The ability to shift focus within three-dimensional space depends on vergence eye movements, which are impaired in ≤40% of individuals with neurodegenerative disorders. Although foundational studies in monkeys have identified neural correlates of vergence in the midbrain, a translational gap persists, leaving the neural basis of vergence dysfunction in humans poorly understood. Through voxel-wise analyses in 66 humans and 19 monkeys with midbrain lesions, we link vergence dysfunction causally to a region rostral to the superior colliculus and centred on the nucleus of the posterior commissure (NPC). Connectivity analyses across species identified a brain circuit linking the NPC to the visual pretectum and midbrain premotor hubs, regions capable of integrating the visual input and motor output necessary for vergence control. Collectively, these findings provide a neuroanatomical basis for vergence dysfunction and demonstrate how lesion mapping can bridge fundamental insights from animal models with clinical observations in humans.

OBJECTIVE:Downbeat nystagmus varies with head position, a phenomenon termed gravity-dependent modulation. We aimed to clarify its mechanism using a velocity-storage model. METHODS:In 10 patients with downbeat nystagmus due to cerebellar disorders, we recorded eye movements at different pitch- and roll-axis head positions. Sine-wave fitting of the nystagmus intensity as a function of head position decomposed the slow-phase velocity of nystagmus into a gravity-dependent component-the amplitude and phase shift of the sine-wave term-and a gravity-independent constant offset. To probe mechanisms, we applied a velocity-storage model simulating the estimation of rotational velocity, gravity orientation, and inertial acceleration, and incorporated a gravity-estimator lesion that produced a gravity-estimation bias. RESULTS:The gravity-dependent component during pitch-axis modulation had a median amplitude of 3.8°/s (interquartile range [IQR] = 2.6) and a phase shift of 158.5° (57.9). During roll-axis modulation, it had an amplitude of 2.1°/s (1.5) and a phase shift of -0.9° (147.6), with two subgroups showing phase shifts near ±90°. The amplitude was significantly larger during pitch- than roll-axis modulation (p < 0.05). The lesion model generated persistent rotational cues that modulated downbeat nystagmus intensity as observed in the patients and additionally explained the interindividual variation in phase shifts and the weaker modulation of downbeat nystagmus during head roll. INTERPRETATION:These findings refine our understanding of cerebellar vestibular processing and provide a computational framework for positional modulation of downbeat nystagmus. The concept of a biased gravity estimate may further account for several clinical phenomena, including atypical patterns of positional nystagmus.

BackgroundEye movements play an essential role in the assessment of the unconscious patient and offer a window to the function of the brain. We review the range of ocular motor and vestibular findings in patients with impaired consciousness and present a practical approach to these patients.MethodsBased on a structured review of the literature (Pubmed, Embase) 54 suitable citations were identified amongst 4,241 total citations. A manual search of the reference list of selected papers added another 57 papers. Based on these publications the spectrum of eye movement abnormalities in the unconscious patient was characterized.ResultsThe pattern of eye movement abnormalities seen in the unconscious patient depends on the underlying cause and the extent/location of brain damage. Conjugate eye deviations may be observed with either supratentorial or infratentorial lesions, while disconjugate deviations may indicate superimposed eye muscle palsies or decompensated strabismus. The presence of a full range of spontaneous horizontal, oscillatory eye movements (e.g., ping-pong gaze) in the comatose patient usually indicates bilateral cerebral hemisphere dysfunction. With vertical spontaneous eye movements, the identification of a slower and faster phase helps to distinguish between nystagmus and ocular bobbing and its variants. Combined with absent reflexively-induced eye movements, typical ocular bobbing strongly suggests a structural pontine lesion, whereas other vertical spontaneous eye movement patterns do not predict specific (focal) damage. The reflexive eye movements, i.e., the vestibulo-ocular reflex (VOR), can be assessed in comatose patients either by head rotations, caloric irrigation or galvanic stimulation. Intact slow-phase responses indicate relatively preserved brainstem function and inability to keep the eyes in an eccentric position suggest a deficient velocity-to-position integrator either from brainstem or cerebellar involvement.ConclusionOcular motor and vestibular testing in unconscious patients offer a unique opportunity to assess both brainstem and cerebellar function and its interplay with higher cortical areas. It may also help predict outcome. Challenges to overcome include a lack of standardized diagnostic approaches to unconscious patients. Quantitative eye movement analysis, based on videooculography (VOG) and artificial intelligence using large multimodal data sets are promising new tools for diagnosis, longitudinal observational studies and prediction of outcome.

