Outcome of severe COVID-19: spotlight on fatigue, fatigability, multidomain complaints and pattern of cognitive deficits in a case series without prior brain dysfunction and without COVID-19-related stroke and/or cardiac arrest.

BACKGROUND: Population-wide surveys and large-scale investigations highlighted the presence of cognitive deficits in the acute and postacute stages of severe COVID-19; a few studies documented their occurrence in cases without prior or COVID-19-related brain damage. The evolution of cognitive deficits in the latter population and their relationship to the post-COVID-19 fatigue syndrome are poorly understood. CASE PRESENTATION: We report the outcome at 12 months after severe COVID-19 involving an intensive care unit stay and mechanical ventilation in six (five Caucasian and one Asian) patients (age range: 53-71 years, mean age 61.7 ± 6.5 years) without history of prior brain dysfunction and without stroke and/or cardiac arrest during or after COVID-19. All patients reported pervading mental and physical fatigue as well as numerous multidomain complaints, which impacted everyday life. Individual patients described mental fatigability, apathy, and/or anxiety. Standardized neuropsychological tests revealed isolated symptoms of cognitive dysfunction or performance at the lower limit of the norm in the attentional, executive, and/or working memory domains in four of the six patients. Somatic scales documented dyspnoea, muscle weakness, olfactory disorder, and/or minor sleep problems in some, but not all, patients. CONCLUSION: Fatigue, fatigability, multidomain complaints, cognitive difficulties, or dysfunction, as well as isolated neurobehavioral and/or psychiatric and/or somatic symptoms, tend to occur in the aftermath of severe COVID-19 and persist at 12 months, even in the absence of prior and/or COVID-19-related brain damage. This clinical situation, which impacts everyday life, calls for a detailed investigation of patients' complaints, its neural underpinning, and an elaboration of specific rehabilitation programs.

An immersive virtual reality tool for assessing left and right unilateral spatial neglect.

The reported rate of the occurrence of unilateral spatial neglect (USN) is highly variable likely due to the lack of validity and low sensitivity of classical tools used to assess it. Virtual reality (VR) assessments try to overcome these limitations by proposing immersive and complex environments. Nevertheless, existing VR-based tasks are mostly focused only on near space and lack analysis of psychometric properties and/or clinical validation. The present study evaluates the clinical validity and sensitivity of a new immersive VR-based task to assess USN in the extra-personal space and examines the neuronal correlates of deficits of far space exploration. The task was administrated to two groups of patients with right (N = 28) or left (N = 11) hemispheric brain lesions, also undergoing classical paper-and-pencil assessment, as well as a group of healthy participants. Our VR-based task detected 44% of neglect cases compared to 31% by paper-and-pencil tests in the total sample. Importantly, 30% of the patients (with right or left brain lesions) with no clear sign of USN on the paper-and-pencil tests performed outside the normal range in the VR-based task. Voxel lesion-symptom mapping revealed that deficits detected in VR were associated with lesions in insular and temporal cortex, part of the neural network involved in spatial processing. These results show that our immersive VR-based task is efficient and sensitive in detecting mild to strong manifestations of USN affecting the extra-personal space, which may be undetected using standard tools.

Virtual reality-based sensorimotor adaptation shapes subsequent spontaneous and naturalistic stimulus-driven brain activity.

Our everyday life summons numerous novel sensorimotor experiences, to which our brain needs to adapt in order to function properly. However, tracking plasticity of naturalistic behavior and associated brain modulations is challenging. Here, we tackled this question implementing a prism adaptation-like training in virtual reality (VRPA) in combination with functional neuroimaging. Three groups of healthy participants (N = 45) underwent VRPA (with a shift either to the left/right side, or with no shift), and performed functional magnetic resonance imaging (fMRI) sessions before and after training. To capture modulations in free-flowing, task-free brain activity, the fMRI sessions included resting-state and free-viewing of naturalistic videos. We found significant decreases in spontaneous functional connectivity between attentional and default mode (DMN)/fronto-parietal networks, only for the adaptation groups, more pronouncedly in the hemisphere contralateral to the induced shift. In addition, VRPA was found to bias visual responses to naturalistic videos: Following rightward adaptation, we found upregulation of visual response in an area in the parieto-occipital sulcus (POS) only in the right hemisphere. Notably, the extent of POS upregulation correlated with the size of the VRPA-induced after-effect measured in behavioral tests. This study demonstrates that a brief VRPA exposure can change large-scale cortical connectivity and correspondingly bias visual responses to naturalistic sensory inputs.

