Ictogenesis proceeds through discrete phases in hippocampal CA1 seizures in mice.

Epilepsy is characterized by spontaneous non-provoked seizures, yet the mechanisms that trigger a seizure and allow its evolution remain underexplored. To dissect out phases of ictogenesis, we evoked hypersynchronous activity with optogenetic stimulation. Focal optogenetic activation of putative excitatory neurons in the mouse hippocampal CA1 reliably evoked convulsive seizures in awake mice. A time-vs-time pulsogram plot characterized the evolution of the EEG pulse response from a light evoked response to induced seizure activity. Our results depict ictogenesis as a stepwise process comprised of three distinctive phases demarcated by two transition points. The induction phase undergoes the first transition to reverberant phase activity, followed by the second transition into the paroxysmal phase or a seizure. Non-seizure responses are confined to either induction or reverberant phases. The pulsogram was then constructed in seizures recorded from a murine model of temporal lobe epilepsy and it depicted a similar reverberance preceding spontaneous seizures. The discovery of these distinct phases of ictogenesis may offer means to abort a seizure before it develops.

NEURAL CORRELATES OF PERCEPTUAL SIMILARITY MASKING IN PRIMATE V1.

Visual detection is a fundamental natural task. Detection becomes more challenging as the similarity between the target and the background in which it is embedded increases, a phenomenon termed "similarity masking". To test the hypothesis that V1 contributes to similarity masking, we used voltage sensitive dye imaging (VSDI) to measure V1 population responses while macaque monkeys performed a detection task under varying levels of target-background similarity. Paradoxically, we find that during an initial transient phase, V1 responses to the target are enhanced, rather than suppressed, by target-background similarity. This effect reverses in the second phase of the response, so that in this phase V1 signals are positively correlated with the behavioral effect of similarity. Finally, we show that a simple model with delayed divisive normalization can qualitatively account for our findings. Overall, our results support the hypothesis that a nonlinear gain control mechanism in V1 contributes to perceptual similarity masking.

Rapid Analysis of Visual Receptive Fields by Iterative Tomography.

Many receptive fields in the early visual system show standard (center-surround) structure and can be analyzed using simple drifting patterns and a difference-of-Gaussians (DoG) model, which treats the receptive field as a linear filter of the visual image. But many other receptive fields show nonlinear properties such as selectivity for direction of movement. Such receptive fields are typically studied using discrete stimuli (moving or flashed bars and edges) and are modelled according to the features of the visual image to which they are most sensitive. Here, we harness recent advances in tomographic image analysis to characterize rapidly and simultaneously both the linear and nonlinear components of visual receptive fields. Spiking and intracellular voltage potential responses to briefly flashed bars are analyzed using non-negative matrix factorization (NNMF) and iterative reconstruction tomography (IRT). The method yields high-resolution receptive field maps of individual neurons and neuron ensembles in primate (marmoset, both sexes) lateral geniculate and rodent (mouse, male) retina. We show that the first two IRT components correspond to DoG-equivalent center and surround of standard [magnocellular (M) and parvocellular (P)] receptive fields in primate geniculate. The first two IRT components also reveal the spatiotemporal receptive field structure of nonstandard (on/off-rectifying) receptive fields. In rodent retina we combine NNMF-IRT with patch-clamp recording and dye injection to directly map spatial receptive fields to the underlying anatomy of retinal output neurons. We conclude that NNMF-IRT provides a rapid and flexible framework for study of receptive fields in the early visual system.

Calcium imaging with genetically encoded indicators in behaving primates.

Understanding the neural basis of behaviour requires studying brain activity in behaving subjects using complementary techniques that measure neural responses at multiple spatial scales, and developing computational tools for understanding the mapping between these measurements. Here we report the first results of widefield imaging of genetically encoded calcium indicator (GCaMP6f) signals from V1 of behaving macaques. This technique provides a robust readout of visual population responses at the columnar scale over multiple mm(2) and over several months. To determine the quantitative relation between the widefield GCaMP signals and the locally pooled spiking activity, we developed a computational model that sums the responses of V1 neurons characterized by prior single unit measurements. The measured tuning properties of the GCaMP signals to stimulus contrast, orientation and spatial position closely match the predictions of the model, suggesting that widefield GCaMP signals are linearly related to the summed local spiking activity.

Spatial precision of population activity in primate area MT.