The evaluation of patients with dizziness and imbalance is always challenging and often frustrating for both patient and physician. Recent advances in both bedside and laboratory examinations have made outcomes more successful and gratifying. When coupled with vestibular evoked myogenic potentials and video ocular counter-roll for evaluation of otolith function, and video head-impulse testing and caloric irrigations for evaluation of semi-circular canal functions, one can now test each of the vestibular end organs. Here we discuss how to apply the latest physiological advances into practical bedside examination techniques to probe the function of individual components within the labyrinth and central vestibular pathways. We also review neurological signs that can be used to differentiate between peripheral and central vestibular disorders.

Introduction:Benign paroxysmal positional vertigo (BPPV) is a common cause of dizziness that is diagnosed by detecting nystagmus through positional maneuvers. Limited access to expert clinicians to correctly perform and interpret the eye movement findings of positional tests can hamper the diagnosis and delay the treatment. We aimed to assess the usability of a smartphone-based eye-tracking application (EyePhone) for self-recording eye movements during positional testing. Methods:Healthy volunteers were enrolled and provided instructions to perform Dix-Hallpike and Supine Roll tests using the EyePhone application to record themselves. A study team member was instructed to observe the process without interfering. They recorded the time each section took and the accuracy of performing positional tests. Usability was assessed using the mHealth App Usability Questionnaire (MAUQ), and expert evaluation of recorded videos determined quality. Results:All participants successfully performed the tests and recorded their eye movements. On average, after watching the instruction, it took participants 3 min 31 s to record the Dix-Hallpike test and 3 min 4 s to record the Supine Roll test. Nine participants completed Dix-Hallpike without major errors, and all completed the Supine Roll successfully. An expert review found that 95% of videos had clear eye visibility. Participants rated the app as easy to use and stated that they would use the app again. Conclusion:We demonstrated the usability and feasibility of the EyePhone app for self-recording positional tests. This application offers the potential for remote BPPV diagnosis and improved patient access to care.

The variability in the evolution, phenomenology, and response to treatment of diseases, even among patients with the same genetic mutation or identical structural or metabolic insults, is a common challenge in contemporary neurology and neuroscience. Why does the human brain react so differently to the same disease or treatment? Genetic variability among individuals might be part of the answer. Epigenetics, how the activity of genes changes with changes in the environment also contributes to the variability. Genes determine the expression profile of molecules within and on the surface of neurons, such as ion channels. This profile influences membrane physiology, which in turn affects the behavior (or misbehavior) of neural circuits and thus the disease phenomenology. The physiology of circuit behavior is extremely complex. In this context, studying eye movements is valuable because normal ocular motor physiology is better understood, the structural correlates of ocular motor disorders are clearer, and the behavioral outcomes of these disorders can be precisely measured and interpreted with mathematical models. Here, we review three disorders characterized by unwanted oscillations of the eyes. While their structural correlates are relatively well defined, the phenomenology and response to treatment of these disorders are surprisingly variable. Mathematical models suggest that the mechanisms for the diverse phenomenology of these three diseases are centered on genetically determined variability in the physiology of neuronal membranes and the internal connections of neural circuits.

