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.

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.

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.

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.

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.

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.

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.

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.

Pupil dynamics during bistable motion perception.

Pupil size not only varies to changes in illumination but is also modulated by several cognitive factors, making it a potentially versatile physiological marker of cortical states. We recorded pupil dynamics while subjects continuously reported their bistable perception of ambiguous moving stimuli, plaids, and partially occluded rotating diamonds. We observed small (about 5% of surface change on average) but reliable pupil dilation around (-300 ms to 1.5 s) the button presses indicating the changes of percepts. We found that 70% of pupil dilation could be accounted for by the motor response. The remaining perceptual component was similar for spontaneously occurring transitions and transitions triggered by physical stimulus manipulations. Moreover, the amplitude of pupil modulation in the spontaneous condition was unrelated to the duration of each perceptual state. It is therefore unlikely that the mechanisms of endogenous perceptual bistability reflect in the pupil. In addition, we measured a clear constriction of the pupil after blinks (about 8% of surface change on average). As pupil changes have the potential to entail retino-cortical activity, their monitoring in studies of visual processing could prove worthwhile.

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.

Superposition catastrophe and form-motion binding.

Numerous studies indicate that perceiving global object motion results from the integration of local component motions across space and time. Less attention has been paid to the issue of motion selection, necessary to avoid spurious associations of component motions belonging to different objects and to solve the so-called "superposition catastrophe problem" (F. Rosenblatt, 1961). We address this issue using outlines of geometrical shapes moving behind apertures that concealed their vertices such that recovering their global motion requires the selection and integration of some, but not all, component motions. Depending on which local motions are selected for motion integration, these stimuli yield the perception of either expansion/contraction, of global translation, or of segments moving independently. We show that the selection process depends on local and global stimulus parameters, including the local direction of figure's line-endings or the spatial configuration of component motions. In contrast, motion selection depends less on the width-i.e., spatial frequency content-or polarity of the edges. Finally, synchronous temporal modulation of component motions in the gamma range has little effect on motion selection. These results indicate that selecting component motions for motion integration is primarily determined by form constraints. As a consequence, current models assuming that mutually consistent component motions are bounded in a velocity space-lacking spatial organization should be revised to account for the present data. Alternately, interactions between visual areas selectively processing form and motion could be introduced in order to account for the perceptual binding of moving objects.

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.

Contour interactions between pairs of Gabors engaged in binocular rivalry reveal a map of the association field.

A psychophysical study was conducted to investigate contour interactions (the 'association field'). Two Gabor patches were presented to one eye, with random-dot patches in corresponding locations of the other eye so as to produce binocular rivalry. Perceptual alternations of the two rivalry processes were monitored continuously by observers and the two time series were cross-correlated. The Gabors were oriented collinearly, obliquely, or orthogonally, and spatial separation was varied. A parallel condition was also included. Correlation between the rivalry processes strongly depended on separation and relative orientation. Correlations between adjacent collinear Gabors was near-perfect and reduced with spatial separation and as relative orientation departed from collinear. Importantly, variations in cross-correlation did not alter the rivalry processes (average dominance duration, and therefore alternation rate, was constant across conditions). Instead, synchronisation of rivalry oscillations accounts for the correlation variations: rivalry alternations were highly synchronised when contour interactions were strong and were poorly synchronised when contour interactions were weak. The level of synchrony between these two stochastic processes, in depending on separation and relative orientation, effectively reveals a map of the association field. These association fields are not greatly affected by contrast, and can be demonstrated between contours that are presented to separate hemispheres.

Dynamic competition between contour integration and contour segmentation probed with moving stimuli.

Line-ends, corners and junctions are important singularities for form analysis, object recognition, depth ordering or motion processing. In this study, we investigate the extent to which processing the motion of line ends depends on the spatial configuration of their immediate surround. To that aim, we used two vertical collinear line segments, translating clockwise or anti-clockwise along a circular path, together with a direction discrimination task. Direction discrimination was measured independently for outer line-ends--at both segments extremities--and inner line-ends--in between collinear segments--using line segments partially occluded by invisible masks such that the direction of either inner or outer line-ends' motion was restricted to a sinusoidal translation along a horizontal axis, and thus irrelevant for the motion task. Under these conditions, access to the direction of inner line-ends is longer and more difficult than it is for outer line-ends. Subsequent experiments show that these effects depend on the degree of collinearity between line segments. Similar experiments were performed after volunteers took a dose of Lorazepam, a benzodiazepine that facilitates the fixation of GABA on GABAA receptors. The results show that the differences between the processing of inner and outer line-ends is reduced, suggesting that the effect of the surround is modulated by inhibitory mechanisms. Using a simple model, we propose that this effect can be explained by a competition between a segmentation process based on surround suppression and contour integration through long-range horizontal connections, at or prior to motion processing stages.