Does hand modulate the reshaping of the attentional system during rightward prism adaptation? An fMRI study.

Adaptation to right-deviating prisms (R-PA), that is, learning to point with the right hand to targets perceived through prisms, has been shown to change spatial topography within the inferior parietal lobule (IPL) by increasing responses to left, central, and right targets on the left hemisphere and decreasing responses to right and central targets on the right hemisphere. As pointed out previously, this corresponds to a switch of the dominance of the ventral attentional network from the right to the left hemisphere. Since the encoding of hand movements in pointing paradigms is side-dependent, the choice of right vs. left hand for pointing during R-PA may influence the visuomotor adaptation process and hence the reshaping of the attentional system. We have tested this hypothesis in normal subjects by comparing activation patterns to visual targets in left, central, and right fields elicited before and after adaptation to rightward-deviating prisms using the right hand (RWRH) with those in two control groups. The first control group underwent adaptation to rightward-deviating prisms using the left hand, whereas the second control group underwent adaptation to leftward-deviating prisms using the right hand. The present study confirmed the previously described enhancement of left and central visual field representation within left IPL following R-PA. It further showed that the use of right vs. left hand during adaptation modulates this enhancement in some but not all parts of the left IPL. Interestingly, in some clusters identified in this study, L-PA with right hand mimics partially the effect of R-PA by enhancing activation elicited by left stimuli in the left IPL and by decreasing activation elicited by right stimuli in the right IPL. Thus, the use of right vs. left hand modulates the R-PA-induced reshaping of the ventral attentional system. Whether the choice of hand during R-PA affects also the reshaping of the dorsal attentional system remains to be determined as well as possible clinical applications of this approach. Depending on the patients' conditions, using the right or the left hand during PA might potentiate the beneficial effects of this intervention.

Choosing Sides: Impact of Prismatic Adaptation on the Lateralization of the Attentional System.

Seminal studies revealed differences between the effect of adaptation to left- vs. right-deviating prisms (L-PA, R-PA) in normal subjects. Whereas L-PA leads to neglect-like shift in attention, demonstrated in numerous visuo-spatial and cognitive tasks, R-PA has only minor effects in specific aspects of a few tasks. The paucity of R-PA effects in normal subjects contrasts with the striking alleviation of neglect symptoms in patients with right hemispheric lesions. Current evidence from activation studies in normal subjects highlights the contribution of regions involved in visuo-motor control during prism exposure and a reorganization of spatial representations within the ventral attentional network (VAN) after the adaptation. The latter depends on the orientation of prisms used. R-PA leads to enhancement of the ipsilateral visual and auditory space within the left inferior parietal lobule (IPL), switching thus the dominance of VAN from the right to the left hemisphere. L-PA leads to enhancement of the ipsilateral space in right IPL, emphasizing thus the right hemispheric dominance of VAN. Similar reshaping has been demonstrated in patients. We propose here a model, which offers a parsimonious explanation of the effect of L-PA and R-PA both in normal subjects and in patients with hemispheric lesions. The model posits that prismatic adaptation induces instability in the synaptic organization of the visuo-motor system, which spreads to the VAN. The effect is lateralized, depending on the side of prism deviation. Successful pointing with prisms implies reaching into the space contralateral, and not ipsilateral, to the direction of prism deviation. Thus, in the hemisphere contralateral to prism deviation, reach-related neural activity decreases, leading to instability of the synaptic organization, which induces a reshuffling of spatial representations in IPL. Although reshuffled spatial representations in IPL may be functionally relevant, they are most likely less efficient than regular representations and may thus cause partial dysfunction. The former explains, e.g., the alleviation of neglect symptoms after R-PA in patients with right hemispheric lesions, the latter the occurrence of neglect-like symptoms in normal subjects after L-PA. Thus, opting for R- vs. L-PA means choosing the side of major IPL reshuffling, which leads to its partial dysfunction in normal subjects and to recruitment of alternative or enhanced spatial representations in patients with hemispheric lesions.

Combined virtual reality and haptic robotics induce space and movement invariant sensorimotor adaptation.