Introduction: This study explores the effects of botulinum neurotoxin (BoNT) on the relationship between dystonia and tremor, specifically focusing on cervical dystonia (CD) and its connection to head tremor.Methods: Fourteen CD patients were recruited; eight (57%) with clinically observable head oscillations were included in further analysis. A high-resolution magnetic search coil system precisely measured head movements, addressing two questions: 1) BoNT’s effects on head movement amplitude, frequency, and regularity, and 2) BoNT’s influence on the relationship between head position and head oscillations. For the first question, temporal head position measurements of three patients were analyzed before and after BoNT injection. The second question examined the effects of BoNT injections on the dependence of the oscillations on the position of the head.Results: Three distinct trends were observed: shifts from regular to irregular oscillations, transitions from irregular to regular oscillations, and an absence of change. Poincaré analysis revealed that BoNT induced changes in regularity, aligning oscillations closer to a consistent “set point” of regularity. BoNT injections reduced head oscillation amplitude, particularly in head orientations linked to high-intensity pre-injection oscillations. Oscillation frequency decreased in most cases, and overall variance in the amplitude of head position decreased post-injection.Discussion: These findings illuminate the complexity of CD but also suggest therapeutic potential for BoNT. They show that co-existing mechanisms contribute to regular and irregular head oscillations in CD, which involve proprioception and central structures like the cerebellum and basal ganglia. These insights advocate for personalized treatment to optimize outcomes that is based on individual head oscillation characteristics.

BACKGROUND:Disconjugate eye movements are essential for depth perception in frontal-eyed species, but their underlying neural substrates are largely unknown. Lesions in the midbrain can cause disconjugate eye movements. While vertically disconjugate eye movements have been linked to defective visuo-vestibular integration, the pathophysiology and neuroanatomy of horizontally disconjugate eye movements remains elusive. METHODS:A patient with a solitary focal midbrain lesion was examined using detailed clinical ocular motor assessments, binocular videooculography and diffusion-weighted MRI, which was co-registered to a high-resolution cytoarchitectonic MR-atlas. RESULTS:The patient exhibited both vertically and horizontally disconjugate eye alignment and nystagmus. Binocular videooculography showed a strong correlation of vertical and horizontal oscillations during fixation but not in darkness. Oscillation intensities and waveforms were modulated by fixation, illumination, and gaze position, suggesting shared visual- and vestibular-related mechanisms. The lesion was mapped to a functionally ill-defined area of the dorsal midbrain, adjacent to the posterior commissure and sparing nuclei with known roles in vertical gaze control. CONCLUSION:A circumscribed region in the dorsal midbrain appears to be a key node for disconjugate eye movements in both vertical and horizontal planes. Lesioning this area produces a unique ocular motor syndrome mirroring hallmarks of developmental strabismus and nystagmus. Further circuit-level studies could offer pivotal insights into shared pathomechanisms of acquired and developmental disorders affecting eye alignment.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder with an estimated prevalence of 5-7 people in 100,000. Clinically characterized by impairments in gait, balance, and eye movements, as well as aggregated Tau pathology, PSP leads to death in approximately 5-8 years. No disease-modifying treatments are currently available. The contribution of Tau pathology to the symptoms of patients with PSP is poorly understood, in part due to lack of a rodent model that recapitulates characteristic aspects of PSP. Here, we assessed the hTau.P301S mouse for key clinical features of PSP, finding progressive impairments in balance and gait coordination. Additionally, we found impairments in fast vertical eye movements, one of the most distinctive features of PSP. Across animals, we found that Tau pathology in motor control regions correlated with motor deficits. These findings highlight the utility of the hP301S mouse in modeling key aspects of PSP.

Repositioning maneuvers for benign paroxysmal positional vertigo (BPPV) designed to induce otoconial movement in one canal can trigger and sometimes unwittingly treat BPPV in other canals. Patients with BPPV are best managed by precisely diagnosing the canal variant and using correctly performed, standardized testing and treatment maneuvers.

