Intravitreal drug delivery in retinal disease : are we out of our depth?

Introduction With the ever-increasing global burden of retinal disease, there is an urgent need to vastly improve formulation strategies that enhance posterior eye delivery of therapeutics. Despite intravitreal administration having demonstrated notable superiority over other routes in enhancing retinal drug availability, there still exist various significant physical/biochemical barriers preventing optimal drug delivery into the retina. A further complication lies with an inability to reliably translate laboratory-based retinal models into a clinical setting. Several formulation approaches have recently been evaluated to improve intravitreal therapeutic outcomes, and our aim in this review is to highlight strategies that hold the most promise. Areas covered We discuss the complex barriers faced by the intravitreal route and examine how formulation strategies including implants, nanoparticulate carriers, viral vectors and sonotherapy have been utilized to attain both sustained delivery and enhanced penetration through to the retina. We conclude by highlighting the advances and limitations of current in vitro, ex vivo and in vivo retinal models in use by researchers globally. Expert opinion Various nanoparticle compositions have demonstrated the ability to overcome the retinal barriers successfully; however, their utility is limited to the laboratory setting. Optimization of these formulations and the development of more robust experimental retinal models are necessary to translate success in the laboratory into clinically efficacious outcomes.

A method for estimating intrinsic noise in electroretinographic (ERG) signals

Purpose To develop a signal processing paradigm for extracting ERG responses to temporal sinusoidal modulation with contrasts ranging from below perceptual threshold to suprathreshold contrasts. To estimate the magnitude of intrinsic noise in ERG signals at different stimulus contrasts. Methods Photopic test stimuli were generated using a 4-primary Maxwellian view optical system. The 4-primary lights were sinusoidally temporally modulated in-phase (36 Hz; 2.5 - 50% Michelson). The stimuli were presented in 1 s epochs separated by a 1 ms blank interval and repeated 160 times (160.16 s duration) during the recording of the continuous flicker ERG from the right eye using DTL fiber electrodes. After artefact rejection, the ERG signal was extracted using Fourier methods in each of the 1 s epochs where a stimulus was presented. The signal processing allows for computation of the intrinsic noise distribution in addition to the signal to noise (SNR) ratio. Results We provide the initial report that the ERG intrinsic noise distribution is independent of stimulus contrast whereas SNR decreases linearly with decreasing contrast until the noise limit at ~2.5%. The 1ms blank intervals between epochs de-correlated the ERG signal at the line frequency (50 Hz) and thus increased the SNR of the averaged response. We confirm that response amplitude increases linearly with stimulus contrast. The phase response shows a shallow positive relationship with stimulus contrast. Conclusions This new technique will enable recording of intrinsic noise in ERG signals above and below perceptual visual threshold and is suitable for measurement of continuous rod and cone ERGs across a range of temporal frequencies, and post-receptoral processing in the primary retinogeniculate pathways at low stimulus contrasts. The intrinsic noise distribution may have application as a biomarker for detecting changes in disease progression or treatment efficacy.

A genetically explicit model of speciation by sensory drive within a continuous population in aquatic environments

BACKGROUND: The sensory drive hypothesis predicts that divergent sensory adaptation in different habitats may lead to premating isolation upon secondary contact of populations. Speciation by sensory drive has traditionally been treated as a special case of speciation as a byproduct of adaptation to divergent environments in geographically isolated populations. However, if habitats are heterogeneous, local adaptation in the sensory systems may cause the emergence of reproductively isolated species from a single unstructured population. In polychromatic fishes, visual sensitivity might become adapted to local ambient light regimes and the sensitivity might influence female preferences for male nuptial color. In this paper, we investigate the possibility of speciation by sensory drive as a byproduct of divergent visual adaptation within a single initially unstructured population. We use models based on explicit genetic mechanisms for color vision and nuptial coloration. RESULTS: We show that in simulations in which the adaptive evolution of visual pigments and color perception are explicitly modeled, sensory drive can promote speciation along a short selection gradient within a continuous habitat and population. We assumed that color perception evolves to adapt to the modal light environment that individuals experience and that females prefer to mate with males whose nuptial color they are most sensitive to. In our simulations color perception depends on the absorption spectra of an individual's visual pigments. Speciation occurred most frequently when the steepness of the environmental light gradient was intermediate and dispersal distance of offspring was relatively small. In addition, our results predict that mutations that cause large shifts in the wavelength of peak absorption promote speciation, whereas we did not observe speciation when peak absorption evolved by stepwise mutations with small effect. CONCLUSION: The results suggest that speciation can occur where environmental gradients create divergent selection on sensory modalities that are used in mate choice. Evidence for such gradients exists from several animal groups, and from freshwater and marine fishes in particular. The probability of speciation in a continuous population under such conditions may then critically depend on the genetic architecture of perceptual adaptation and female mate choice.

