An easy-to-implement, non-invasive head restraint method for monkey fMRI.

Functional magnetic resonance imaging (fMRI) in behaving monkeys has a strong potential to bridge the gap between human neuroimaging and primate neurophysiology. In monkey fMRI, to restrain head movements, researchers usually surgically implant a plastic head-post on the skull. Although time-proven to be effective, this technique could create burdens for animals, including a risk of infection and discomfort. Furthermore, the presence of extraneous objects on the skull, such as bone screws and dental cement, adversely affects signals near the cortical surface. These side effects are undesirable in terms of both the practical aspect of efficient data collection and the spirit of "refinement" from the 3R's. Here, we demonstrate that a completely non-invasive fMRI scan in awake monkeys is possible by using a plastic head mask made to fit the skull of individual animals. In all of the three monkeys tested, longitudinal, quantitative assessment of head movements showed that the plastic mask has effectively suppressed head movements, and we were able to obtain reliable retinotopic BOLD signals in a standard retinotopic mapping task. The present, easy-to-make plastic mask has a strong potential to simplify fMRI experiments in awake monkeys, while giving data that is as good as or even better quality than that obtained with the conventional head-post method.

[Cortical Regions Contributing to the Reconstruction of the 3D Visual World].

Humans can immediately perceive a rich and stable 3D visual world even though the visual inputs on the retina are 2D. Which raises the question; which cortical regions are responsible for reconstructing stereoscopic perception? In this article, I would like to outline the general research methods of stereopsis and introduce our recent research projects that show that the middle-or higher-order visual areas, V3A and V3B/KO, located adjacent to the interparietal sulcus, play an important role in the reconstruction of the 3D visual world.

Modulations of depth responses in the human brain by object context: Does biological relevance matter?

Depth sensitivity has been shown to be modulated by object context (plausibility). It is possible that it is behavioural relevance rather than object plausibility per se which drives this effect. Here, we manipulated the biological relevance of objects (face or a non-face) and tested whether object relevance affects behavioural sensitivity and neural responses to depth-position. In a first experiment, we presented human observers with disparity-defined faces and non-faces, and observers were asked to judge the depth position of the target under signal-noise and clear (fine) task conditions. In the second experiment, we concurrently measured behavioural and fMRI responses to depth. We found that behavioural performance varied across stimulus conditions such that they were significantly worse for the upright face than the inverted face and the random shape in the SNR task, but worse for the random shape than the upright face in the feature task. Pattern analysis of fMRI responses revealed that activity of FFA was distinctly different during depth judgments of the upright face versus the other two stimuli, with its responses (and to a stronger extent, those of V3) appearing functionally-relevant to behavioural performance. We speculate that FFA is not only involved in object analysis, but exerts considerable influence on stereoscopic mechanisms as early as in V3 based on a broader appreciation of the stimulus' behavioural relevance.Significance StatementWe asked how disparity sensitivity is modulated by object (biological) relevance using behavioural and neuroimaging paradigms. We show that behavioural sensitivity to depth-position changes in biological (face) vs non-biological (random surface) contexts, and that these changes are task-dependent. Imaging results highlight a potentially key role of the fusiform region for governing the modulation of stereo encoding by object relevance. These findings highlight powerful interactions between object recognition mechanisms and stereoencoding, such that the utility of disparity information may be up/down weighed depending on the biological relevance of the object.

Assessment of olfactory information in the human brain using 7-Tesla functional magnetic resonance imaging.

Olfaction could prove to be an early marker of neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. To use olfaction for disease diagnosis, elucidating the standard olfactory functions in healthy humans is necessary. However, the olfactory function in the human brain is less frequently assessed because of methodological difficulties associated with olfactory-related cerebral areas. Using ultra-high fields (UHF), functional magnetic resonance imaging (fMRI) with high spatial resolution and sensitivity may allow for the measurement of activation in the cerebral areas. This study aimed to apply 7-Tesla fMRI to assess olfactory function in the human brain by exposing individuals to four different odorants for 8 s. We found that olfactory stimulation mainly activated the piriform and orbitofrontal cortex in addition to the amygdala. Among these regions, univariate fMRI analysis indicated that subjective odor intensity significantly correlated with the averaged fMRI signals in the piriform cortex but not with subjective hedonic tone in any region. In contrast, multivariate fMRI analysis showed that subjective hedonic tone could be discriminated from the fMRI response patterns in the posterior orbitofrontal cortex. Thus, the piriform cortex is mainly associated with subjective odor intensity, whereas the posterior orbitofrontal cortex are involved in the discrimination of the subjective hedonic tone of the odorant. UHF-fMRI may be useful for assessing olfactory function in the human brain.