Geometry and the visual brain.

Receptive fields structure of neurons in primary visual cortex suggests that they process visual stimuli in the frequency domain, in a way similar to the frequency analysis performed in the auditory system. As a consequence, both psychophysicists and electrophysiologists have long probed the visual system using extended sine wave gratings that are well localized in the frequency domain but poorly defined in visual space. Meanwhile, how the brain processes the geometrical properties and the spatial and temporal relationships between stimulus parts has received less attention. Recent progress in visual neuroscience that uncovered long-range horizontal connections between cortical neurons and revealed the complex architecture of primary visual cortex and feedback connectivity led to new insights concerned with the processing of geometrical properties of visual stimuli in V1. This paper presents a short historical perspective of the emergence of new issues related to the cortical architecture and its functional consequences on the processing of geometrical properties.

Crossmodal integration for perception and action.

The integration of information from different sensory modalities has many advantages for human observers, including increase of salience, resolution of perceptual ambiguities, and unified perception of objects and surroundings. Several behavioral, electrophysiological and neuroimaging data collected in various tasks, including localization and detection of spatial events, crossmodal perception of object properties and scene analysis are reviewed here. All the results highlight the multiple faces of crossmodal interactions and provide converging evidence that the brain takes advantages of spatial and temporal coincidence between spatial events in the crossmodal binding of spatial features gathered through different modalities. Furthermore, the elaboration of a multimodal percept appears to be based on an adaptive combination of the contribution of each modality, according to the intrinsic reliability of sensory cue, which itself depends on the task at hand and the kind of perceptual cues involved in sensory processing. Computational models based on bayesian sensory estimation provide valuable explanations of the way perceptual system could perform such crossmodal integration. Recent anatomical evidence suggest that crossmodal interactions affect early stages of sensory processing, and could be mediated through a dynamic recurrent network involving backprojections from multimodal areas as well as lateral connections that can modulate the activity of primary sensory cortices, though future behavioral and neurophysiological studies should allow a better understanding of the underlying mechanisms.

The "silent" surround of V1 receptive fields: theory and experiments.

The spiking response of a primary visual cortical cell to a stimulus placed within its receptive field can be up- and down-regulated by the simultaneous presentation of objects or scenes placed in the "silent" regions which surround the receptive field. We here review recent progresses that have been made both at the experimental and theoretical levels in the description of these so-called "Center/Surround" modulations and in the understanding of their neural basis. Without denying the role of a modulatory feedback from higher cortical areas, recent results support the view that some of these phenomena result from the dynamic interplay between feedforward projections and horizontal intracortical connectivity in V1. Uncovering the functional role of the contextual periphery of cortical receptive fields has become an area of active investigation. The detailed comparison of electrophysiological and psychophysical data reveals strong correlations between the integrative behavior of V1 cells and some aspects of "low-level" and "mid-level" conscious perception. These suggest that as early as the V1 stage, the visual system is able to make use of contextual cues to recover local visual scene properties or correct their interpretation. Promising ideas have emerged on the importance of such a strategy for the coding of visual scenes, and the processing of static and moving objects.

Perceptual grouping in the Ternus display: evidence for an 'association field' in apparent motion.

We present psychophysical experiments designed to reveal the role of facilitative contour interactions (the so-called 'association field') in apparent motion. We use the Ternus display (a trio of horizontally aligned elements oscillating in apparent motion). This display is perceived in 'element' motion when interframe intervals (IFIs) are short, and in 'group' motion when IFIs are long. Using Gabor elements arranged collinearly or in parallel, IFI is varied to find group motion thresholds. Consistent with a role for collinearity in perceptual grouping, thresholds are lower for collinear displays. The collinear vs. parallel comparison is made while manipulating contrast, spatial frequency, eccentricity, phase, orientation jitter and element separation. Results show a clear effect of contrast not observed in lateral masking paradigms or in 'pathfinder' stimuli, with higher contrast promoting within-frame grouping, and evidence of facilitatory interactions among parallel elements (although over a smaller scale). The tendency for collinear displays to group more than parallel displays declined with eccentricity with no clear difference evident at 12 deg. These changes in group motion thresholds indicate changing association strengths among the elements and is accounted for in terms of an association field. Alternative accounts in terms of second-order collector units or visible persistence are considered but are not supported by the data.