What Sensory Signals are About

Kathleen Akins argues that "the traditional view" of sensory systems assumes too quickly that their function is detecting features of the outside environment. Instead, some systems are "narcissistic"--their signals tell their own states--and others may send signals that are not about anything at all. But Akins overlooks that "traditionalists" may argue, with Millikan, that the function of sensory systems may be steering motor routines. Aboutness comes in as how the systems have steered in ways evolution liked--by gearing steering to external features. Color vision and olfaction, for example, are thus, about external features.

Bi-sensory, striped representations: comparative insights from owl and platypus

Bi-sensory striped arrays are described in owl and platypus that share some similarities with the other variant of bi-sensory striped array found in primate and carnivore striate cortex: ocular dominance columns. Like ocular dominance columns, the owl and platypus striped systems each involve two different topographic arrays that are cut into parallel stripes, and interdigitated, so that higher-order neurons can integrate across both arrays. Unlike ocular dominance stripes, which have a separate array for each eye, the striped array in the middle third of the owl tectum has a separate array for each cerebral hemisphere. Binocular neurons send outputs from both hemispheres to the striped array where they are segregated into parallel stripes according to hemisphere of origin. In platypus primary somatosensory cortex (SI), the two arrays of interdigitated stripes are derived from separate sensory systems in the bill, 40,000 electroreceptors and 60,000 mechanoreceptors. The stripes in platypus SI cortex produce bimodal electrosensory-mechanosensory neurons with specificity for the time-of-arrival difference between the two systems. This thunder-and-lightning system would allow the platypus to estimate the distance of the prey using time disparities generated at the bill between the earlier electrical wave and the later mechanical wave caused by the motion of benthic prey. The functional significance of parallel, striped arrays is not clear, even for the highly-studied ocular dominance system, but a general strategy is proposed here that is based on the detection of temporal disparities between the two arrays that can be used to estimate distance. (C) 2004 Elsevier Ltd. All rights reserved.

Sensory Processing in Aquatic Environments

Research on sensory processing or the way animals see, hear, smell, taste, feel and electrically and magnetically sense their environment has advanced a great deal over the last fifteen years. This book discusses the most important themes that have emerged from recent research and provides a summary of likely future directions. The book starts with two sections on the detection of sensory signals over long and short ranges by aquatic animals, covering the topics of navigation, communication, and finding food and other localized sources. The next section, the co-evolution of signal and sense, deals with how animals decide whether the source is prey, predator or mate by utilizing receptors that have evolved to take full advantage of the acoustical properties of the signal. Organisms living in the deep-sea environment have also received a lot of recent attention, so the next section deals with visual adaptations to limited light environments where sunlight is replaced by bioluminescence and the visual system has undergone changes to optimize light capture and sensitivity. The last section on central co-ordination of sensory systems covers how signals are processed and filtered for use by the animal. This book will be essential reading for all researchers and graduate students interested in sensory systems.