The middle temporal (MT) area is a cortical area integral to the "where" pathway of primate visual processing, signaling the movement and position of objects in the visual world. The receptive field of a single MT neuron is sensitive to the direction of object motion but is too large to signal precise spatial position. Here, we asked if the activity of MT neurons could be combined to support the high spatial precision required in the where pathway. With the use of multielectrode arrays, we recorded simultaneously neural activity at 24-65 sites in area MT of anesthetized marmoset monkeys. We found that although individual receptive fields span more than 5° of the visual field, the combined population response can support fine spatial discriminations (<0.2°). This is because receptive fields at neighboring sites overlapped substantially, and changes in spatial position are therefore projected onto neural activity in a large ensemble of neurons. This fine spatial discrimination is supported primarily by neurons with receptive fields flanking the target locations. Population performance is degraded (by 13-22%) when correlations in neural activity are ignored, further reflecting the contribution of population neural interactions. Our results show that population signals can provide high spatial precision despite large receptive fields, allowing area MT to represent both the motion and the position of objects in the visual world.

Emergence of complex wave patterns in primate cerebral cortex.

Slow brain rhythms are attributed to near-simultaneous (synchronous) changes in activity in neuron populations in the brain. Because they are slow and widespread, synchronous rhythms have not been considered crucial for information processing in the waking state. Here we adapted methods from turbulence physics to analyze δ-band (1-4 Hz) rhythms in local field potential (LFP) activity, in multielectrode recordings from cerebral cortex in anesthetized marmoset monkeys. We found that synchrony contributes only a small fraction (less than one-fourth) to the local spatiotemporal structure of δ-band signals. Rather, δ-band activity is dominated by propagating plane waves and spatiotemporal structures, which we call complex waves. Complex waves are manifest at submillimeter spatial scales, and millisecond-range temporal scales. We show that complex waves can be characterized by their relation to phase singularities within local nerve cell networks. We validate the biological relevance of complex waves by showing that nerve cell spike rates are higher in presence of complex waves than in the presence of synchrony and that there are nonrandom patterns of evolution from one type of complex wave to another. We conclude that slow brain rhythms predominantly indicate spatiotemporally organized activity in local nerve cell circuits, not synchronous activity within and across brain regions.

Local and Global Correlations between Neurons in the Middle Temporal Area of Primate Visual Cortex.

In humans and other primates, the analysis of visual motion includes populations of neurons in the middle-temporal (MT) area of visual cortex. Motion analysis will be constrained by the structure of neural correlations in these populations. Here, we use multi-electrode arrays to measure correlations in anesthetized marmoset, a New World monkey where area MT lies exposed on the cortical surface. We measured correlations in the spike count between pairs of neurons and within populations of neurons, for moving dot fields and moving gratings. Correlations were weaker in area MT than in area V1. The magnitude of correlations in area MT diminished with distance between receptive fields, and difference in preferred direction. Correlations during presentation of moving gratings were stronger than those during presentation of moving dot fields, extended further across cortex, and were less dependent on the functional properties of neurons. Analysis of the timescales of correlation suggests presence of 2 mechanisms. A local mechanism, associated with near-synchronous spiking activity, is strongest in nearby neurons with similar direction preference and is independent of visual stimulus. A global mechanism, operating over larger spatial scales and longer timescales, is independent of direction preference and is modulated by the type of visual stimulus presented.

Convergence across tactile afferent types in primary and secondary somatosensory cortices.

Integration of information by convergence of inputs onto sensory cortical neurons is a requisite for processing higher-order stimulus features. Convergence across defined peripheral input classes has generally been thought to occur at levels beyond the primary sensory cortex, however recent work has shown that this does not hold for the convergence of slowly-adapting and rapidly-adapting inputs in primary somatosensory cortex. We have used a new analysis method for multi-unit recordings, to show convergence of inputs deriving from the rapidly-adapting and Pacinian channels in a proportion of neurons in both primary and secondary somatosensory cortex in the anaesthetised cat. We have validated this method using single-unit recordings. The secondary somatosensory cortex has a greater proportion of sites that show convergence of this type than primary somatosensory cortex. These findings support the hypothesis that the more complex features processed in higher cortical areas require a greater degree of convergence across input classes, but also shows that this convergence is apparent in the primary somatosensory cortex.

Integration and segregation of multiple motion signals by neurons in area MT of primate.

We used multielectrode arrays to measure the response of populations of neurons in primate middle temporal area to the transparent motion of two superimposed dot fields moving in different directions. The shape of the population response was well predicted by the sum of the responses to the constituent fields. However, the population response profile for transparent dot fields was similar to that for coherent plaid motion and hence an unreliable cue to transparency. We then used single-unit recording to characterize component and pattern cells from their response to drifting plaids. Unlike for plaids, component cells responded to the average direction of superimposed dot fields, whereas pattern cells could signal the constituent motions. This observation provides support for a strong prediction of the Simoncelli and Heeger (1998) model of motion analysis in area middle temporal, and suggests that pattern cells have a special status in the processing of superimposed dot fields.

Current steering in retinal stimulation via a quasimonopolar stimulation paradigm.