Prism adaptation is a method for studying visuomotor plasticity in healthy individuals, as well as for rehabilitating patients suffering spatial neglect. We developed a new set-up based on virtual-reality (VR) and haptic-robotics allowing us to induce sensorimotor adaptation and to reproduce the effect of prism adaptation in a more ecologically valid, yet experimentally controlled context. Participants were exposed to an immersive VR environment while controlling a virtual hand via a robotic-haptic device to reach virtual objects. During training, a rotational shift was induced between the position of the participant's real hand and that of the virtual hand in order to trigger sensorimotor recalibration. The use of VR and haptic-robotics allowed us to simulate and test multiple components of sensorimotor adaptation: training either peripersonal or extrapersonal space and testing generalization for the non-trained sector of space, and using active versus robot-guided reaching movements. Results from 60 neurologically intact participants show that participants exposed to the virtual shift were able to quickly adapt their reaching movements to aim correctly at the target objects. When the shift was removed, participants showed a systematic deviation of their movements during open-loop tasks in the direction opposite to that of the shift, which generalized to un-trained portions of space and occurred also when their movements were robotically-guided during the adaptation. Interestingly, follow-up questionnaires revealed that when the adaptation training was robotically-guided, participants were largely unaware of the mismatch between their hand and the virtual hand's position. The stability of the aftereffects, despite the changing experimental parameters, suggests that the induced sensory-motor adaptation does not rely on low-level processing of sensory stimuli during the training, but taps into high-level representations of space. Importantly, the flexibility of the trained space and the option of robotically-guided movements open novel possibilities of fine-tuning the training to patients' level of spatial and motor impairment, thus possibly resulting in a better outcome.

A brief exposure to rightward prismatic adaptation changes resting-state network characteristics of the ventral attentional system.

A brief session of rightward prismatic adaptation (R-PA) has been shown to alleviate neglect symptoms in patients with right hemispheric damage, very likely by switching hemispheric dominance of the ventral attentional network (VAN) from the right to the left and by changing task-related activity within the dorsal attentional network (DAN). We have investigated this very rapid change in functional organisation with a network approach by comparing resting-state connectivity before and after a brief exposure i) to R-PA (14 normal subjects; experimental condition) or ii) to plain glasses (12 normal subjects; control condition). A whole brain analysis (comprising 129 regions of interest) highlighted R-PA-induced changes within a bilateral, fronto-temporal network, which consisted of 13 nodes and 11 edges; all edges involved one of 4 frontal nodes, which were part of VAN. The analysis of network characteristics within VAN and DAN revealed a R-PA-induced decrease in connectivity strength between nodes and a decrease in local efficiency within VAN but not within DAN. These results indicate that the resting-state connectivity configuration of VAN is modulated by R-PA, possibly by decreasing its modularity.

Prism adaptation enhances decoupling between the default mode network and the attentional networks.

Prism adaptation (PA) is a procedure used for studying visuomotor plasticity in healthy individuals, as well as for alleviating spatial neglect in patients. The adaptation is achieved by performing goal-directed movements while wearing prismatic lenses that induce a lateral displacement of visual information. This results in an initial movement error that is compensated by a recalibration of sensory-motor coordinates; consequently, a lateral bias in both motor and perceptual measurements occurs after prism removal, i.e., after effects. Neuroimaging studies have shown that a brief exposure to a rightward-shifting prism changes the activations in the inferior parietal lobule (IPL) and modulates interhemispheric balance during attention tasks. However, it is yet unknown how PA changes global interplay between cortical networks as evident from task-free resting state connectivity. Thus we compared resting state functional connectivity patterns before ('Pre') and after ('Post') participants performed a session of pointing movements with a rightward-shifting prism (N = 14) or with neutral lenses (as a control condition; N = 12). Global connectivity analysis revealed significant decreases in functional connectivity following PA in two nodes of the Default Mode Network (DMN), and in the left anterior insula. Further analyses of these regions showed specific connectivity decrease between either of the DMN nodes and areas within the attentional networks, including the inferior frontal gyrus, the anterior insula and the right superior temporal sulcus. On the other hand, the anterior insula decreased its connectivity to a large set of areas, all within the boundaries of the DMN. These results demonstrate that a brief exposure to PA enhances the decoupling between the DMN and the attention networks. The change in interplay between those pre-existing networks might be the basis of the rapid and wide-ranged behavioural changes induce by PA in healthy individuals.

Implicit representation of the auditory space: contribution of the left and right hemispheres.