IntroductionIn patients with unilateral loss of vestibular function (UVL) vibration of the skull leads to a response of the vestibulo-ocular reflex (VOR) called vibration-induced nystagmus (VIN), with slow phases usually directed toward the paretic ear. This response is thought to result from the difference between the neural discharge in semicircular canal afferents from the healthy and the affected labyrinth. The brain interprets this difference as a sustained imbalance in angular (rotational) vestibular tone, which in natural circumstances would only occur when the head was rotating at a constant acceleration.MethodsTo study this effect, we used a contemporary model of the neural network that combines sensory information about head rotation, translation, and tilt relative to gravity to estimate head orientation and motion. Based on the model we hypothesize that in patients with UVL, the brain may estimate not only a “virtual” rotation from the induced canal imbalance but also a subsequent “virtual” translation from the incorrect computation of the orientation of the head relative to gravity. If this is the case, the pattern of vibration-induced nystagmus will depend on the orientation of the head relative to gravity during the stimulation. This model predicts that this “virtual” translation will alter the baseline VIN elicited with the head upright; augmenting it when the affected ear is down and diminishing it when the affected ear is up.ResultsConfirming this hypothesis, we recorded VIN in 3 patients with UVL (due to vestibular neuritis) in upright, right ear-down, and left ear-down positions and each showed the expected pattern.DiscussionFrom a practical, clinical view, our results and modeling suggest that positional VIN might reveal a hidden imbalance in angular vestibular tone in patients with UVL, when patients have equivocal signs of a vestibular imbalance, such as a minute amount of spontaneous or vibration-induced nystagmus with the head upright. This research provides insights into the underlying mechanisms of vestibular processing, the analysis of nystagmus in patients with UVL, and guides the design of a new bedside diagnostic test to assess vestibular function in patients with dizziness and imbalance.

Purpose of Review:The potential diagnostic value of radiographic, horizontal, conjugate gaze deviation (Rad h-CGD) was first recognized in 2003 by Simon et al. Thereafter, interest grew related to its potential use as a marker of different neurologic and vestibular disorders. Over the past 20 years, we have identified clinical correlates of Rad h-CGD including those caused by supratentorial and infratentorial lesions. We propose clinicians and radiologists will better diagnose and manage patients by knowing the different diagnostic possibilities for Rad h-CGD. Findings:We report different clinical correlates of Rad h-CGD relevant for localizing and lateralizing lesions. We measured the angle of deviation and correlated it with the clinical findings and underlying mechanisms. We then reviewed important data from the previous literature relevant to the localization of each lesion and combined it with our experience into the design of a practical algorithm to interpret Rad h-CGD. Summary:Using Rad h-CGD provides useful information about the diagnosis and localization and may reveal subtle ocular findings not clear on physical examination. However, Rad h-CGD alone cannot distinguish between supratentorial and infratentorial lesions, and therefore, the clinical context is critical. Moreover, although Rad h-CGD occurs with strokes due to large vessel occlusion, it could also be seen with an acute vestibular syndrome, secondary to a peripheral vestibular neuritis. Other possibilities include ischemic events in the cerebellum, brainstem, and labyrinth.

Frontal-eyed species use a combination of conjugate and vergence eye movements, termed 3-D gaze, to scan their environment1–3. The neural circuits mediating conjugate gaze have been extensively characterized, but those governing vergence remain disproportionately obscure4. Here, we combine lesion and deep brain stimulation data from 67 humans and 19 monkeys to causally link vergence function to a midbrain region rostral to the superior colliculus, encompassing the nucleus of the posterior commissure (NPC), and aligning with the location of neurons whose activity correlates with vergence in monkeys5,6. Cross-species eye movement analysis suggests the NPC region houses a vergence integrator maintaining stable eye alignment in depth5,7,8. Multimodal connectivity revealed NPC connections to the pretectum and the supraoculomotor area, brain regions previously linked to visual maps of 3-D space and premotor control of the near response, enabling focus across varying viewing distances9. Collectively, these results suggest the NPC region is a key node for 3-D visuomotor transformations. These findings bridge a translational gap between physiological observations in monkeys and clinical disorders in humans, revealing a subcortical circuit for 3-D vision.

