Spatial and Temporal Abnormalities of Spontaneous Fixational Saccades and Their Correlates With Positive and Cognitive Symptoms in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Visual fixation is a dynamic process, with the spontaneous occurrence of microsaccades and macrosaccades. These fixational saccades are sensitive to the structural and functional alterations of the cortical-subcortical-cerebellar circuit. Given that dysfunctional cortical-subcortical-cerebellar circuit contributes to cognitive and behavioral impairments in schizophrenia, we hypothesized that patients with schizophrenia would exhibit abnormal fixational saccades and these abnormalities would be associated with the clinical manifestations. STUDY DESIGN: Saccades were recorded from 140 drug-naïve patients with first-episode schizophrenia and 160 age-matched healthy controls during ten separate trials of 6-second steady fixations. Positive and negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Cognition was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB). STUDY RESULTS: Patients with schizophrenia exhibited fixational saccades more vertically than controls, which was reflected in more vertical saccades with angles around 90° and a greater vertical shift of horizontal saccades with angles around 0° in patients. The fixational saccades, especially horizontal saccades, showed longer durations, faster peak velocities, and larger amplitudes in patients. Furthermore, the greater vertical shift of horizontal saccades was associated with higher PANSS total and positive symptom scores in patients, and the longer duration of horizontal saccades was associated with lower MCCB neurocognitive composite, attention/vigilance, and speed of processing scores. Finally, based solely on these fixational eye movements, a K-nearest neighbors model classified patients with an accuracy of 85%. Conclusions: Our results reveal spatial and temporal abnormalities of fixational saccades and suggest fixational saccades as a promising biomarker for cognitive and positive symptoms and for diagnosis of schizophrenia.

Environment-Responsive Peptide Dimers Bind and Stabilize Double-Stranded RNA.

Double-stranded RNAs (dsRNA) possess immense potential for biomedical applications. However, their therapeutic utility is limited by low stability and poor cellular uptake. Different strategies have been explored to enhance the stability of dsRNA, including the incorporation of modified nucleotides, and the use of diverse carrier systems. Nevertheless, these have not resulted in a broadly applicable approach thereby preventing the wide-spread application of dsRNA for therapeutic purposes. Herein, we report the design of dimeric stapled peptides based on the RNA-binding protein TAV2b. These dimers are obtained via disulfide formation and mimic the natural TAV2b assembly. They bind and stabilize dsRNA in the presence of serum, protecting it from degradation. In addition, peptide binding also promotes cellular uptake of dsRNA. Importantly, peptide dimers monomerize under reducing conditions which results in a loss of RNA binding. These findings highlight the potential of peptide-based RNA binders for the stabilization and protection of dsRNA, representing an appealing strategy towards the environment-triggered release of RNA. This can broaden the applicability of dsRNA, such as short interfering RNAs (siRNA), for therapeutic applications.

Effects of acute high intraocular pressure on red-green and blue-yellow cortical color responses in non-human primates.

Glaucoma is a leading cause of irreversible blindness worldwide, and intraocular pressure (IOP) is an established and modifiable risk factor for both chronic and acute glaucoma. The relationship between color vision deficits and chronic glaucoma has been described previously. However, the effects of acute glaucoma or acute primary angle closure, which has high prevalence in China, on color vision remains unclear. To address the above question, red-green or blue-yellow color responses in V1, V2, and V4 of seven rhesus macaques were monitored using intrinsic-signal optical imaging while monocular anterior chamber perfusions were performed to reversibly elevate IOP acutely over a clinically observed range of 30 to 90 mmHg. We found that the cortical population responses to both red-green and blue-yellow grating stimuli, systematically decreased as IOP increased from 30 to 90 mmHg. Although a similar decrement in magnitude was noted in V1, V2, and V4, blue-yellow responses were consistently more impaired than red-green responses at all levels of acute IOP elevation and in all monitored visual areas. This physiological study in non-human primates demonstrates that acute IOP elevations substantially depress the ability of the visual cortex to register color information. This effect is more severe for blue-yellow responses than for red-green responses, suggesting selective impairment of the koniocellular pathways compared with the parvocellular pathways. Together, we infer that blue-yellow color vision might be the most vulnerable visual function in acute glaucoma patients.

