Virtual Reality Assisted Motor Imagery for Early Post-Stroke Recovery: A Review.

Stroke is a serious neurological disease that may lead to long-term disabilities and even death for stroke patients worldwide. The acute period, ( ≤ 1 mo post-stroke), is crucial for rehabilitation but the current standard clinical practice may be ineffective for patients with severe motor impairment, since most rehabilitation programs involve physical movement. Imagined movement - the so-called motor imagery (MI) - has been shown to activate motor areas of the brain without physical movement. MI therefore offers an opportunity for early rehabilitation of stroke patients. MI, however, is not widely employed in clinical practice due to a lack of evidence-based research. Here, we review MI-based approaches to rehabilitation of stroke patients and immersive virtual reality (VR) technologies to potentially assist MI and thus, promote recovery of motor function.

Orientation pinwheels in primary visual cortex of a highly visual marsupial.

Primary visual cortices in many mammalian species exhibit modular and periodic orientation preference maps arranged in pinwheel-like layouts. The role of inherited traits as opposed to environmental influences in determining this organization remains unclear. Here, we characterize the cortical organization of an Australian marsupial, revealing pinwheel organization resembling that of eutherian carnivores and primates but distinctly different from the simpler salt-and-pepper arrangement of eutherian rodents and rabbits. The divergence of marsupials from eutherians 160 million years ago and the later emergence of rodents and rabbits suggest that the salt-and-pepper structure is not the primitive ancestral form. Rather, the genetic code that enables complex pinwheel formation is likely widespread, perhaps extending back to the common therian ancestors of modern mammals.

Robust Coding of Eye Position in Posterior Parietal Cortex despite Context-Dependent Tuning.

Neurons in posterior parietal cortex (PPC) encode many aspects of the sensory world (e.g., scene structure), the posture of the body, and plans for action. For a downstream computation, however, only some of these dimensions are relevant; the rest are "nuisance variables" because their influence on neural activity changes with sensory and behavioral context, potentially corrupting the read-out of relevant information. Here we show that a key postural variable for vision (eye position) is represented robustly in male macaque PPC across a range of contexts, although the tuning of single neurons depended strongly on context. Contexts were defined by different stages of a visually guided reaching task, including (1) a visually sparse epoch, (2) a visually rich epoch, (3) a "go" epoch in which the reach was cued, and (4) during the reach itself. Eye position was constant within trials but varied across trials in a 3 × 3 grid spanning 24° × 24°. Using demixed principal component analysis of neural spike-counts, we found that the subspace of the population response encoding eye position is orthogonal to that encoding task context. Accordingly, a context-naive (fixed-parameter) decoder was nevertheless able to estimate eye position reliably across contexts. Errors were small given the sample size (∼1.78°) and would likely be even smaller with larger populations. Moreover, they were comparable to that of decoders that were optimized for each context. Our results suggest that population codes in PPC shield encoded signals from crosstalk to support robust sensorimotor transformations across contexts.SIGNIFICANCE STATEMENT Neurons in posterior parietal cortex (PPC) which are sensitive to gaze direction are thought to play a key role in spatial perception and behavior (e.g., reaching, navigation), and provide a potential substrate for brain-controlled prosthetics. Many, however, change their tuning under different sensory and behavioral contexts, raising the prospect that they provide unreliable representations of egocentric space. Here, we analyze the structure of encoding dimensions for gaze direction and context in PPC during different stages of a visually guided reaching task. We use demixed dimensionality reduction and decoding techniques to show that the coding of gaze direction in PPC is mostly invariant to context. This suggests that PPC can provide reliable spatial information across sensory and behavioral contexts.

Liquid-Crystal Display (LCD) of achromatic, mean-modulated flicker in clinical assessment and experimental studies of visual systems.

