients with α-synucleinopathies (αSYN): Parkinson's disease (PD) and multiple system atrophy (MSA). Isolated REM (rapid eye movement) Sleep Behavior Disorder (iRBD) is a prodromal stage of PD and MSA and a prime candidate for investigating early oculo-pupillo-motor abnormalities that may precede or predict conversion to clinically manifest αSYN. Objective: Determine whether saccade, pupil, and blink responses in iRBD are normal or similar to those identified in PD and MSA. Methods: Video-based eye-tracking was conducted with 68 patients with iRBD, 49 with PD, 17 with MSA, and 95 healthy controls (CTRL) performing an interleaved pro-/anti-saccade task that probed sensory, motor, and cognitive processes involved in eye movement control. Results: Horizontal saccade and blink behavior was intact in iRBD, but abnormal in PD and MSA. iRBD patients, however, demonstrated reduced pupil dilation size, which closely resembled the changes found in PD and MSA. In the iRBD group, the extent of these pupillary changes appeared to correlate with the degree of hyposmia and reduction in dopamine transporter imaging signal. Conclusions: Pupil abnormalities were present in iRBD, but blink and horizontal saccade responses were intact. Future longitudinal studies are required to determine which prodromal pupil abnormalities predict conversion from iRBD to PD or MSA and to identify the time window, in relation to conversion, when horizontal saccade responses become abnormal.

Oculomotor behaviour changes in patients with Parkinson’s disease (PD) are a promising source of prodromal disease markers. Capitalizing on this phenomenon to facilitate early diagnosis requires oculomotor assessment in prodromal cohorts. We examined oculomotor behaviour in non-manifesting LRRK2 G2019S mutation carriers (LRRK2-NM), who have heightened PD risk. Seventeen LRRK2-NM participants, 47 patients with idiopathic PD, and 63 healthy age-matched control participants completed an interleaved pro- and antisaccade task while undergoing video-based eye-tracking. We analyzed between-group differences in saccade, pupil, blink, and fixation acquisition behaviour. Patients with PD showed previously demonstrated abnormalities (saccade hypometria, antisaccade errors). Relative to controls, LRRK2-NM participants and patients with PD both displayed increased short-latency prosaccades and reduced pupil velocity, plus altered fixation acquisition—less preemptive returning of gaze to the future fixation point location. Interestingly, the effect on blink probability was opposite—higher than controls in LRRK2-NM participants but lower in patients with PD. Future longitudinal studies must confirm the viability of these features as prodromal PD markers.

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

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 with 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.

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.