Constrained peptides mimic a viral suppressor of RNA silencing.

The design of high-affinity, RNA-binding ligands has proven very challenging. This is due to the unique structural properties of RNA, often characterized by polar surfaces and high flexibility. In addition, the frequent lack of well-defined binding pockets complicates the development of small molecule binders. This has triggered the search for alternative scaffolds of intermediate size. Among these, peptide-derived molecules represent appealing entities as they can mimic structural features also present in RNA-binding proteins. However, the application of peptidic RNA-targeting ligands is hampered by a lack of design principles and their inherently low bio-stability. Here, the structure-based design of constrained α-helical peptides derived from the viral suppressor of RNA silencing, TAV2b, is described. We observe that the introduction of two inter-side chain crosslinks provides peptides with increased α-helicity and protease stability. One of these modified peptides (B3) shows high affinity for double-stranded RNA structures including a palindromic siRNA as well as microRNA-21 and its precursor pre-miR-21. Notably, B3 binding to pre-miR-21 inhibits Dicer processing in a biochemical assay. As a further characteristic this peptide also exhibits cellular entry. Our findings show that constrained peptides can efficiently mimic RNA-binding proteins rendering them potentially useful for the design of bioactive RNA-targeting ligands.

Synergistic DNA- and Protein-Based Recognition Promote an RNA-Templated Bio-orthogonal Reaction.

Biomolecular assemblies composed of proteins and oligonucleotides play a central role in biological processes. While in nature, oligonucleotides and proteins usually assemble via non-covalent interactions, synthetic conjugates have been developed which covalently link both modalities. The resulting peptide-oligonucleotide conjugates have facilitated novel biological applications as well as the design of functional supramolecular systems and materials. However, despite the importance of concerted protein/oligonucleotide recognition in nature, conjugation approaches have barely utilized the synergistic recognition abilities of such complexes. Herein, the structure-based design of peptide-DNA conjugates that bind RNA through Watson-Crick base pairing combined with peptide-mediated major groove recognition is reported. Two distinct conjugate families with tunable binding characteristics have been designed to adjacently bind a particular RNA sequence. In the resulting ternary complex, their peptide elements are located in proximity, a feature that was used to enable an RNA-templated click reaction. The introduced structure-based design approach opens the door to novel functional biomolecular assemblies.

Hierarchical Representation for Chromatic Processing across Macaque V1, V2, and V4.

The perception of color is an internal label for the inferred spectral reflectance of visible surfaces. To study how spectral representation is transformed through modular subsystems of successive cortical areas, we undertook simultaneous optical imaging of intrinsic signals in macaque V1, V2, and V4, supplemented by higher-resolution electrophysiology and two-photon imaging in awake macaques. We find a progressive evolution in the scale and precision of chromotopic maps, expressed by a uniform blob-like architecture of hue responses within each area. Two-photon imaging reveals enhanced hue-specific cell clustering in V2 compared with V1. A phenomenon of endspectral (red and blue) responses that is clear in V1, recedes in V2, and is virtually absent in V4. The increase in mid- and extra-spectral hue representations through V2 and V4 reflects the nature of hierarchical processing as higher areas read out locations in chromatic space from progressive integration of signals relayed by V1.

The Therapeutic Potential of PTEN Modulation: Targeting Strategies from Gene to Protein.

Two decades have passed since the discovery of the tumor suppressor, PTEN. A multitude of biological functions have since been revealed, suggesting potential therapeutic applications for both PTEN activation (e.g., cancer) and inhibition (e.g., neuroregeneration). Nevertheless, PTEN's therapeutic suitability has been called into question due to its "risky" profile as a tumor suppressor. To evaluate PTEN function and its various roles in disease a number of molecules have so far been developed. However, intrinsic problems associated with phosphatase inhibition and PTEN's complex regulation via post-translational modifications hinder straightforward access to selective modulators. For this reason, central questions associated with PTEN targeting remain unanswered. In this perspective, we summarize current PTEN-targeting strategies and discuss potential approaches to modulate its functional dose, considering all stages of PTEN biogenesis from direct protein modulation to the targeting of relevant miRNAs as well as the PTEN gene and mRNA.

