Method to Quickly Map Multifocal Pupillary Response Fields (mPRF) Using Frequency Tagging.

We present a method for mapping multifocal Pupillary Response Fields in a short amount of time using a visual stimulus covering 40° of the visual angle divided into nine contiguous sectors simultaneously modulated in luminance at specific, incommensurate, temporal frequencies. We test this multifocal Pupillary Frequency Tagging (mPFT) approach with young healthy participants (N = 36) and show that the spectral power of the sustained pupillary response elicited by 45 s of fixation of this multipartite stimulus reflects the relative contribution of each sector/frequency to the overall pupillary response. We further analyze the phase lag for each temporal frequency as well as several global features related to pupil state. Test/retest performed on a subset of participants indicates good repeatability. We also investigate the existence of structural (RNFL)/functional (mPFT) relationships. We then summarize the results of clinical studies conducted with mPFT on patients with neuropathies and retinopathies and show that the features derived from pupillary signal analyses, the distribution of spectral power in particular, are homologous to disease characteristics and allow for sorting patients from healthy participants with excellent sensitivity and specificity. This method thus appears as a convenient, objective, and fast tool for assessing the integrity of retino-pupillary circuits as well as idiosyncrasies and permits to objectively assess and follow-up retinopathies or neuropathies in a short amount of time.

Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction.

White matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined nonhuman primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculomotor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This nonhuman primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair promyelinating/neuroprotective therapies to the clinic for myelin disorders, such as MS.

Jumpy and Jerky: When Peripheral Vision Faces Reverse-Phi.

When an annulus in fast apparent motion reverses its contrast over time, the foveal and peripheral percepts are strikingly different. In central vision, the annulus appears to follow the same path as an annulus without flicker, whereas in the periphery, the stimulus seems to randomly jump across the screen. The illusion strength depends on motion speed and reversal rate. Our observations suggest that it results from a balance between conflicting phi and reverse-phi motion, positional uncertainty, and attention. In addition to illustrating the differences between central and peripheral motion processing, this illusion shows that both discrete positional sampling and motion energy combine to generate motion percepts, although with eccentricity dependent weights that are themselves affected by attention.

Cursive Eye-Writing With Smooth-Pursuit Eye-Movement Is Possible in Subjects With Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing a progressive motor weakness of all voluntary muscles, whose progression challenges communication modalities such as handwriting or speech. The current study investigated whether ALS subjects can use Eye-On-Line (EOL), a novel eye-operated communication device allowing, after training, to voluntarily control smooth-pursuit eye-movements (SPEM) so as to eye-write in cursive. To that aim, ALS participants (n = 12) with preserved eye-movements but impaired handwriting were trained during six on-site visits. The primary outcome of the study was the recognition of eye-written digits (0-9) from ALS and healthy control subjects by naïve "readers." Changes in oculomotor performance and the safety of EOL were also evaluated. At the end of the program, 69.4% of the eye-written digits from 11 ALS subjects were recognized by naïve readers, similar to the 67.3% found for eye-written digits from controls participants, with however, large inter-individual differences in both groups of "writers." Training with EOL was associated with a transient fatigue leading one ALS subject to drop out the study at the fifth visit. Otherwise, itching eyes was the most common adverse event (3 subjects). This study shows that, despite the impact of ALS on the motor system, most ALS participants could improve their mastering of eye-movements, so as to produce recognizable eye-written digits, although the eye-traces sometimes needed smoothing to ease digit legibility from both ALS subjects and control participants. The capability to endogenously and voluntarily generate eye-traces using EOL brings a novel way to communicate for disabled individuals, allowing creative personal and emotional expression.

Effects of pupillary responses to luminance and attention on visual spatial discrimination.