Achromatic, mean-modulated flicker-wherein luminance increments and decrements of equal magnitude are applied, over time, to a test field-is commonly used in both clinical assessment of vision and experimental studies of visual systems. However, presenting flicker on computer-controlled displays is problematic; displays typically introduce luminance artifacts at high flicker frequency or contrast, potentially interfering with the validity of findings. Here, we present a battery of tests used to weigh the relative merits of two displays for presenting achromatic, mean-modulated flicker. These tests revealed marked differences between a new high-performance liquid-crystal display (LCD; EIZO ColorEdge CG247X) and a new consumer-grade LCD (Dell U2415b), despite displays' vendor-supplied specifications being almost identical. We measured displayed luminance using a spot meter and a linearized photodiode. We derived several measures, including spatial uniformity, the effect of viewing angle, response times, Fourier amplitude spectra, and cycle-averaged luminance. We presented paired luminance pulses to quantify the displays' nonlinear dynamics. The CG247X showed relatively good spatial uniformity (e.g., at moderate luminance, standard deviation 2.8% versus U2415b's 5.3%). Fourier transformation of nominally static test patches revealed spectra free of artifacts, with the exception of a frame response. The CG247X's rise and fall times depended on both the luminance from which, and to which, it responded, as is to be generally expected from LCDs. Despite this nonlinear behaviour, we were able to define a contrast and frequency range wherein the CG247X appeared largely artifact-free; the relationship between nominal luminance and displayed luminance was accurately modelled using a causal, linear time-invariant system. This range included contrasts up to 80%, and flicker frequencies up to 30 Hz. This battery of tests should prove useful to others conducting clinical assessment of vision and experimental studies of visual systems.

Mechanisms of Feature Selectivity and Invariance in Primary Visual Cortex.

Visual object identification requires both selectivity for specific visual features that are important to the object's identity and invariance to feature manipulations. For example, a hand can be shifted in position, rotated, or contracted but still be recognized as a hand. How are the competing requirements of selectivity and invariance built into the early stages of visual processing? Typically, cells in the primary visual cortex are classified as either simple or complex. They both show selectivity for edge-orientation but complex cells develop invariance to edge position within the receptive field (spatial phase). Using a data-driven model that extracts the spatial structures and nonlinearities associated with neuronal computation, we quantitatively describe the balance between selectivity and invariance in complex cells. Phase invariance is frequently partial, while invariance to orientation and spatial frequency are more extensive than expected. The invariance arises due to two independent factors: (1) the structure and number of filters and (2) the form of nonlinearities that act upon the filter outputs. Both vary more than previously considered, so primary visual cortex forms an elaborate set of generic feature sensitivities, providing the foundation for more sophisticated object processing.

Motion Perception in the Common Marmoset.

Visual motion processing is a well-established model system for studying neural population codes in primates. The common marmoset, a small new world primate, offers unparalleled opportunities to probe these population codes in key motion processing areas, such as cortical areas MT and MST, because these areas are accessible for imaging and recording at the cortical surface. However, little is currently known about the perceptual abilities of the marmoset. Here, we introduce a paradigm for studying motion perception in the marmoset and compare their psychophysical performance with human observers. We trained two marmosets to perform a motion estimation task in which they provided an analog report of their perceived direction of motion with an eye movement to a ring that surrounded the motion stimulus. Marmosets and humans exhibited similar trade-offs in speed versus accuracy: errors were larger and reaction times were longer as the strength of the motion signal was reduced. Reverse correlation on the temporal fluctuations in motion direction revealed that both species exhibited short integration windows; however, marmosets had substantially less nondecision time than humans. Our results provide the first quantification of motion perception in the marmoset and demonstrate several advantages to using analog estimation tasks.

Comparison of contrast-dependent phase sensitivity in primary visual cortex of mouse, cat and macaque.

Neurones in the primary visual cortex (V1) are classified into simple and complex types. Simple cells are phase-sensitive, that is, they modulate their responses according to the position and brightness polarity of edges in their receptive fields. Complex cells are phase invariant, that is, they respond to edges in their receptive fields regardless of location or brightness polarity. Simple and complex cells are quantified by the degree of sensitivity to the spatial phases of drifting sinusoidal gratings. Some V1 complex cells become more phase-sensitive at low contrasts. Here we use a standardized analysis method for data derived from grating stimuli developed for macaques to reanalyse data previously collected from cats, and also collect and analyse the responses of 73 mouse V1 neurons. The analysis provides the first consistent comparative study of contrast-dependent phase sensitivity in V1 of mouse, cat and macaque monkey.