DR HAGIS-a fundus image database for the automatic extraction of retinal surface vessels from diabetic patients.

A database of retinal fundus images, the DR HAGIS database, is presented. This database consists of 39 high-resolution color fundus images obtained from a diabetic retinopathy screening program in the UK. The NHS screening program uses service providers that employ different fundus and digital cameras. This results in a range of different image sizes and resolutions. Furthermore, patients enrolled in such programs often display other comorbidities in addition to diabetes. Therefore, in an effort to replicate the normal range of images examined by grading experts during screening, the DR HAGIS database consists of images of varying image sizes and resolutions and four comorbidity subgroups: collectively defined as the diabetic retinopathy, hypertension, age-related macular degeneration, and Glaucoma image set (DR HAGIS). For each image, the vasculature has been manually segmented to provide a realistic set of images on which to test automatic vessel extraction algorithms. Modified versions of two previously published vessel extraction algorithms were applied to this database to provide some baseline measurements. A method based purely on the intensity of images pixels resulted in a mean segmentation accuracy of 95.83% ([Formula: see text]), whereas an algorithm based on Gabor filters generated an accuracy of 95.71% ([Formula: see text]).

Breaking cover: neural responses to slow and fast camouflage-breaking motion.

Primates need to detect and recognize camouflaged animals in natural environments. Camouflage-breaking movements are often the only visual cue available to accomplish this. Specifically, sudden movements are often detected before full recognition of the camouflaged animal is made, suggesting that initial processing of motion precedes the recognition of motion-defined contours or shapes. What are the neuronal mechanisms underlying this initial processing of camouflaged motion in the primate visual brain? We investigated this question using intrinsic-signal optical imaging of macaque V1, V2 and V4, along with computer simulations of the neural population responses. We found that camouflaged motion at low speed was processed as a direction signal by both direction- and orientation-selective neurons, whereas at high-speed camouflaged motion was encoded as a motion-streak signal primarily by orientation-selective neurons. No population responses were found to be invariant to the camouflage contours. These results suggest that the initial processing of camouflaged motion at low and high speeds is encoded as direction and motion-streak signals in primate early visual cortices. These processes are consistent with a spatio-temporal filter mechanism that provides for fast processing of motion signals, prior to full recognition of camouflage-breaking animals.

Collinear facilitation and contour integration in autism: evidence for atypical visual integration.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, atypical communication and a restricted repertoire of interests and activities. Altered sensory and perceptual experiences are also common, and a notable perceptual difference between individuals with ASD and controls is their superior performance in visual tasks where it may be beneficial to ignore global context. This superiority may be the result of atypical integrative processing. To explore this claim we investigated visual integration in adults with ASD (diagnosed with Asperger's Syndrome) using two psychophysical tasks thought to rely on integrative processing-collinear facilitation and contour integration. We measured collinear facilitation at different flanker orientation offsets and contour integration for both open and closed contours. Our results indicate that compared to matched controls, ASD participants show (i) reduced collinear facilitation, despite equivalent performance without flankers; and (ii) less benefit from closed contours in contour integration. These results indicate weaker visuospatial integration in adults with ASD and suggest that further studies using these types of paradigms would provide knowledge on how contextual processing is altered in ASD.

Orientation-cue invariant population responses to contrast-modulated and phase-reversed contour stimuli in macaque V1 and V2.

Visual scenes can be readily decomposed into a variety of oriented components, the processing of which is vital for object segregation and recognition. In primate V1 and V2, most neurons have small spatio-temporal receptive fields responding selectively to oriented luminance contours (first order), while only a subgroup of neurons signal non-luminance defined contours (second order). So how is the orientation of second-order contours represented at the population level in macaque V1 and V2? Here we compared the population responses in macaque V1 and V2 to two types of second-order contour stimuli generated either by modulation of contrast or phase reversal with those to first-order contour stimuli. Using intrinsic signal optical imaging, we found that the orientation of second-order contour stimuli was represented invariantly in the orientation columns of both macaque V1 and V2. A physiologically constrained spatio-temporal energy model of V1 and V2 neuronal populations could reproduce all the recorded population responses. These findings suggest that, at the population level, the primate early visual system processes the orientation of second-order contours initially through a linear spatio-temporal filter mechanism. Our results of population responses to different second-order contour stimuli support the idea that the orientation maps in primate V1 and V2 can be described as a spatial-temporal energy map.