The optic quality of the eyes is, at least in part, determined by pupil size. Large pupils let more light enter the eyes, but degrade the point spread function, and thus the spatial resolution that can be achieved (Campbell & Gregory, 1960). In natural conditions, the pupil is mainly driven by the luminance (and possibly the color and contrast) at the gazed location, but is also modulated by attention and cognitive factors. Whether changes in eyes' optics related to pupil size modulation by luminance and attention impacts visual processing was assessed in two experiments. In Experiment 1, we measured pupil size using a constantly visible display made of four disks with different luminance levels, with no other task than fixating the disks in succession. The results confirmed that pupil size depends on the luminance of the gazed stimulus. Experiment 2, using similar settings as Experiment 1, used a two-interval forced-choice design to test whether discriminating high spatial frequencies that requires covert attention to parafoveal stimuli is better during the fixation of bright disks that entails a small pupil size, and hence better eyes' optics, as compared to fixating dark disks that entails a large pupil size, and hence poorer eyes' optics. As in Experiment 1, we observed large modulations of pupil size depending on the luminance of the gazed stimulus, but pupil dynamics was more variable, with marked pupil dilation during stimulus encoding, presumably because the demanding spatial frequency discrimination task engaged attention. However, discrimination performance and mean pupil size were not correlated. Despite this lack of correlation, the slopes of pupil dilation during stimulus encoding were correlated to performance, while the slopes of pupil dilation during decision-making were not. We discuss these results regarding the possible functional roles of pupil size modulations.

A novel method of inducing endogenous pupil oscillations to detect patients with unilateral optic neuritis.

PURPOSE: To use and test a new method of inducing endogenously generated pupillary oscillations (POs) in patients with unilateral optic neuritis (ON), to describe a signal analysis approach quantifying pupil activity and to evaluate the extent to which POs permit to discriminate patients from control participants. METHOD: Pupil size was recorded with an eye-tracker and converted in real time to modulate the luminance of a stimulus (a 20° disk) presented in front of participants. With this biofeedback setting, an increasing pupil size transforms into a high luminance, entraining a pupil constriction that in turn decreases the stimulus luminance, and so on, resulting in endogenously generated POs. POs were recorded for 30 seconds in the affected eye, in the fellow eye and in binocular conditions with 22 patients having a history of unilateral ON within a period of 5 years, and with 22 control participants. Different signal analysis methods were used to quantify the power and frequency of POs. RESULTS: On average, pupil size oscillated at around 1 Hz. The amplitude of POs appears not to be a reliable marker of ON. In contrast, the frequency of POs was significantly lower, and was more variable over time, in the patients' affected eye, as compared to their fellow eye and to the binocular condition. No such differences were found in control participants. Receiver operating characteristic analyses based on the frequency and the variability of POs to classify patients and control participants gave an area under the curve of 0.82, a sensitivity of 82% (95%CI: 60%-95%) and a specificity of 77% (95%CI: 55%-92%). CONCLUSIONS: The new method used to induce POs allowed characterizing the visual afferent pathway defect in ON patients with encouraging accuracy. The method was fast, easy to use, only requiring that participants look ahead, and allows testing many stimulus parameters (e.g. color, stimulus location, size, etc).

Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology.

The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path: a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an "omics"-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer's disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group "Alzheimer Precision Medicine" (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND.

Continuous Auditory Feedback of Eye Movements: An Exploratory Study toward Improving Oculomotor Control.

As eye movements are mostly automatic and overtly generated to attain visual goals, individuals have a poor metacognitive knowledge of their own eye movements. We present an exploratory study on the effects of real-time continuous auditory feedback generated by eye movements. We considered both a tracking task and a production task where smooth pursuit eye movements (SPEM) can be endogenously generated. In particular, we used a visual paradigm which enables to generate and control SPEM in the absence of a moving visual target. We investigated whether real-time auditory feedback of eye movement dynamics might improve learning in both tasks, through a training protocol over 8 days. The results indicate that real-time sonification of eye movements can actually modify the oculomotor behavior, and reinforce intrinsic oculomotor perception. Nevertheless, large inter-individual differences were observed preventing us from reaching a strong conclusion on sensorimotor learning improvements.

Sustained smooth pursuit eye movements with eye-induced reverse-phi motion.