Spatial cues contribute to the ability to segregate sound sources and thus facilitate their detection and recognition. This implicit use of spatial cues can be preserved in cases of cortical spatial deafness, suggesting that partially distinct neural networks underlie the explicit sound localization and the implicit use of spatial cues. We addressed this issue by assessing 40 patients, 20 patients with left and 20 patients with right hemispheric damage, for their ability to use auditory spatial cues implicitly in a paradigm of spatial release from masking (SRM) and explicitly in sound localization. The anatomical correlates of their performance were determined with voxel-based lesion-symptom mapping (VLSM). During the SRM task, the target was always presented at the centre, whereas the masker was presented at the centre or at one of the two lateral positions on the right or left side. The SRM effect was absent in some but not all patients; the inability to perceive the target when the masker was at one of the lateral positions correlated with lesions of the left temporo-parieto-frontal cortex or of the right inferior parietal lobule and the underlying white matter. As previously reported, sound localization depended critically on the right parietal and opercular cortex. Thus, explicit and implicit use of spatial cues depends on at least partially distinct neural networks. Our results suggest that the implicit use may rely on the left-dominant position-linked representation of sound objects, which has been demonstrated in previous EEG and fMRI studies.

Remodelling the attentional system after left hemispheric stroke: Effect of leftward prismatic adaptation.

Left hemispheric stroke is known to be associated with right neglect and/or not lateralized attentional deficits. The former appears to respond favourably to leftward prismatic adaptation (L-PA), as reported in a case of a large left stroke. In normal subjects, brief exposure to L-PA was shown to enhance the representation of the right visual field within the right inferior parietal lobule, emphasizing thus right hemispheric dominance within the ventral attentional system. We have investigated whether L-PA does the same in left hemispheric stroke by comparing neural responses to left, central and right stimuli before and after a brief exposure to L-PA. Neural responses to visual stimuli were significantly modulated within a large part of the occipito-temporal cortex and in smaller clusters in the angular gyrus, the anterior temporal lobe and the insula, corresponding to decrease in activity. Within the occipito-temporal region the decrease concerned predominantly neural activity elicited by left stimuli, downregulating thus the representation of the contralateral visual field, which is characteristic of the higher-order visual areas in this region.

Exploring auditory neglect: Anatomo-clinical correlations of auditory extinction.

BACKGROUND: The key symptoms of auditory neglect include left extinction on tasks of dichotic and/or diotic listening and rightward shift in locating sounds. The anatomical correlates of the latter are relatively well understood, but no systematic studies have examined auditory extinction. Here, we performed a systematic study of anatomo-clinical correlates of extinction by using dichotic and/or diotic listening tasks. METHODS: In total, 20 patients with right hemispheric damage (RHD) and 19 with left hemispheric damage (LHD) performed dichotic and diotic listening tasks. Either task consists of the simultaneous presentation of word pairs; in the dichotic task, 1 word is presented to each ear, and in the diotic task, each word is lateralized by means of interaural time differences and presented to one side. RESULTS AND CONCLUSION: RHD was associated with exclusively contralesional extinction in dichotic or diotic listening, whereas in selected cases, LHD led to contra- or ipsilesional extinction. Bilateral symmetrical extinction occurred in RHD or LHD, with dichotic or diotic listening. The anatomical correlates of these extinction profiles offer an insight into the organisation of the auditory and attentional systems. First, left extinction in dichotic versus diotic listening involves different parts of the right hemisphere, which explains the double dissociation between these 2 neglect symptoms. Second, contralesional extinction in the dichotic task relies on homologous regions in either hemisphere. Third, ipsilesional extinction in dichotic listening after LHD was associated with lesions of the intrahemispheric white matter, interrupting callosal fibres outside their midsagittal or periventricular trajectory. Fourth, bilateral symmetrical extinction was associated with large parieto-fronto-temporal LHD or smaller parieto-temporal RHD, which suggests that divided attention, supported by the right hemisphere, and auditory streaming, supported by the left, likely play a critical role.

Keeping track of sound objects in space: The contribution of early-stage auditory areas.