The mechanism for processing random-dot motion at various speeds in early visual cortices.

All moving objects generate sequential retinotopic activations representing a series of discrete locations in space and time (motion trajectory). How direction-selective neurons in mammalian early visual cortices process motion trajectory remains to be clarified. Using single-cell recording and optical imaging of intrinsic signals along with mathematical simulation, we studied response properties of cat visual areas 17 and 18 to random dots moving at various speeds. We found that, the motion trajectory at low speed was encoded primarily as a direction signal by groups of neurons preferring that motion direction. Above certain transition speeds, the motion trajectory is perceived as a spatial orientation representing the motion axis of the moving dots. In both areas studied, above these speeds, other groups of direction-selective neurons with perpendicular direction preferences were activated to encode the motion trajectory as motion-axis information. This applied to both simple and complex neurons. The average transition speed for switching between encoding motion direction and axis was about 31°/s in area 18 and 15°/s in area 17. A spatio-temporal energy model predicted the transition speeds accurately in both areas, but not the direction-selective indexes to random-dot stimuli in area 18. In addition, above transition speeds, the change of direction preferences of population responses recorded by optical imaging can be revealed using vector maximum but not vector summation method. Together, this combined processing of motion direction and axis by neurons with orthogonal direction preferences associated with speed may serve as a common principle of early visual motion processing.

Four projection streams from primate V1 to the cytochrome oxidase stripes of V2.

In the primate visual system, areas V1 and V2 distribute information they receive from the retina to all higher cortical areas, sorting this information into dorsal and ventral streams. Therefore, knowledge of the organization of projections between V1 and V2 is crucial to understand how the cortex processes visual information. In primates, parallel output pathways from V1 project to distinct V2 stripes. The traditional tripartite division of V1-to-V2 projections was recently replaced by a bipartite scheme, in which thin stripes receive V1 inputs from blob columns, and thick and pale stripes receive common input from interblob columns. Here, we demonstrate that thick and pale stripes, instead, receive spatially segregated V1 inputs and that the interblob is partitioned into two compartments: the middle of the interblob projecting to pale stripes and the blob/interblob border region projecting to thick stripes. Double-labeling experiments further demonstrate that V1 cells project to either thick or pale stripes, but rarely to both. We also find laminar specialization of V1 outputs, with layer 4B contributing projections mainly to thick stripes, and no projections to one set of pale stripes. These laminar differences suggest different contribution of magno, parvo, and konio inputs to each V1 output pathway. These results provide a new foundation for parallel processing models of the visual system by demonstrating four V1-to-V2 pathways: blob columns-to-thin stripes, blob/interblob border columns-to-thick stripes, interblob columns-to-pale(lateral) stripes, layer 2/3-4A interblobs-to-pale(medial) stripes.

Independent components of the haemodynamic response in intrinsic optical imaging.

Functional brain imaging methods are prone to contamination from global vascular artefacts. A variety of methods have been proposed to help segment functional from non-specific changes. Here we quantify the improvement in the signal to noise ratio (SNR) of functional maps, derived from intrinsic optical imaging studies of macaque visual cortex, through the application of Extended Spatial Decorrelation (ESD). The resulting independent component maps and their corresponding time courses reveal for the first time a fast vascular component in the haemodynamic response. ESD is a blind source separation algorithm that utilises spatial statistical features in brain images to separate the recorded mixed sources into independent components. We have investigated differential and single condition experiments using a variety of visual stimuli. To calculate the improvement of the SNR in decibel (dB) we back project separated components onto the original single trial data and analyse the corresponding Fourier spectrum. The application of ESD improved SNR in the functional brain maps from 0.52 to 16.88 dB on differential imaging data and from 1.69 to 12.83 dB in the case of single condition experiments. Analysing the independent components further we found that they can separate different functional compartments of the cortical vasculature. Some of the components, classified as arterial through slit spectroscopy, revealed a strong fast response to the stimulus onset/offset starting approximately 0.2 s after the change of the stimulus and reaching a peak after approximately 0.4 s. This fast haemodynamic response raises new questions concerning the spatial specificity of the so-called "initial dip".