PURPOSE: Research to restore some degree of vision to patients suffering from retinal degeneration is becoming increasingly more promising. Several groups have chosen electrical stimulation of the remaining network of a degenerate retina as a means to generate discrete light percepts (phosphenes). Approaches vary significantly, with the greatest difference being the location of the stimulating electrode itself. METHODS: Suprachoroidal positioning offers excellent mechanical stability and surgical simplicity; however, at the cost of activation thresholds and focused stimulation due to the distance from the electrodes to the target neurons. Past studies proposed a hexapolar electrode configuration to focus the cortical activation and minimize cross-talk between electrodes during concurrent stimulation. The high impedance nature of the choroid and pigment epithelium, however, cause current to shunt between the stimulating and return electrodes, resulting in even higher activation thresholds. In our study, we analyzed the effect of stimulating the feline retina using a quasimonopolar stimulation by simultaneously stimulating a hexapolar and distant monopolar return configurations. RESULTS: Results of in vivo studies showed that quasimonopolar stimulation can be used to maintain the activation containment properties of hexapolar stimulation, while lowering the activation threshold to values almost equivalent to those of monopolar stimulation. CONCLUSIONS: The optimal stimulus was found to be composed of a subthreshold monopolar stimulus combined with a suprathreshold hexapolar stimulation. This resulted in a decrease of activation threshold of 60% with respect to hexapolar alone, but with no discernible deleterious effect on the charge containment of a pure hexapolar stimulation.

Threshold analysis of a quasimonopolar stimulation paradigm in visual prosthesis.

The complexity of surgical implantation has always been a significant obstacle in the development of visual prosthetics. Implanting in the epi and sub-retinal spaces allows the prosthesis direct access to the retina, resulting in lower stimulation thresholds, potentially at the expense of robust mechanical stability and interface longevity. Implanting the stimulating electrode in the supra-choroidal space greatly simplifies surgery and improves mechanical stability. This is achieved at the cost of a higher activation threshold and reduced focus of the electric field at the target site of stimulation, given the increased distance between the stimulating electrodes and the target tissue. In order to contain the spread of the stimulating field, the authors proposed a hexagonal arrangement of return electrodes, at a further cost to the stimulation threshold over that of a monopolar stimulation paradigm. This study analyses the effect on activation thresholds of activating simultaneously the hexpolar guard electrodes and the distant monopolar return in what we have termed a quasimonopolar configuration. Results show that introducing a small element of monopolar stimulation significantly lowers the activation threshold otherwise required by a pure hexpolar return.

ARM-based visual processing system for prosthetic vision.

A growing number of prosthetic devices have been shown to provide visual perception to the profoundly blind through electrical neural stimulation. These first-generation devices offer promising outcomes to those affected by degenerative disorders such as retinitis pigmentosa. Although prosthetic approaches vary in their placement of the stimulating array (visual cortex, optic-nerve, epi-retinal surface, sub-retinal surface, supra-choroidal space, etc.), most of the solutions incorporate an externally-worn device to acquire and process video to provide the implant with instructions on how to deliver electrical stimulation to the patient, in order to elicit phosphenized vision. With the significant increase in availability and performance of low power-consumption smart phone and personal device processors, the authors investigated the use of a commercially available ARM (Advanced RISC Machine) device as an externally-worn processing unit for a prosthetic neural stimulator for the retina. A 400 MHz Samsung S3C2440A ARM920T single-board computer was programmed to extract 98 values from a 1.3 Megapixel OV9650 CMOS camera using impulse, regional averaging and Gaussian sampling algorithms. Power consumption and speed of video processing were compared to results obtained to similar reported devices. The results show that by using code optimization, the system is capable of driving a 98 channel implantable device for the restoration of visual percepts to the blind.

Simulating prosthetic vision: II. Measuring functional capacity.

Investigators of microelectronic visual prosthesis devices have found that some aspects of vision can be restored in the form of spots of light in the visual field, so-called "phosphenes", from which more rich and complex scenes may be composed. However, questions still surround the capabilities of how such a form of vision can allow its recipients to "see" and to carry out everyday activities. Through simulations of prosthetic vision, researchers can experience first-hand many performance and behavioral aspects of prosthetic vision, and studies conducted on a larger population can inform the performance and behavioral preferences in general and in individual cases. This review examines the findings from the various investigations of the functional capacity of prosthetic vision conducted through simulations, especially on the topics of letter acuity, reading, navigation, learning and visual scanning adaptation. Central to the review, letter acuity is posited as a reference measurement so that results and performance trends across the various simulation models and functional assessment tasks can be more readily compared and generalized. Future directions for simulation based research are discussed with respect to designing a functional visual prosthesis, improving functional vision in near-term low-phosphene-count devices, and pursuing image processing strategies to impart the most comprehensible prosthetic vision.