The influential dual-stream model of auditory processing stipulates that information pertaining to the meaning and to the position of a given sound object is processed in parallel along two distinct pathways, the ventral and dorsal auditory streams. Functional independence of the two processing pathways is well documented by conscious experience of patients with focal hemispheric lesions. On the other hand there is growing evidence that the meaning and the position of a sound are combined early in the processing pathway, possibly already at the level of early-stage auditory areas. Here, we investigated how early auditory areas integrate sound object meaning and space (simulated by interaural time differences) using a repetition suppression fMRI paradigm at 7 T. Subjects listen passively to environmental sounds presented in blocks of repetitions of the same sound object (same category) or different sounds objects (different categories), perceived either in the left or right space (no change within block) or shifted left-to-right or right-to-left halfway in the block (change within block). Environmental sounds activated bilaterally the superior temporal gyrus, middle temporal gyrus, inferior frontal gyrus, and right precentral cortex. Repetitions suppression effects were measured within bilateral early-stage auditory areas in the lateral portion of the Heschl's gyrus and posterior superior temporal plane. Left lateral early-stages areas showed significant effects for position and change, interactions Category x Initial Position and Category x Change in Position, while right lateral areas showed main effect of category and interaction Category x Change in Position. The combined evidence from our study and from previous studies speaks in favour of a position-linked representation of sound objects, which is independent from semantic encoding within the ventral stream and from spatial encoding within the dorsal stream. We argue for a third auditory stream, which has its origin in lateral belt areas and tracks sound objects across space.

Supramodal effect of rightward prismatic adaptation on spatial representations within the ventral attentional system.

Rightward prismatic adaptation (R-PA) was shown to alleviate not only visuo-spatial but also auditory symptoms in neglect. The neural mechanisms underlying the effect of R-PA have been previously investigated in visual tasks, demonstrating a shift of hemispheric dominance for visuo-spatial attention from the right to the left hemisphere both in normal subjects and in patients. We have investigated whether the same neural mechanisms underlie the supramodal effect of R-PA on auditory attention. Normal subjects underwent a brief session of R-PA, which was preceded and followed by an fMRI evaluation during which subjects detected targets within the left, central and right space in the auditory or visual modality. R-PA-related changes in activation patterns were found bilaterally in the inferior parietal lobule. In either modality, the representation of the left, central and right space increased in the left IPL, whereas the representation of the right space decreased in the right IPL. Thus, a brief exposure to R-PA modulated the representation of the auditory and visual space within the ventral attentional system. This shift in hemispheric dominance for auditory spatial attention offers a parsimonious explanation for the previously reported effects of R-PA on auditory symptoms in neglect.

For Better or Worse: The Effect of Prismatic Adaptation on Auditory Neglect.

Patients with auditory neglect attend less to auditory stimuli on their left and/or make systematic directional errors when indicating sound positions. Rightward prismatic adaptation (R-PA) was repeatedly shown to alleviate symptoms of visuospatial neglect and once to restore partially spatial bias in dichotic listening. It is currently unknown whether R-PA affects only this ear-related symptom or also other aspects of auditory neglect. We have investigated the effect of R-PA on left ear extinction in dichotic listening, space-related inattention assessed by diotic listening, and directional errors in auditory localization in patients with auditory neglect. The most striking effect of R-PA was the alleviation of left ear extinction in dichotic listening, which occurred in half of the patients with initial deficit. In contrast to nonresponders, their lesions spared the right dorsal attentional system and posterior temporal cortex. The beneficial effect of R-PA on an ear-related performance contrasted with detrimental effects on diotic listening and auditory localization. The former can be parsimoniously explained by the SHD-VAS model (shift in hemispheric dominance within the ventral attentional system; Clarke and Crottaz-Herbette 2016), which is based on the R-PA-induced shift of the right-dominant ventral attentional system to the left hemisphere. The negative effects in space-related tasks may be due to the complex nature of auditory space encoding at a cortical level.

A Brief Exposure to Leftward Prismatic Adaptation Enhances the Representation of the Ipsilateral, Right Visual Field in the Right Inferior Parietal Lobule.

A brief exposure to rightward prismatic adaptation (PA) was shown to shift visual field representation within the inferior parietal lobule (IPL) from the right to the left hemisphere. This change in hemispheric dominance could be interpreted as (1) a general effect of discrepancy in visuomotor alignment caused by PA or (2) a direction-specific effect of rightward PA. To test these hypotheses, we compared the effects of rightward and leftward PA on visual representation in normal human subjects. Three groups of normal subjects underwent an fMRI evaluation using a simple visual detection task before and after brief PA exposure using leftward- or rightward-deviating prisms or no prisms (L-PA, R-PA, neutral groups). A two-way ANOVA group × session revealed a significant interaction suggesting that PA-induced modulation is direction specific. Post hoc analysis showed that L-PA enhanced the representation of the right visual field within the right IPL. Thus, a brief exposure to L-PA enhanced right hemispheric dominance within the ventral attentional system, which is the opposite effect of the previously described shift in hemispheric dominance following R-PA. The direction-specific effects suggest that the underlying neural mechanisms involve the fine-tuning of specific visuomotor networks. The enhancement of right hemispheric dominance following L-PA offers a parsimonious explanation for neglect-like symptoms described previously in normal subjects.