Objective Acute dizziness/vertigo is usually due to benign inner‐ear causes but is occasionally due to dangerous neurologic ones, particularly stroke. Because symptoms and signs overlap, misdiagnosis is frequent and overuse of neuroimaging is common. We assessed the accuracy of bedside findings to differentiate peripheral vestibular from central neurologic causes. Methods We performed a systematic search (MEDLINE and Embase) to identify studies reporting on diagnostic accuracy of physical examination in adults with acute, prolonged dizziness/vertigo (“acute vestibular syndrome” [AVS]). Diagnostic test properties were calculated for findings. Results were stratified by examiner type and stroke location. Results We identified 6,089 citations and included 14 articles representing 10 study cohorts (n = 800). The Head Impulse, Nystagmus, Test of Skew (HINTS) eye movement battery had high sensitivity 95.3% (95% confidence interval [CI] = 92.5–98.1) and specificity 92.6% (95% CI = 88.6–96.5). Sensitivity was similar by examiner type (subspecialists 94.3% [95% CI = 88.2–100.0] vs non‐subspecialists 95.0% [95% CI = 91.2–98.9], p = 0.55), but specificity was higher among subspecialists (97.6% [95% CI = 94.9–100.0] vs 89.1% [95% CI = 83.0–95.2], p = 0.007). HINTS sensitivity was lower in anterior cerebellar artery (AICA) than posterior inferior cerebellar artery (PICA) strokes (84.0% [95% CI = 65.3–93.6] vs 97.7% [95% CI = 93.3–99.2], p = 0.014) but was “rescued” by the addition of bedside hearing tests (HINTS+). Severe (grade 3) gait/truncal instability had high specificity 99.2% (95% CI = 97.8–100.0) but low sensitivity 35.8% (95% CI = 5.2–66.5). Early magnetic resonance imaging (MRI)‐diffusion‐weighted imaging (DWI; within 24–48 hours) was falsely negative in 15% of strokes (sensitivity 85.1% [95% CI = 79.2–91.0]). Interpretation In AVS, HINTS examination by appropriately trained clinicians can differentiate peripheral from central causes and has higher diagnostic accuracy for stroke than MRI‐DWI in the first 24–48 hours. These techniques should be disseminated to all clinicians evaluating dizziness/vertigo. ANN NEUROL 2023;94:295–308

When the demands for visual stabilization during head rotations overwhelm the ability of the vestibuloocular reflex (VOR) to produce compensatory eye movements, the brain produces corrective saccades that bring gaze toward the fixation target, even without visual cues (covert saccades). What triggers covert saccades and what might be the role of prediction in their generation are unknown. We studied 14 subjects with acute vestibular neuritis. To minimize variability of the stimulus, head impulses were imposed with a motorized torque generator with the subject on a bite bar. Predictable and unpredictable (timing, amplitude, direction) stimuli were compared. Distributions of covert corrective saccade latencies were analyzed with a "LATER" (linear approach to threshold with ergodic rate) approach. On the affected side, VOR gain was higher (0.47 ± 0.28 vs. 0.39 ± 0.22, P ≪ 0.001) with predictable than unpredictable head impulses, and gaze error at the end of the head movement was less (5.4 ± 3.3° vs. 6.9 ± 3.3°, P ≪ 0.001). Analyzing trials with covert saccades, gaze error at saccade end was significantly less with predictable than unpredictable head impulses (4.2 ± 2.8° vs. 5.5 ± 3.2°, P ≪ 0.001). Furthermore, covert corrective saccades occurred earlier with predictable than unpredictable head impulses (140 ± 37 vs. 153 ± 37 ms, P ≪ 0.001). Using a LATER analysis with reciprobit plots, we were able to divide covert corrective saccades into two classes, early and late, with a break point in the range of 88-98 ms. We hypothesized two rise-to-threshold decision mechanisms for triggering early and late covert corrective saccades, with the first being most engaged when stimuli are predictable.NEW & NOTEWORTHY We successfully used a LATER (linear approach to threshold with ergodic rate) analysis of the latencies of corrective saccades in patients with acute vestibular neuritis. We found two types of covert saccades: early (<90 ms) and late (>90 ms) covert saccades. Predictability led to an increase in VOR gain and a decrease in saccade latency.