Spatiotemporal dynamics of responses to biological motion in the human brain.

We sought to understand the spatiotemporal characteristics of biological motion perception. We presented observers with biological motion walkers that differed in terms of form coherence or kinematics (i.e., the presence or absence of natural acceleration). Participants were asked to discriminate the facing direction of the stimuli while their magnetoencephalographic responses were concurrently imaged. We found that two univariate response components can be observed around ~200 msec and ~650 msec post-stimulus onset, each engaging lateral-occipital and parietal cortex prior to temporal and frontal cortex. Moreover, while univariate responses show biological motion form-specificity only after 300 msec, multivariate patterns specific to form can be well discriminated from those for local cues as early as 100 msec after stimulus onset. By finally examining the representational similarity of fMRI and MEG patterned responses, we show that early responses to biological motion are most likely sourced to occipital cortex while later responses likely originate from extrastriate body areas.

Human Depth Sensitivity Is Affected by Object Plausibility.

Using behavioral and fMRI paradigms, we asked how the physical plausibility of complex 3-D objects, as defined by the object's congruence with 3-D Euclidean geometry, affects behavioral thresholds and neural responses to depth information. Stimuli were disparity-defined geometric objects rendered as random dot stereograms, presented in plausible and implausible variations. In the behavior experiment, observers were asked to complete (1) a noise-based depth task that involved judging the depth position of a target embedded in noise and (2) a fine depth judgment task that involved discriminating the nearer of two consecutively presented targets. Interestingly, results indicated greater behavioral sensitivities of depth judgments for implausible versus plausible objects across both tasks. In the fMRI experiment, we measured fMRI responses concurrently with behavioral depth responses. Although univariate responses for depth judgments were largely similar across cortex regardless of object plausibility, multivariate representations for plausible and implausible objects were notably distinguishable along depth-relevant intermediate regions V3 and V3A, in addition to object-relevant LOC. Our data indicate significant modulations of both behavioral judgments of and neural responses to depth by object context. We conjecture that disparity mechanisms interact dynamically with the object recognition problem in the visual system such that disparity computations are adjusted based on object familiarity.

Threat Anticipation in Pulvinar and in Superficial Layers of Primary Visual Cortex (V1). Evidence from Layer-Specific Ultra-High Field 7T fMRI.

The perceptual system gives priority to threat-relevant signals with survival value. In addition to the processing initiated by sensory inputs of threat signals, prioritization of threat signals may also include processes related to threat anticipation. These neural mechanisms remain largely unknown. Using ultra-high-field 7 tesla (7T) fMRI, we show that anticipatory processing takes place in the early stages of visual processing, specifically in the pulvinar and V1. When anticipation of a threat-relevant fearful face target triggered false perception of not-presented target, there was enhanced activity in the pulvinar as well as in the V1 superficial-cortical-depth (layers 1-3). The anticipatory activity was absent in the LGN or higher visual cortical areas (V2-V4). The effect in V1 was specific to the perception of fearful face targets and did not generalize to happy face targets. A preliminary analysis showed that the connectivity between the pulvinar and V1 superficial-cortical-depth was enhanced during false perception of threat, indicating that the pulvinar and V1 may interact in preparation of anticipated threat. The anticipatory processing supported by the pulvinar and V1 may play an important role in non-sensory-input-driven anxiety states.

Areal differences in depth cue integration between monkey and human.

Electrophysiological evidence suggested primarily the involvement of the middle temporal (MT) area in depth cue integration in macaques, as opposed to human imaging data pinpointing area V3B/kinetic occipital area (V3B/KO). To clarify this conundrum, we decoded monkey functional MRI (fMRI) responses evoked by stimuli signaling near or far depths defined by binocular disparity, relative motion, and their combination, and we compared results with those from an identical experiment previously performed in humans. Responses in macaque area MT are more discriminable when two cues concurrently signal depth, and information provided by one cue is diagnostic of depth indicated by the other. This suggests that monkey area MT computes fusion of disparity and motion depth signals, exactly as shown for human area V3B/KO. Hence, these data reconcile previously reported discrepancies between depth processing in human and monkey by showing the involvement of the dorsal stream in depth cue integration using the same technique, despite the engagement of different regions.

Cortical and subcortical responses to biological motion.