Orientation selectivity in the common marmoset (Callithrix jacchus): the periodicity of orientation columns in V1 and V2.

Orientation selectivity is a ubiquitous property of the primary visual cortex of mammals. Within the primate, orientation selectivity is arranged into vertical columns that are organized into a regular patchy pattern. Previous studies, in old world primates, have noted an anisotropy in this arrangement that appears to be due to the presence of ocular dominance columns within the same tissue. In addition, orientation selective responses appear to be arranged into bands of activity within the adjoining extrastriate region V2. Little is known about the precise arrangement of orientation columns within V2. In this study, we examined the layout of orientation columns within both V1 and V2 of a new world primate, the common marmoset, using optical imaging. New world primates have the advantage that, unlike the macaque, V2 exists on the cortical surface, a requirement for this form of optical mapping. We found the arrangement of orientation columns to be isotropic within marmoset V1 with an average repeat distance of around 575 mum, smaller than the repeat distance previously reported for the macaque. We found no evidence of ocular dominance within the animals tested supporting the claim that ocular dominance columns when present distort the mapping of orientation in V1. In V2 we found that orientation columns were larger and as in other primates were represented in discrete bands throughout V2. Orientation columns were spaced on average around 1 mm apart. This suggests that, at least in the marmoset, the visual system maps orientation at a different scale within V1 and V2.

A continuous smooth map of space in the primary visual cortex of the common marmoset.

We examined the fine-scale mapping of the visual world within the primary visual cortex of the marmoset monkey (Callithrix jacchus) using differential optical imaging. We stimulated two sets of complementary stripe-like locations in turn, subtracting them to generate the cortical representations of continuous bands of visual space. Rotating this stimulus configuration makes it possible to map different spatial axes within the primary visual cortex. In a similar manner, shifting the stimulated locations between trials makes it possible to map retinotopy at an even finer scale. Using these methods we found no evidence of any local anisotropies or distortions in the cortical representation of visual space. This is despite the fact that orientation preference is mapped in a discontinuous manner across the surface of marmoset V1. Overall, our results indicate that space is mapped in a continuous and smooth manner in the primary visual cortex of the common marmoset.

Interactions between pattern and color in the visual system: temporal aspects of the McCollough effect.

The perception of the color of a surface can be influenced by many factors including its material properties and the composition of the illuminant. McCollough demonstrated that sensory conditioning could also influence the perception of surface color by inducing a long-lasting pattern specific color aftereffect. This effect has been extensively studied since its original report and a number of increasingly complex explanations have been proposed. In this article I examine the temporal properties of a simple learning model of the McCollough effect (ME). This model has previously been used to account for quantitative data sets obtained from a series of monocular and binocular variants of the ME. The model replicates the acquisition and decay of the ME, pre- and post-induction interference effects, and can also simulate the effects of various cholinergic and anticholinergic drugs that have been shown to influence ME induction and decay.

Optical imaging of the retinotopic organization of V1 in the common marmoset.

We examined the retinotopic mapping of the visual world in the primary visual cortex of the marmoset monkey using differential optical imaging. Two sets of complementary stripe-like locations were visually stimulated in turn. Their difference depicts the cortical representations of continuous bands of visual space. By rotating the sets of stripe-like locations it is possible to map different spatial axes. Analogous to the macaque we found that the V1/V2 border represented the vertical meridian, while horizontal, 45-, and 135-degree angled stripes of space were also represented in a continuous manner. We developed a new automatic method of calculating local measures of cortical magnification from our optical retinotopic maps. Using this method we found no evidence of any local anisotropies in cortical representation. Overall our results indicate that space is mapped isotropically in the primary visual cortex of the common marmoset.