Synaptic Basis for Contrast-Dependent Shifts in Functional Identity in Mouse V1.

A central transformation that occurs within mammalian visual cortex is the change from linear, polarity-sensitive responses to nonlinear, polarity-insensitive responses. These neurons are classically labelled as either simple or complex, respectively, on the basis of their response linearity (Skottun et al., 1991). While the difference between cell classes is clear when the stimulus strength is high, reducing stimulus strength diminishes the differences between the cell types and causes some complex cells to respond as simple cells (Crowder et al., 2007; van Kleef et al., 2010; Hietanen et al., 2013). To understand the synaptic basis for this shift in behavior, we used in vivo whole-cell recordings while systematically shifting stimulus contrast. We find systematic shifts in the degree of complex cell responses in mouse primary visual cortex (V1) at the subthreshold level, demonstrating that synaptic inputs change in concert with the shifts in response linearity and that the change in response linearity is not simply due to the threshold nonlinearity. These shifts are consistent with a visual cortex model in which the recurrent amplification acts as a critical component in the generation of complex cell responses (Chance et al., 1999).

Contrast-dependent phase sensitivity in area MT of macaque visual cortex.

In primate visual cortex (V1), about half the neurons are sensitive to the spatial phases of grating stimuli and generate highly modulated responses to drifting gratings (simple cells). The remaining cells show far less phase sensitivity and relatively unmodulated responses to moving gratings (complex cells). In the second visual area (V2) and the motion processing area MT (or V5), the majority of cells have unmodulated responses to drifting gratings - they are phase invariant. At just-detectable contrasts, 44% of V1 complex cells show highly modulated responses, but this contrast-dependent phase sensitivity is found in only 7% of V2 complex cells. We recorded from 149 cells in macaque MT - 142 classed as complex cells at high contrast. Approximately 14% (20/142) of MT complex cells showed significantly modulated responses to drifting gratings at just-detectable contrasts. A general feature of MT cells is that they can be divided into pattern and component selective types, but we found no correlation between this classification and contrast-dependent phase sensitivity. Phase sensitivity in MT is discussed in relation to MT's input structure.

Electrical receptive fields of retinal ganglion cells: Influence of presynaptic neurons.

Implantable retinal stimulators activate surviving neurons to restore a sense of vision in people who have lost their photoreceptors through degenerative diseases. Complex spatial and temporal interactions occur in the retina during multi-electrode stimulation. Due to these complexities, most existing implants activate only a few electrodes at a time, limiting the repertoire of available stimulation patterns. Measuring the spatiotemporal interactions between electrodes and retinal cells, and incorporating them into a model may lead to improved stimulation algorithms that exploit the interactions. Here, we present a computational model that accurately predicts both the spatial and temporal nonlinear interactions of multi-electrode stimulation of rat retinal ganglion cells (RGCs). The model was verified using in vitro recordings of ON, OFF, and ON-OFF RGCs in response to subretinal multi-electrode stimulation with biphasic pulses at three stimulation frequencies (10, 20, 30 Hz). The model gives an estimate of each cell's spatiotemporal electrical receptive fields (ERFs); i.e., the pattern of stimulation leading to excitation or suppression in the neuron. All cells had excitatory ERFs and many also had suppressive sub-regions of their ERFs. We show that the nonlinearities in observed responses arise largely from activation of presynaptic interneurons. When synaptic transmission was blocked, the number of sub-regions of the ERF was reduced, usually to a single excitatory ERF. This suggests that direct cell activation can be modeled accurately by a one-dimensional model with linear interactions between electrodes, whereas indirect stimulation due to summated presynaptic responses is nonlinear.

Long-term sensorimotor adaptation in the ocular following system of primates.