Using fMRI and multivariate analyses we sought to understand the neural representations of articulated body shape and local kinematics in biological motion. We show that in addition to a cortical network that includes areas identified previously for biological motion perception, including the posterior superior temporal sulcus, inferior frontal gyrus, and ventral body areas, the ventral lateral nucleus, a presumably motoric thalamic area is sensitive to both form and kinematic information in biological motion. Our findings suggest that biological motion perception is not achieved as an end-point of segregated cortical form and motion networks as often suggested, but instead involves earlier parts in the visual system including a subcortical network.

Functional Organization of Flash-Induced V1 Offline Reactivation.

The primary visual cortex exhibits a late, long response with a latency of >300 ms and an immediate early response that occurs ∼100 ms after a visual stimulus. The late response is thought to contribute to visual functions such as sensory perception, iconic memory, working memory, and forming connections between temporally separated stimuli. However, how the visual late response is generated and organized is not completely understood. In the mouse primary visual cortex in vivo, we isolated long-delayed responses by using a brief light-flash stimulus for which the stimulus late response occurred long after the stimulus offset and was not contaminated by the instantaneous response evoked by the stimulus. Using whole-cell patch-clamp recordings, we demonstrated that the late rebound response was shaped by a net-balanced increase in excitatory and inhibitory synaptic conductances, whereas transient imbalances were caused by intermittent inhibitory barrage. In contrast to the common assumption that the neocortical late response reflects a feedback signal from the downstream higher-order cortical areas, our pharmacological and optogenetic analyses demonstrated that the late responses likely have a thalamic origin. Therefore, the late component of a sensory-evoked cortical response should be interpreted with caution. SIGNIFICANCE STATEMENT: The long-delayed responses of neocortical neurons are thought to arise from cortical feedback activity that is related to sensory perception and cognition. The mechanism of neocortical late responses was investigated using multiple electrophysiological techniques and the findings indicate that it actually arises from the thalamus. In addition, during the late response, excitation and inhibition are balanced, but inhibition is dominant in patterning action potentials.

Differential processing of binocular and monocular gloss cues in human visual cortex.

The visual impression of an object's surface reflectance ("gloss") relies on a range of visual cues, both monocular and binocular. Whereas previous imaging work has identified processing within ventral visual areas as important for monocular cues, little is known about cortical areas involved in processing binocular cues. Here, we used human functional MRI (fMRI) to test for brain areas selectively involved in the processing of binocular cues. We manipulated stereoscopic information to create four conditions that differed in their disparity structure and in the impression of surface gloss that they evoked. We performed multivoxel pattern analysis to find areas whose fMRI responses allow classes of stimuli to be distinguished based on their depth structure vs. material appearance. We show that higher dorsal areas play a role in processing binocular gloss information, in addition to known ventral areas involved in material processing, with ventral area lateral occipital responding to both object shape and surface material properties. Moreover, we tested for similarities between the representation of gloss from binocular cues and monocular cues. Specifically, we tested for transfer in the decoding performance of an algorithm trained on glossy vs. matte objects defined by either binocular or by monocular cues. We found transfer effects from monocular to binocular cues in dorsal visual area V3B/kinetic occipital (KO), suggesting a shared representation of the two cues in this area. These results indicate the involvement of mid- to high-level visual circuitry in the estimation of surface material properties, with V3B/KO potentially playing a role in integrating monocular and binocular cues.

Late development of cue integration is linked to sensory fusion in cortex.

Adults optimize perceptual judgements by integrating different types of sensory information [1, 2]. This engages specialized neural circuits that fuse signals from the same [3-5] or different [6] modalities. Whereas young children can use sensory cues independently, adult-like precision gains from cue combination only emerge around ages 10 to 11 years [7-9]. Why does it take so long to make best use of sensory information? Existing data cannot distinguish whether this (1) reflects surprisingly late changes in sensory processing (sensory integration mechanisms in the brain are still developing) or (2) depends on post-perceptual changes (integration in sensory cortex is adult-like, but higher-level decision processes do not access the information) [10]. We tested visual depth cue integration in the developing brain to distinguish these possibilities. We presented children aged 6-12 years with displays depicting depth from binocular disparity and relative motion and made measurements using psychophysics, retinotopic mapping, and pattern classification fMRI. Older children (>10.5 years) showed clear evidence for sensory fusion in V3B, a visual area thought to integrate depth cues in the adult brain [3-5]. By contrast, in younger children (<10.5 years), there was no evidence for sensory fusion in any visual area. This significant age difference was paired with a shift in perceptual performance around ages 10 to 11 years and could not be explained by motion artifacts, visual attention, or signal quality differences. Thus, whereas many basic visual processes mature early in childhood [11, 12], the brain circuits that fuse cues take a very long time to develop.

Neocortical Rebound Depolarization Enhances Visual Perception.