Cognitive systems associated with the hippocampus of the human brain and their role in behaviour and neurodegenerative disease

Cognitive systems research involves the synthesis of ideas from natural and artificial systems in the analysis, understanding, and design of all intelligent systems. This chapter discusses the cognitive systems associated with the hippocampus (HC) of the human brain and their possible role in behaviour and neurodegenerative disease. The hippocampus (HC) is concerned with the analysis of highly abstract data derived from all sensory systems but its specific role remains controversial. Hence, there have been three major theories concerning its function, viz., the memory theory, the spatial theory, and the behavioral inhibition theory. The memory theory has its origin in the surgical destruction of the HC, which results in severe anterograde and partial retrograde amnesia. The spatial theory has its origin in the observation that neurons in the HC of animals show activity related to their location within the environment. By contrast, the behavioral inhibition theory suggests that the HC acts as a ‘comparator’, i.e., it compares current sensory events with expected or predicted events. If a set of expectations continues to be verified then no alteration of behavior occurs. If, however, a ‘mismatch’ is detected then the HC intervenes by initiating appropriate action by active inhibition of current motor programs and initiation of new data gathering. Understanding the cognitive systems of the hippocampus in humans may aid in the design of intelligent systems involved in spatial mapping, memory, and decision making. In addition, this information may lead to a greater understanding of the course of clinical dementia in the various neurodegenerative diseases in which there is significant damage to the HC.

Inner-ear morphology of the New Zealand Kiwi (Apteryx mantelli) suggests high-frequency specialization

The sensory systems of the New Zealand kiwi appear to be uniquely adapted to occupy a nocturnal ground-dwelling niche. In addition to well-developed tactile and olfactory systems, the auditory system shows specializations of the ear, which are maintained along the central nervous system. Here, we provide a detailed description of the auditory nerve, hair cells, and stereovillar bundle orientation of the hair cells in the North Island brown kiwi. The auditory nerve of the kiwi contained about 8,000 fibers. Using the number of hair cells and innervating nerve fibers to calculate a ratio of average innervation density showed that the afferent innervation ratio in kiwi was denser than in most other birds examined. The average diameters of cochlear afferent axons in kiwi showed the typical gradient across the tonotopic axis. The kiwi basilar papilla showed a clear differentiation of tall and short hair cells. The proportion of short hair cells was higher than in the emu and likely reflects a bias towards higher frequencies represented on the kiwi basilar papilla. The orientation of the stereovillar bundles in the kiwi basilar papilla showed a pattern similar to that in most other birds but was most similar to that of the emu. Overall, many features of the auditory nerve, hair cells, and stereovilli bundle orientation in the kiwi are typical of most birds examined. Some features of the kiwi auditory system do, however, support a high-frequency specialization, specifically the innervation density and generally small size of hair-cell somata, whereas others showed the presumed ancestral condition similar to that found in the emu.

Seeing and hearing speech, sounds, and signs: functional magnetic resonance studies on fluent and dyslexic readers

Speech has both auditory and visual components (heard speech sounds and seen articulatory gestures). During all perception, selective attention facilitates efficient information processing and enables concentration on high-priority stimuli. Auditory and visual sensory systems interact at multiple processing levels during speech perception and, further, the classical motor speech regions seem also to participate in speech perception. Auditory, visual, and motor-articulatory processes may thus work in parallel during speech perception, their use possibly depending on the information available and the individual characteristics of the observer. Because of their subtle speech perception difficulties possibly stemming from disturbances at elemental levels of sensory processing, dyslexic readers may rely more on motor-articulatory speech perception strategies than do fluent readers. This thesis aimed to investigate the neural mechanisms of speech perception and selective attention in fluent and dyslexic readers. We conducted four functional magnetic resonance imaging experiments, during which subjects perceived articulatory gestures, speech sounds, and other auditory and visual stimuli. Gradient echo-planar images depicting blood oxygenation level-dependent contrast were acquired during stimulus presentation to indirectly measure brain hemodynamic activation. Lip-reading activated the primary auditory cortex, and selective attention to visual speech gestures enhanced activity within the left secondary auditory cortex. Attention to non-speech sounds enhanced auditory cortex activity bilaterally; this effect showed modulation by sound presentation rate. A comparison between fluent and dyslexic readers' brain hemodynamic activity during audiovisual speech perception revealed stronger activation of predominantly motor speech areas in dyslexic readers during a contrast test that allowed exploration of the processing of phonetic features extracted from auditory and visual speech. The results show that visual speech perception modulates hemodynamic activity within auditory cortex areas once considered unimodal, and suggest that the left secondary auditory cortex specifically participates in extracting the linguistic content of seen articulatory gestures. They are strong evidence for the importance of attention as a modulator of auditory cortex function during both sound processing and visual speech perception, and point out the nature of attention as an interactive process (influenced by stimulus-driven effects). Further, they suggest heightened reliance on motor-articulatory and visual speech perception strategies among dyslexic readers, possibly compensating for their auditory speech perception difficulties.