The sudden movement of a wide-field image leads to a reflexive eye tracking response referred to as short-latency ocular following. If the image motion occurs soon after a saccade the initial speed of the ocular following is enhanced, a phenomenon known as post-saccadic enhancement. We show in macaque monkeys that repeated exposure to the same stimulus regime over a period of months leads to progressive increases in the initial speeds of ocular following. The improvement in tracking speed occurs for ocular following with and without a prior saccade. As a result of the improvement in ocular following speeds, the influence of post-saccadic enhancement wanes with increasing levels of training. The improvement in ocular following speed following repeated exposure to the same oculomotor task represents a novel form of sensori-motor learning in the context of a reflexive movement.

Neural Responses to Multielectrode Stimulation of Healthy and Degenerate Retina.

Purpose: Simultaneous stimulation of multiple retinal electrodes in normally sighted animals shows promise in improving the resolution of retinal prostheses. However, the effects of simultaneous stimulation on degenerate retinae remain unknown. Therefore, we investigated the characteristics of cortical responses to multielectrode stimulation of the degenerate retina. Methods: Four adult cats were bilaterally implanted with retinal electrode arrays in the suprachoroidal space after unilateral adenosine triphosphate (ATP)-induced retinal photoreceptor degeneration. Functional and structural changes were characterized by using electroretinogram a-wave amplitude and optical coherence tomography. Multiunit activity was recorded from both hemispheres of the visual cortex. Responses to single- and multielectrode stimulation of the ATP-injected and fellow control eyes were characterized and compared. Results: The retinae of ATP-injected eyes displayed structural and functional changes consistent with mid- to late-stage photoreceptor degeneration and remodeling. Responses to multielectrode stimulation of the ATP-injected eyes exhibited shortened latencies, lower saturated spike counts, and higher thresholds, compared to stimulation of the fellow control eyes. Electrical receptive field sizes were significantly larger in the ATP-injected eye than in the control eye, and positively correlated with the extent of degeneration. Conclusions: Significant differences exist between cortical responses to stimulation of healthy and degenerate retinae. Our results highlight the importance of using a retinal degeneration model when evaluating the efficacy of novel stimulation paradigms.

Psychophysical measurement of marmoset acuity and myopia.

The common marmoset has attracted increasing interest as a model for visual neuroscience. A measurement of fundamental importance to ensure the validity of visual studies is spatial acuity. The marmoset has excellent acuity that has been reported at the fovea to be nearly half that of the human (Ordy and Samorajski []: Vision Res 8:1205-1225), a value that is consistent with them having similar photoreceptor densities combined with their smaller eye size (Troilo et al. []: Vision Res 33:1301-1310). Of interest, the marmoset exhibits a higher proportion of cones than rods in peripheral vision than human or macaque, which in principle could endow them with better peripheral acuity depending on how those signals are pooled in subsequent processing. Here, we introduce a simple behavioral paradigm to measure acuity and then test how acuity in the marmoset scales with eccentricity. We trained subjects to fixate a central point and detect a peripheral Gabor by making a saccade to its location. First, we found that accurate assessment of acuity required correction for myopia in all adult subjects. This is an important point because marmosets raised in laboratory conditions often have mild to severe myopia (Graham and Judge []: Vision Res 39:177-187), a finding that we confirm, and that would limit their utility for studies of vision if uncorrected. With corrected vision, we found that their acuity scales with eccentricity similar to that of humans and macaques, having roughly half the value of the human and with no clear departure for higher acuity in the periphery. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 300-313, 2017.

Prediction of cortical responses to simultaneous electrical stimulation of the retina.