Animals are constantly exposed to the time-varying visual world. Because visual perception is modulated by immediately prior visual experience, visual cortical neurons may register recent visual history into a specific form of offline activity and link it to later visual input. To examine how preceding visual inputs interact with upcoming information at the single neuron level, we designed a simple stimulation protocol in which a brief, orientated flashing stimulus was subsequently coupled to visual stimuli with identical or different features. Using in vivo whole-cell patch-clamp recording and functional two-photon calcium imaging from the primary visual cortex (V1) of awake mice, we discovered that a flash of sinusoidal grating per se induces an early, transient activation as well as a long-delayed reactivation in V1 neurons. This late response, which started hundreds of milliseconds after the flash and persisted for approximately 2 s, was also observed in human V1 electroencephalogram. When another drifting grating stimulus arrived during the late response, the V1 neurons exhibited a sublinear, but apparently increased response, especially to the same grating orientation. In behavioral tests of mice and humans, the flashing stimulation enhanced the detection power of the identically orientated visual stimulation only when the second stimulation was presented during the time window of the late response. Therefore, V1 late responses likely provide a neural basis for admixing temporally separated stimuli and extracting identical features in time-varying visual environments.

fMRI Analysis-by-Synthesis Reveals a Dorsal Hierarchy That Extracts Surface Slant.

The brain's skill in estimating the 3-D orientation of viewed surfaces supports a range of behaviors, from placing an object on a nearby table, to planning the best route when hill walking. This ability relies on integrating depth signals across extensive regions of space that exceed the receptive fields of early sensory neurons. Although hierarchical selection and pooling is central to understanding of the ventral visual pathway, the successive operations in the dorsal stream are poorly understood. Here we use computational modeling of human fMRI signals to probe the computations that extract 3-D surface orientation from binocular disparity. To understand how representations evolve across the hierarchy, we developed an inference approach using a series of generative models to explain the empirical fMRI data in different cortical areas. Specifically, we simulated the responses of candidate visual processing algorithms and tested how well they explained fMRI responses. Thereby we demonstrate a hierarchical refinement of visual representations moving from the representation of edges and figure-ground segmentation (V1, V2) to spatially extensive disparity gradients in V3A. We show that responses in V3A are little affected by low-level image covariates, and have a partial tolerance to the overall depth position. Finally, we show that responses in V3A parallel perceptual judgments of slant. This reveals a relatively short computational hierarchy that captures key information about the 3-D structure of nearby surfaces, and more generally demonstrates an analysis approach that may be of merit in a diverse range of brain imaging domains.

Brightness masking is modulated by disparity structure.

The luminance contrast at the borders of a surface strongly influences surface's apparent brightness, as demonstrated by a number of classic visual illusions. Such phenomena are compatible with a propagation mechanism believed to spread contrast information from borders to the interior. This process is disrupted by masking, where the perceived brightness of a target is reduced by the brief presentation of a mask (Paradiso & Nakayama, 1991), but the exact visual stage that this happens remains unclear. In the present study, we examined whether brightness masking occurs at a monocular-, or a binocular-level of the visual hierarchy. We used backward masking, whereby a briefly presented target stimulus is disrupted by a mask coming soon afterwards, to show that brightness masking is affected by binocular stages of the visual processing. We manipulated the 3-D configurations (slant direction) of the target and mask and measured the differential disruption that masking causes on brightness estimation. We found that the masking effect was weaker when stimuli had a different slant. We suggest that brightness masking is partly mediated by mid-level neuronal mechanisms, at a stage where binocular disparity edge structure has been extracted.

7 tesla FMRI reveals systematic functional organization for binocular disparity in dorsal visual cortex.

The binocular disparity between the views of the world registered by the left and right eyes provides a powerful signal about the depth structure of the environment. Despite increasing knowledge of the cortical areas that process disparity from animal models, comparatively little is known about the local architecture of stereoscopic processing in the human brain. Here, we take advantage of the high spatial specificity and image contrast offered by 7 tesla fMRI to test for systematic organization of disparity representations in the human brain. Participants viewed random dot stereogram stimuli depicting different depth positions while we recorded fMRI responses from dorsomedial visual cortex. We repeated measurements across three separate imaging sessions. Using a series of computational modeling approaches, we report three main advances in understanding disparity organization in the human brain. First, we show that disparity preferences are clustered and that this organization persists across imaging sessions, particularly in area V3A. Second, we observe differences between the local distribution of voxel responses in early and dorsomedial visual areas, suggesting different cortical organization. Third, using modeling of voxel responses, we show that higher dorsal areas (V3A, V3B/KO) have properties that are characteristic of human depth judgments: a simple model that uses tuning parameters estimated from fMRI data captures known variations in human psychophysical performance. Together, these findings indicate that human dorsal visual cortex contains selective cortical structures for disparity that may support the neural computations that underlie depth perception.

fMRI evidence for areas that process surface gloss in the human visual cortex.