Octopamine neurons mediate flight-induced modulation of visual processing in Drosophila melanogaster

Activity-dependent modulation of sensory systems has been documented in many organisms, and is likely to be essential for appropriate processing of information during different behavioral states. However, the mechanisms underlying these phenomena, and often their functional consequences, remain poorly characterized. I investigated the role of octopamine neurons in the flight-dependent modulation observed in visual interneurons in the fruit fly Drosophila melanogaster. The vertical system (VS) cells exhibit a boost in their response to visual motion during flight compared to quiescence. Pharmacological application of octopamine evokes responses in quiescent flies that mimic those observed during flight, and octopamine neurons that project to the optic lobes increase in activity during flight. Using genetic tools to manipulate the activity of octopamine neurons, I find that they are both necessary and sufficient for the flight-induced visual boost. This work provides the first evidence that endogenous release of octopamine is involved in state-dependent modulation of visual interneurons in flies. Further, I investigated the role of a single pair of octopamine neurons that project to the optic lobes, and found no evidence that chemical synaptic transmission via these neurons is necessary for the flight boost. However, I found some evidence that activation of these neurons may contribute to the flight boost. Wind stimuli alone are sufficient to generate transient increases in the VS cell response to motion vision, but result in no increase in baseline membrane potential. These results suggest that the flight boost originates not from a central command signal during flight, but from mechanosensory stimuli relayed via the octopamine system. Lastly, in an attempt to understand the functional consequences of the flight boost observed in visual interneurons, we measured the effect of inactivating octopamine neurons in freely flying flies. We found that flies whose octopamine neurons we silenced accelerate less than wild-type flies, consistent with the hypothesis that the flight boost we observe in VS cells is indicative of a gain control mechanism mediated by octopamine neurons. Together, this work serves as the basis for a mechanistic and functional understanding of octopaminergic modulation of vision in flying flies.

Predictive coding and the slowness principle: an information-theoretic approach.

Understanding the guiding principles of sensory coding strategies is a main goal in computational neuroscience. Among others, the principles of predictive coding and slowness appear to capture aspects of sensory processing. Predictive coding postulates that sensory systems are adapted to the structure of their input signals such that information about future inputs is encoded. Slow feature analysis (SFA) is a method for extracting slowly varying components from quickly varying input signals, thereby learning temporally invariant features. Here, we use the information bottleneck method to state an information-theoretic objective function for temporally local predictive coding. We then show that the linear case of SFA can be interpreted as a variant of predictive coding that maximizes the mutual information between the current output of the system and the input signal in the next time step. This demonstrates that the slowness principle and predictive coding are intimately related.

A benchmark comparison between reconfigurable, intelligent and autonomous wireless inertial measurement and photonic technologies in rehabilitation

Advanced sensory systems address a number of major obstacles towards the provision for cost effective and proactive rehabilitation. Many of these systems employ technologies such as high-speed video or motion capture to generate quantitative measurements. However these solutions are accompanied by some major limitations including extensive set-up and calibration, restriction to indoor use, high cost and time consuming data analysis. Additionally many do not quantify improvement in a rigorous manner for example gait analysis for 5 minutes as opposed to 24 hour ambulatory monitoring. This work addresses these limitations using low cost, wearable wireless inertial measurement as a mobile and minimal infrastructure alternative. In cooperation with healthcare professionals the goal is to design and implement a reconfigurable and intelligent movement capture system. A key component of this work is an extensive benchmark comparison with the 'gold standard' VICON motion capture system.

Influence of the thalamus on spatial visual processing in frontal cortex.