Reshaping the brain after stroke: The effect of prismatic adaptation in patients with right brain damage.

Prismatic adaptation has been repeatedly reported to alleviate neglect symptoms; in normal subjects, it was shown to enhance the representation of the left visual space within the left inferior parietal cortex. Our study aimed to determine in humans whether similar compensatory mechanisms underlie the beneficial effect of prismatic adaptation in neglect. Fifteen patients with right hemispheric lesions and 11 age-matched controls underwent a prismatic adaptation session which was preceded and followed by fMRI using a visual detection task. In patients, the prismatic adaptation session improved the accuracy of target detection in the left and central space and enhanced the representation of this visual space within the left hemisphere in parts of the temporal convexity, inferior parietal lobule and prefrontal cortex. Across patients, the increase in neuronal activation within the temporal regions correlated with performance improvements in this visual space. In control subjects, prismatic adaptation enhanced the representation of the left visual space within the left inferior parietal lobule and decreased it within the left temporal cortex. Thus, a brief exposure to prismatic adaptation enhances, both in patients and in control subjects, the competence of the left hemisphere for the left space, but the regions extended beyond the inferior parietal lobule to the temporal convexity in patients. These results suggest that the left hemisphere provides compensatory mechanisms in neglect by assuming the representation of the whole space within the ventral attentional system. The rapidity of the change suggests that the underlying mechanism relies on uncovering pre-existing synaptic connections.

Modulation of visual attention by prismatic adaptation.

Visuo-motor adaptation via rightward-deviating prisms has been repeatedly shown to alleviate lateralized deficits in neglect, including detection of targets as well as endogenous and exogenous orienting of attention. We review here evidence relevant to the underlying neural mechanisms. Rightward prismatic adaptation was shown to shift visual field representation from right to left inferior parietal lobule, changing thus hemispheric dominance within the ventral attentional system. This change is likely to redirect visual input to the dorsal attentional system and to re-install balance between its left- and right-hemispheric components in neglect. We propose a model based on the shift in hemispheric dominance within the ventral attentional system (SHD-VAS), which offers a parsimonious explanation for the effect of rightward prismatic adaptation on spatial bias in neglect and on behavioral data in normal subjects.

Cue-dependent circuits for illusory contours in humans.

Objects' borders are readily perceived despite absent contrast gradients, e.g. due to poor lighting or occlusion. In humans, a visual evoked potential (VEP) correlate of illusory contour (IC) sensitivity, the "IC effect", has been identified with an onset at ~90 ms and generators within bilateral lateral occipital cortices (LOC). The IC effect is observed across a wide range of stimulus parameters, though until now it always involved high-contrast achromatic stimuli. Whether IC perception and its brain mechanisms differ as a function of the type of stimulus cue remains unknown. Resolving such will provide insights on whether there is a unique or multiple solutions to how the brain binds together spatially fractionated information into a cohesive perception. Here, participants discriminated IC from no-contour (NC) control stimuli that were either comprised of low-contrast achromatic stimuli or instead isoluminant chromatic contrast stimuli (presumably biasing processing to the magnocellular and parvocellular pathways, respectively) on separate blocks of trials. Behavioural analyses revealed that ICs were readily perceived independently of the stimulus cue--i.e. when defined by either chromatic or luminance contrast. VEPs were analysed within an electrical neuroimaging framework and revealed a generally similar timing of IC effects across both stimulus contrasts (i.e. at ~90 ms). Additionally, an overall phase shift of the VEP on the order of ~30 ms was consistently observed in response to chromatic vs. luminance contrast independently of the presence/absence of ICs. Critically, topographic differences in the IC effect were observed over the ~110-160 ms period; different configurations of intracranial sources contributed to IC sensitivity as a function of stimulus contrast. Distributed source estimations localized these differences to LOC as well as V1/V2. The present data expand current models by demonstrating the existence of multiple, cue-dependent circuits in the brain for generating perceptions of illusory contours.