The gain and speed of smooth pursuit eye movements quickly drop whenever a moving tracked target disappears behind an occluder. The present study tests to what extent pursuit maintenance after target disappearance depends on the occluder's characteristics. In all experiments, a target moving for 2500 ms, (or 1250 ms) at 13.3°/s (or 26.6°/s), disappears behind an occluder for 700 ms (or 350 ms). Participants are asked to maintain their pursuit eye movements as long as possible after target disappearance. Experiment 1 compares smooth pursuit with four types of occluders and shows that a texture of flickering disks allows maintaining pursuit for long durations. Experiment 2 investigates the capability to maintain pursuit with occluders of varying flickering frequencies (3, 5, 10, 20, and 30 Hz). It is found that after target disappearance, smooth pursuit is maintained for longer durations with flicker at 10 and 20 Hz, relative to other flickering frequencies (3, 5, and 30 Hz). Experiment 3 tests whether disk size and disk density of a flickering occluding texture influence smooth pursuit maintenance. Finally, Experiment 4 tests the influence of the contrast distribution of the flickering disks on pursuit maintenance. Altogether, the results show that individuals can maintain smooth pursuit for long durations after target disappearance behind an occluding texture of disks flickering at temporal frequency above 5 Hz with balanced contrast. It is suggested that eye-induced reverse-phi motion responses in MT/MST neurons provide a positive visual feedback to the pursuit system, allowing generating smooth pursuit in the absence of explicit stimulus motion.

OB3D, a new set of 3D objects available for research: a web-based study.

Studying object recognition is central to fundamental and clinical research on cognitive functions but suffers from the limitations of the available sets that cannot always be modified and adapted to meet the specific goals of each study. We here present a new set of 3D scans of real objects available on-line as ASCII files, OB3D. These files are lists of dots, each defined by a triplet of spatial coordinates and their normal that allow simple and highly versatile transformations and adaptations. We performed a web-based experiment to evaluate the minimal number of dots required for the denomination and categorization of these objects, thus providing a reference threshold. We further analyze several other variables derived from this data set, such as the correlations with object complexity. This new stimulus set, which was found to activate the Lower Occipital Complex (LOC) in another study, may be of interest for studies of cognitive functions in healthy participants and patients with cognitive impairments, including visual perception, language, memory, etc.

Beta, but not gamma, band oscillations index visual form-motion integration.

Electrophysiological oscillations in different frequency bands co-occur with perceptual, motor and cognitive processes but their function and respective contributions to these processes need further investigations. Here, we recorded MEG signals and seek for percept related modulations of alpha, beta and gamma band activity during a perceptual form/motion integration task. Participants reported their bound or unbound perception of ambiguously moving displays that could either be seen as a whole square-like shape moving along a Lissajou's figure (bound percept) or as pairs of bars oscillating independently along cardinal axes (unbound percept). We found that beta (15-25 Hz), but not gamma (55-85 Hz) oscillations, index perceptual states at the individual and group level. The gamma band activity found in the occipital lobe, although significantly higher during visual stimulation than during base line, is similar in all perceptual states. Similarly, decreased alpha activity during visual stimulation is not different for the different percepts. Trial-by-trial classification of perceptual reports based on beta band oscillations was significant in most observers, further supporting the view that modulation of beta power reliably index perceptual integration of form/motion stimuli, even at the individual level.

Impaired saccadic eye movement in primary open-angle glaucoma.

PURPOSE: Our study aimed at investigating the extent to which saccadic eye movements are disrupted in patients with primary open-angle glaucoma (POAG). This approach followed upon the discovery of differences in the eye-movement behavior of POAG patients during the exploration of complex visual scenes. METHODS: The eye movements of 8 POAG patients and 4 healthy age-matched controls were recorded. Four of the patients had documented visual field scotoma, and 4 had no identifiable scotoma on visual field testing. The eye movements were monitored as the observers watched static and kinetic targets. The gain, latency, and velocity-peak latency of the saccades recorded were then analyzed. RESULTS: In POAG patients, with abnormal visual fields, watching a static target, the saccades were delayed and their accuracy was reduced, compared with those of normal observers. In POAG patients, with normal and abnormal visual fields, watching a kinetic target, a task involving precise motion analysis, the latency and accuracy of the saccades were impaired, compared with those of normal observers. CONCLUSIONS: Our findings suggest that POAG alters saccade programming and execution particularly in the case of moving targets.