Surface gloss is an important cue to the material properties of objects. Recent progress in the study of macaque's brain has increased our understating of the areas involved in processing information about gloss, however the homologies with the human brain are not yet fully understood. Here we used human functional magnetic resonance imaging (fMRI) measurements to localize brain areas preferentially responding to glossy objects. We measured cortical activity for thirty-two rendered three-dimensional objects that had either Lambertian or specular surface properties. To control for differences in image structure, we overlaid a grid on the images and scrambled its cells. We found activations related to gloss in the posterior fusiform sulcus (pFs) and in area V3B/KO. Subsequent analysis with Granger causality mapping indicated that V3B/KO processes gloss information differently than pFs. Our results identify a small network of mid-level visual areas whose activity may be important in supporting the perception of surface gloss.

New type of Sendai virus vector provides transgene-free iPS cells derived from chimpanzee blood.

Induced pluripotent stem cells (iPSCs) are potentially valuable cell sources for disease models and future therapeutic applications; however, inefficient generation and the presence of integrated transgenes remain as problems limiting their current use. Here, we developed a new Sendai virus vector, TS12KOS, which has improved efficiency, does not integrate into the cellular DNA, and can be easily eliminated. TS12KOS carries KLF4, OCT3/4, and SOX2 in a single vector and can easily generate iPSCs from human blood cells. Using TS12KOS, we established iPSC lines from chimpanzee blood, and used DNA array analysis to show that the global gene-expression pattern of chimpanzee iPSCs is similar to those of human embryonic stem cell and iPSC lines. These results demonstrated that our new vector is useful for generating iPSCs from the blood cells of both human and chimpanzee. In addition, the chimpanzee iPSCs are expected to facilitate unique studies into human physiology and disease.

Topographic representation of an occluded object and the effects of spatiotemporal context in human early visual areas.

Occlusion is a primary challenge facing the visual system in perceiving object shapes in intricate natural scenes. Although behavior, neurophysiological, and modeling studies have shown that occluded portions of objects may be completed at the early stage of visual processing, we have little knowledge on how and where in the human brain the completion is realized. Here, we provide functional magnetic resonance imaging (fMRI) evidence that the occluded portion of an object is indeed represented topographically in human V1 and V2. Specifically, we find the topographic cortical responses corresponding to the invisible object rotation in V1 and V2. Furthermore, by investigating neural responses for the occluded target rotation within precisely defined cortical subregions, we could dissociate the topographic neural representation of the occluded portion from other types of neural processing such as object edge processing. We further demonstrate that the early topographic representation in V1 can be modulated by prior knowledge of a whole appearance of an object obtained before partial occlusion. These findings suggest that primary "visual" area V1 has the ability to process not only visible or virtually (illusorily) perceived objects but also "invisible" portions of objects without concurrent visual sensation such as luminance enhancement to these portions. The results also suggest that low-level image features and higher preceding cognitive context are integrated into a unified topographic representation of occluded portion in early areas.

A non-device-specific approach to display characterization based on linear, nonlinear, and hybrid search algorithms.

In almost all of the recent vision experiments, stimuli are controlled via computers and presented on display devices such as cathode ray tubes (CRTs). Display characterization is a necessary procedure for such computer-aided vision experiments. The standard display characterization called "gamma correction" and the following linear color transformation procedure are established for CRT displays and widely used in the current vision science field. However, the standard two-step procedure is based on the internal model of CRT display devices, and there is no guarantee as to whether the method is applicable to the other types of display devices such as liquid crystal display and digital light processing. We therefore tested the applicability of the standard method to these kinds of new devices and found that the standard method was not valid for these new devices. To overcome this problem, we provide several novel approaches for vision experiments to characterize display devices, based on linear, nonlinear, and hybrid search algorithms. These approaches never assume any internal models of display devices and will therefore be applicable to any display type. The evaluations and comparisons of chromaticity estimation accuracies based on these new methods with those of the standard procedure proved that our proposed methods largely improved the calibration efficiencies for non-CRT devices. Our proposed methods, together with the standard one, have been implemented in a MATLAB-based integrated graphical user interface software named Mcalibrator2. This software can enhance the accuracy of vision experiments and enable more efficient display characterization procedures. The software is now available publicly for free.