Simulating prosthetic vision: I. Visual models of phosphenes.

With increasing research advances and clinical trials of visual prostheses, there is significant demand to better understand the perceptual and psychophysical aspects of prosthetic vision. In prosthetic vision a visual scene is composed of relatively large, isolated, spots of light so-called "phosphenes", very much like a magnified pictorial print. The utility of prosthetic vision has been studied by investigators in the form of virtual-reality visual models (simulations) of prosthetic vision administered to normally sighted subjects. In this review, the simulations from these investigations are examined with respect to how they visually render the phosphenes and the virtual-reality apparatus involved. A comparison is made between these simulations and the actual descriptions of phosphenes reported from human trials of visual prosthesis devices. For the results from these simulation studies to be relevant to the experience of visual prosthesis recipients, it is important that, the simulated phosphenes must be consistent with the descriptions from human trials. A standardized simulation and reporting framework is proposed so that future simulations may be configured to be more realistic to the experience of implant recipients, and the simulation parameters from different investigators may be more readily extracted, and study results more fittingly compared.

Optical imaging of electrically evoked visual signals in cats: I. Responses to corneal and intravitreal electrical stimulation.

Microelectronic retinal prostheses have been shown to restore the perception of light to the blind through electrical stimulation. Conventional recording techniques such as recording electrode arrays on the visual cortex can give a basic understanding of the events that occur during such stimulation events, but their finite size and number limits the spatial resolution achievable with them. Optical imaging of intrinsic signals (OIS imaging) allows for greater resolution (approximately 50 microm) of the activity in the cortex. This can be used to facilitate a greater understanding of the complex neurophysiological events that allow prosthetic vision. This paper shows responses to visual and electrical stimulation of the retina, and demonstrates that OIS imaging may be an effective technique in further refining stimulation techniques and implant designs for retinal prostheses.

Optical imaging of electrically evoked visual signals in cats: II. ICA "harmonic filtering" noise reduction.

Optical imaging of intrinsic signals (OIS) is a tool for visualizing differential areas in the primary visual cortex devoted to visual functions such as ocular dominance and spatial orientation preferences. The OIS methodology was employed to verify visual cortical response to a retinal vision prosthesis whereby electrical stimulation is applied to the neural retina in order to elicit visual percepts. However, OIS recording is quite susceptible to cardiac and respiratory artifact, and inherent noise related to the measurement process. This complicates the identification of evoked signals using standard ensemble averaging based image processing. We therefore developed an independent component analysis (ICA) "harmonic filtering" technique to improve the signal-to-noise ratio. This technique is capable of reducing noise components, highlighting response signals to visual and electrical stimuli. Particularly, we demonstrated extraction of an ocular dominance map due to corneal stimulation and localized cortical activation due to intravitreal stimulation.

Psychophysics of prosthetic vision: II. stochastic sampling, the phosphene image, and noise.

Stimulation of the diseased retina via an intraocular electrode array is a proposed means of restoring some vision to the profoundly blind. A prosthetic device to this end would involve post-implantation calibration (analogous to cochlear implant fitting), wherein the subject indicates those discrete positions in the visual field where luminous percepts are elicited. This procedure would be a source of noise, because the indicated positions would only approximate the actual positions in the visual field. Put differently, the procedure introduces sampling jitter, and would therefore affect clinical outcomes such as mobility and reading speeds. The nature of this noise is the concern of the present paper; we derive an expression for the noise power spectrum as it relates to the statistical nature of the sampling jitter. We show that, generally, jitter has greater effect on higher spatial-frequencies, that is, those areas of the implantee's visual perception that represent fine detail are more prone to noise. More specifically, the noise spectrum depends on the characteristic function of the random variable describing the sampling jitter. Our results signal the need for experimental work that characterizes sampling jitter in implantees, plus the need for simulations that allow a better understanding of perception and the noisy phosphene image.

Learning prosthetic vision: a virtual-reality study.

Acceptance of prosthetic vision will be heavily dependent on the ability of recipients to form useful information from such vision. Training strategies to accelerate learning and maximize visual comprehension would need to be designed in the light of the factors affecting human learning under prosthetic vision. Some of these potential factors were examined in a visual acuity study using the Landolt C optotype under virtual-reality simulation of prosthetic vision. Fifteen normally sighted subjects were tested for 10-20 sessions. Potential learning factors were tested at p < 0.05 with regression models. Learning was most evident across-sessions, though 17% of sessions did express significant within-session trends. Learning was highly concentrated toward a critical range of optotype sizes, and subjects were less capable in identifying the closed optotype (a Landolt C with no gap, forming a closed annulus). Training for implant recipients should target these critical sizes and the closed optotype to extend the limit of visual comprehension. Although there was no evidence that image processing affected overall learning, subjects showed varying personal preferences.