OBJECTIVE: Simultaneous electrical stimulation of multiple electrodes has shown promise in diversifying the responses that can be elicited by retinal prostheses compared to interleaved single electrode stimulation. However, the effects of interactions between electrodes are not well understood and clinical trials with simultaneous stimulation have produced inconsistent results. We investigated the effects of multiple electrode stimulation of the retina by developing a model of cortical responses to retinal stimulation. APPROACH: Electrical stimuli consisting of temporally sparse, biphasic current pulses, with amplitudes sampled from a bi-dimensional Gaussian distribution, were simultaneously delivered to the retina across a 42-channel electrode array implanted in the suprachoroidal space of anesthetized cats. Visual cortex activity was recorded using penetrating microelectrode arrays. These data were used to identify a linear-nonlinear model of cortical responses to retinal stimulation. The ability of the model to generalize was tested by predicting responses to non-white patterned stimuli. MAIN RESULTS: The model accurately predicted two cortical activity measures: multi-unit neural responses and evoked potential responses to white noise stimuli. The model also provides information about electrical receptive fields, including the relative effects of each stimulating electrode on every recording site. SIGNIFICANCE: We have demonstrated a simple model that accurately describes cortical responses to simultaneous stimulation of a suprachoroidal retinal prosthesis. Overall, our results demonstrate that cortical responses to simultaneous multi-electrode stimulation of the retina are repeatable and predictable, and that interactions between electrodes during simultaneous stimulation are predominantly linear. The model shows promise for determining optimal stimulation paradigms for exploiting interactions between electrodes to shape neural activity, thereby improving outcomes for patients with retinal prostheses.

Sensory experience modifies feature map relationships in visual cortex.

The extent to which brain structure is influenced by sensory input during development is a critical but controversial question. A paradigmatic system for studying this is the mammalian visual cortex. Maps of orientation preference (OP) and ocular dominance (OD) in the primary visual cortex of ferrets, cats and monkeys can be individually changed by altered visual input. However, the spatial relationship between OP and OD maps has appeared immutable. Using a computational model we predicted that biasing the visual input to orthogonal orientation in the two eyes should cause a shift of OP pinwheels towards the border of OD columns. We then confirmed this prediction by rearing cats wearing orthogonally oriented cylindrical lenses over each eye. Thus, the spatial relationship between OP and OD maps can be modified by visual experience, revealing a previously unknown degree of brain plasticity in response to sensory input.

Frequency Responses of Rat Retinal Ganglion Cells.

There are 15-20 different types of retinal ganglion cells (RGC) in the mammalian retina, each encoding different aspects of the visual scene. The mechanism by which post-synaptic signals from the retinal network generate spikes is determined by each cell's intrinsic electrical properties. Here we investigate the frequency responses of morphologically identified rat RGCs using intracellular injection of sinusoidal current waveforms, to assess their intrinsic capabilities with minimal contributions from the retinal network. Recorded cells were classified according to their morphological characteristics (A, B, C or D-type) and their stratification (inner (i), outer (o) or bistratified) in the inner plexiform layer (IPL). Most cell types had low- or band-pass frequency responses. A2, C1 and C4o cells were band-pass with peaks of 15-30 Hz and low-pass cutoffs above 56 Hz (A2 cells) and ~42 Hz (C1 and C4o cells). A1 and C2i/o cells were low-pass with peaks of 10-15 Hz (cutoffs 19-25 Hz). Bistratified D1 and D2 cells were also low-pass with peaks of 5-10 Hz (cutoffs ~16 Hz). The least responsive cells were the B2 and C3 types (peaks: 2-5 Hz, cutoffs: 8-11 Hz). We found no difference between cells stratifying in the inner and outer IPL (i.e., ON and OFF cells) or between cells with large and small somas or dendritic fields. Intrinsic physiological properties (input resistance, spike width and sag) had little impact on frequency response at low frequencies, but account for 30-40% of response variability at frequencies >30 Hz.

A Simple and Accurate Model to Predict Responses to Multi-electrode Stimulation in the Retina.

Implantable electrode arrays are widely used in therapeutic stimulation of the nervous system (e.g. cochlear, retinal, and cortical implants). Currently, most neural prostheses use serial stimulation (i.e. one electrode at a time) despite this severely limiting the repertoire of stimuli that can be applied. Methods to reliably predict the outcome of multi-electrode stimulation have not been available. Here, we demonstrate that a linear-nonlinear model accurately predicts neural responses to arbitrary patterns of stimulation using in vitro recordings from single retinal ganglion cells (RGCs) stimulated with a subretinal multi-electrode array. In the model, the stimulus is projected onto a low-dimensional subspace and then undergoes a nonlinear transformation to produce an estimate of spiking probability. The low-dimensional subspace is estimated using principal components analysis, which gives the neuron's electrical receptive field (ERF), i.e. the electrodes to which the neuron is most sensitive. Our model suggests that stimulation proportional to the ERF yields a higher efficacy given a fixed amount of power when compared to equal amplitude stimulation on up to three electrodes. We find that the model captures the responses of all the cells recorded in the study, suggesting that it will generalize to most cell types in the retina. The model is computationally efficient to evaluate and, therefore, appropriate for future real-time applications including stimulation strategies that make use of recorded neural activity to improve the stimulation strategy.