A Bayesian computational model for online character recognition and disability assessment during cursive eye writing.

This research involves a novel apparatus, in which the user is presented with an illusion inducing visual stimulus. The user perceives illusory movement that can be followed by the eye, so that smooth pursuit eye movements can be sustained in arbitrary directions. Thus, free-flow trajectories of any shape can be traced. In other words, coupled with an eye-tracking device, this apparatus enables "eye writing," which appears to be an original object of study. We adapt a previous model of reading and writing to this context. We describe a probabilistic model called the Bayesian Action-Perception for Eye On-Line model (BAP-EOL). It encodes probabilistic knowledge about isolated letter trajectories, their size, high-frequency components of the produced trajectory, and pupil diameter. We show how Bayesian inference, in this single model, can be used to solve several tasks, like letter recognition and novelty detection (i.e., recognizing when a presented character is not part of the learned database). We are interested in the potential use of the eye writing apparatus by motor impaired patients: the final task we solve by Bayesian inference is disability assessment (i.e., measuring and tracking the evolution of motor characteristics of produced trajectories). Preliminary experimental results are presented, which illustrate the method, showing the feasibility of character recognition in the context of eye writing. We then show experimentally how a model of the unknown character can be used to detect trajectories that are likely to be new symbols, and how disability assessment can be performed by opportunistically observing characteristics of fine motor control, as letter are being traced. Experimental analyses also help identify specificities of eye writing, as compared to handwriting, and the resulting technical challenges.

Speeding up the brain: when spatial facilitation translates into latency shortening.

Waves of activity following a focal stimulation are reliably observed to spread across the cortical tissue. The origin of these waves remains unclear and the underlying mechanisms and function are still debated. In this study, we ask whether waves of activity modulate the magnetoencephalography (MEG) signals recorded in humans during visual stimulation with Gabor patches sequentially flashed along a vertical path, eliciting a perception of vertical apparent motion. Building upon the functional properties of long-rang horizontal connections, proposed to contribute to spreading activity, we specifically probe the amplitude and latency of MEG responses as a function of Gabor contrast and orientation. The results indicate that in the left hemisphere the response amplitude is enhanced and the half height response latency is shortened for co-aligned Gabor as compared to misaligned Gabor patches at a low but not at a high contrast. Building upon these findings, we develop a biologically plausible computational model that performs a "spike time alignment" of the responses to elongated contours with varying contrast, endowing them with a phase advance relative to misaligned contours.

Perceptual alternations between unbound moving contours and bound shape motion engage a ventral/dorsal interplay.

Visual shape and motion information, processed in distinct brain regions, should be combined to elicit a unitary coherent percept of an object in motion. In an fMRI study, we identified brain regions underlying the perceptual binding of motion and shape independently of the features-contrast, motion, and shape-used to design the moving displays. These displays alternately elicited a bound (moving diamond) or an unbound (disconnected moving segments) percept, and were either physically unchanging yet perceptually bistable or physically changing over time. The joint analysis of the blood-oxygen-level-dependent (BOLD) signals recorded during bound or unbound perception with these different stimuli revealed a network comprising the occipital lobe and ventral and dorsal visual regions. Bound percepts correlated with in-phase BOLD increases within the occipital lobe and a ventral area and decreased activity in a dorsal area, while unbound percepts elicited moderate BOLD modulations in these regions. This network was similarly activated by bistable unchanging displays and by displays periodically changing over time. The uncovered interplay between the two regions is proposed to reflect a generic binding process that dynamically weights the perceptual evidence supporting the different shape and motion interpretations according to the reliability of the neural activity in these regions.

Cursive writing with smooth pursuit eye movements.

The eyes never cease to move: ballistic saccades quickly turn the gaze toward peripheral targets, whereas smooth pursuit maintains moving targets on the fovea where visual acuity is best. Despite the oculomotor system being endowed with exquisite motor abilities, any attempt to generate smooth eye movements against a static background results in saccadic eye movements. Although exceptions to this rule have been reported, volitional control over smooth eye movements is at best rudimentary. Here, I introduce a novel, temporally modulated visual display, which, although static, sustains smooth eye movements in arbitrary directions. After brief training, participants gain volitional control over smooth pursuit eye movements and can generate digits, letters, words, or drawings at will. For persons deprived of limb movement, this offers a fast, creative, and personal means of linguistic and emotional expression.