Each of our movements activates our own sensory receptors, and therefore keeping track of self-movement is a necessary part of analysing sensory input. One way in which the brain keeps track of self-movement is by monitoring an internal copy, or corollary discharge, of motor commands. This concept could explain why we perceive a stable visual world despite our frequent quick, or saccadic, eye movements: corollary discharge about each saccade would permit the visual system to ignore saccade-induced visual changes. The critical missing link has been the connection between corollary discharge and visual processing. Here we show that such a link is formed by a corollary discharge from the thalamus that targets the frontal cortex. In the thalamus, neurons in the mediodorsal nucleus relay a corollary discharge of saccades from the midbrain superior colliculus to the cortical frontal eye field. In the frontal eye field, neurons use corollary discharge to shift their visual receptive fields spatially before saccades. We tested the hypothesis that these two components-a pathway for corollary discharge and neurons with shifting receptive fields-form a circuit in which the corollary discharge drives the shift. First we showed that the known spatial and temporal properties of the corollary discharge predict the dynamic changes in spatial visual processing of cortical neurons when saccades are made. Then we moved from this correlation to causation by isolating single cortical neurons and showing that their spatial visual processing is impaired when corollary discharge from the thalamus is interrupted. Thus the visual processing of frontal neurons is spatiotemporally matched with, and functionally dependent on, corollary discharge input from the thalamus. These experiments establish the first link between corollary discharge and visual processing, delineate a brain circuit that is well suited for mediating visual stability, and provide a framework for studying corollary discharge in other sensory systems.

What motion distributions yield global transparency and spatial segmentation?

We have examined the ability of observers to parse bimodal local-motion distributions into two global motion surfaces, either overlapping (yielding transparent motion) or spatially segregated (yielding a motion boundary). The stimuli were random dot kinematograms in which the direction of motion of each dot was drawn from one of two rectangular probability distributions. A wide range of direction distribution widths and separations was tested. The ability to discriminate the direction of motion of one of the two motion surfaces from the direction of a comparison stimulus was used as an objective test of the perception of two discrete surfaces. Performance for both transparent and spatially segregated motion was remarkably good, being only slightly inferior to that achieved with a single global motion surface. Performance was consistently better for segregated motion than for transparency. Whereas transparent motion was only perceived with direction distributions which were separated by a significant gap, segregated motion could be seen with abutting or even partially overlapping direction distributions. For transparency, the critical gap increased with the range of directions in the distribution. This result does not support models in which transparency depends on detection of a minimum size of gap defining a bimodal direction distribution. We suggest, instead, that the operations which detect bimodality are scaled (in the direction domain) with the overall range of distributions. This yields a flexible, adaptive system that determines whether a gap in the direction distribution serves as a segmentation cue or is smoothed as part of a unitary computation of global motion.

Continuity - based and discontinuity - based segmentation in transparent and spatially segregated global motion

The mechanisms underlying the parsing of a spatial distribution of velocity vectors into two adjacent (spatially segregated) or overlapping (transparent) motion surfaces were examined using random dot kinematograms. Parsing might occur using either of two principles. Surfaces might be defined on the basis of similarity of motion vectors and then sharp perceptual boundaries drawn between different surfaces (continuity-based segmentation). Alternatively, detection of a high gradient of direction or speed separating the motion surfaces might drive the process (discontinuity-based segmentation). To establish which method is used, we examined the effect of blurring the motion direction gradient. In the case of a sharp direction gradient, each dot had one of two directions differing by 135°. With a shallow gradient, most dots had one of two directions but the directions of the remainder spanned the range between one motion-defined surface and the other. In the spatial segregation case the gradient defined a central boundary separating two regions. In the transparent version the dots were randomly positioned. In both cases all dots moved with the same speed and existed for only two frames before being randomly replaced. The ability of observers to parse the motion distribution was measured in terms of their ability to discriminate the direction of one of the two surfaces. Performance was hardly affected by spreading the gradient over at least 25% of the dots (corresponding to a 1° strip in the segregation case). We conclude that detection of sharp velocity gradients is not necessary for distinguishing different motion surfaces.