Spectral distribution of local field potential responses to electrical stimulation of the retina.

OBJECTIVE: Different frequency bands of the local field potential (LFP) have been shown to reflect neuronal activity occurring at varying cortical scales. As such, recordings of the LFP may offer a novel way to test the efficacy of neural prostheses and allow improvement of stimulation strategies via neural feedback. Here we use LFP measurements from visual cortex to characterize neural responses to electrical stimulation of the retina. We aim to show that the LFP is a viable signal that contains sufficient information to optimize the performance of sensory neural prostheses. APPROACH: Clinically relevant electrode arrays were implanted in the suprachoroidal space of one eye in four felines. LFPs were simultaneously recorded in response to stimulation of individual electrodes using penetrating microelectrode arrays from the visual cortex. The frequency response of each electrode was extracted using multi-taper spectral analysis and the uniqueness of the responses was determined via a linear decoder. MAIN RESULTS: We found that cortical LFPs are reliably modulated by electrical stimulation of the retina and that the responses are spatially localized. We further characterized the spectral distribution of responses, with maximum information being contained in the low and high gamma bands. Finally, we found that LFP responses are unique to a large range of stimulus parameters (∼40) with a maximum conveyable information rate of 6.1 bits. SIGNIFICANCE: These results show that the LFP can be used to validate responses to electrical stimulation of the retina and we provide the first steps towards using these responses to provide more efficacious stimulation strategies.

Contrast and response gain control depend on cortical map architecture.

Visual cortical neurons are sensitive to visual stimulus contrast and most cells adapt their sensitivity to the prevailing visual environment. Specifically, they match the steepest region of their contrast response function to the prevailing contrast (contrast gain control), and reduce spike rates to limit saturation (response gain control). Most neurons are also tuned for stimulus orientation, and neurons with similar orientation preference are clustered together into iso-orientation zones arranged around pinwheels, i.e. points where all orientations are represented. Here we investigated the relationship between the contrast adaptation properties of neurons and their location relative to pinwheels in the orientation preference map. We measured orientation preference maps in cat cortex using optical intrinsic signal imaging. We then characterized the contrast adaptation properties of single neurons located close to pinwheels, in iso-orientation zones, and at regions in between. We found little evidence of differential contrast sensitivity of neurons adapted to zero contrast. However, after adaptation to their preferred orientation at high contrast, changes in both contrast and response gain were greater for neurons near pinwheels compared with other map regions. Therefore, in the adapted state, which is probably typical during natural viewing, there is a spatial map of contrast sensitivity that is associated with the orientation preference map. This differential adaptation revealed a new dimension of cortical functional organization, linking the contrast adaptation of cells with the orientation preference of their nearest neighbours.

Prosthetic vision: devices, patient outcomes and retinal research.

Retinal disease and its associated retinal degeneration can lead to the loss of photoreceptors and therefore, profound blindness. While retinal degeneration destroys the photoreceptors, the neural circuits that convey information from the eye to the brain are sufficiently preserved to make it possible to restore sight using prosthetic devices. Typically, these devices consist of a digital camera and an implantable neurostimulator. The image sensor in a digital camera has the same spatiotopic arrangement as the photoreceptors of the retina. Therefore, it is possible to extract meaningful spatial information from an image and deliver it via an array of stimulating electrodes directly to the surviving retinal circuits. Here, we review the structure and function of normal and degenerate retina. The different approaches to prosthetic implant design are described in the context of human and preclinical trials. In the last section, we review studies of electrical properties of the retina and its response to electrical stimulation. These types of investigation are currently assessing a number of key challenges identified in human trials, including stimulation efficacy, spatial localisation, desensitisation to repetitive stimulation and selective activation of retinal cell populations.