Repetition blindness for natural images of objects with viewpoint changes.

When stimuli are repeated in a rapid serial visual presentation (RSVP), observers sometimes fail to report the second occurrence of a target. This phenomenon is referred to as "repetition blindness" (RB). We report an RSVP experiment with photographs in which we manipulated object viewpoints between the first and second occurrences of a target (0°, 45°, or 90° changes), and spatial frequency (SF) content. Natural images were spatially filtered to produce low, medium, or high SF stimuli. RB was observed for all filtering conditions. Surprisingly, for full-spectrum (FS) images, RB increased significantly as the viewpoint reached 90°. For filtered images, a similar pattern of results was found for all conditions except for medium SF stimuli. These findings suggest that object recognition in RSVP are subtended by viewpoint-specific representations for all spatial frequencies except medium ones.

Magnetoencephalographic signatures of visual form and motion binding.

This study investigates neural magneto-encephalographic (MEG) correlates of visual form and motion binding. Steady-state visual evoked fields (SSVEF) were recorded in MEG while observers reported their bound or unbound perception of moving bars arranged in a square shape. By using pairs of oscillating vertical and horizontal bars, "frequency-tagged" at f1 and f2, we identified a region with enhanced sustained power at 2f1+2f2 intermodulation frequency correlated with perceptual reports. Intermodulation power is more important during perceptual form/motion integration than during the perceptual segmentation of the stimulus into individual component motions, indicating that intermodulation frequency power is a neuromarker of form/motion integration. Source reconstruction of cortical activities at the relevant frequencies further reveals well segregated activity in the occipital lobe at the fundamental of the stimulation, f1 and f2, widely spread activity at 2f1 and 2f2 and a focal activity in the medial part of the right precentral sulcus region at the intermodulation component, 2f1+2f2. The present findings indicate that motion tagging provides a powerful way of investigating the processes underlying visual form/motion binding non-invasively in humans.

Coupled dynamics of bistable distant motion displays.

This study explores the extent to which a display changing periodically in perceptual interpretation through smooth periodic physical changes-an inducer-is able to elicit perceptual switches in an intrinsically bistable distant probe display. Four experiments are designed to examine the coupling strength and bistable dynamics with displays of varying degree of ambiguity, similarity, and symmetry-in motion characteristics-as a function of their locations in visual space. The results show that periodic fluctuations of a remote inducer influence a bistable probe and regulate its dynamics through coupling. Coupling strength mainly depends on the relative locations of the probe display and the contextual inducer in the visual field, with stronger coupling when both displays are symmetrical around the vertical meridian and weaker coupling otherwise. Smaller effects of common fate and symmetry are also found. Altogether, the results suggest that long-range interhemispheric connections, presumably involving the corpus callosum, are able to synchronize perceptual transitions across the vertical meridian. If true, bistable dynamics may provide a behavioral method to probe interhemispheric connectivity in behaving human. Consequences of these findings for studies using stimuli symmetrical around the vertical meridian are evaluated.

Phase delays within visual cortex shape the response to steady-state visual stimulation.

Although the spatial organization of visual areas can be revealed by functional Magnetic Resonance Imaging (fMRI), the synoptic, non-invasive access to the temporal characteristics of the information flow amongst distributed visual processes remains a technical and methodological challenge. Using frequency-encoded steady-state visual stimulation together with a combination of time-resolved functional magnetic source imaging from magnetoencephalography (MEG) and anatomical magnetic resonance imaging (MRI), this study evidences maps of visuotopic sustained oscillatory neural responses distributed across the visual cortex. Our results further reveal relative phase delays across responding striate and extra-striate visual areas, which thereby shape the chronometry of neural processes amongst these regions. The methodology developed in this study points at further developments in time-resolved analyses of distributed visual processes in the millisecond range, and to new ways of exploring the dynamics of functional processes within the human visual cortex non-invasively.