Percepts evoked by multi-electrode stimulation of human visual cortex.

BACKGROUND: Direct electrical stimulation of early visual cortex evokes the perception of small spots of light known as phosphenes. Previous studies have examined the location, size, and brightness of phosphenes evoked by stimulation of single electrodes. While it has been envisioned that concurrent stimulation of many electrodes could be used as the basis for a visual cortical prosthesis, the percepts resulting from multi-electrode stimulation have not been fully characterized. OBJECTIVE: To understand the rules governing perception of phosphenes evoked by multi-electrode stimulation of visual cortex. METHODS: Multi-electrode stimulation was conducted in human epilepsy patients. We examined the number and spatial arrangement of phosphenes evoked by stimulation of individual multi-electrode groups (n = 8), and the ability of subjects to discriminate between the pattern of phosphenes generated by stimulation of different multi-electrode groups (n = 7). RESULTS: Simultaneous stimulation of pairs of electrodes separated by greater than 4 mm tended to produce perception of two distinct phosphenes. Simultaneous stimulation of three electrodes gave rise to a consistent spatial pattern of phosphenes, but with significant variation in the absolute location, size, and orientation of that pattern perceived on each trial. Although multi-electrode stimulation did not produce perception of recognizable forms, subjects could use the pattern of phosphenes evoked by stimulation to perform simple discriminations. CONCLUSIONS: The number of phosphenes produced by multi-electrode stimulation can be predicted using a model for spread of activity in early visual cortex, but there are additional subtle effects that must be accounted for.

Sequence of visual cortex stimulation affects phosphene brightness in blind subjects.

BACKGROUND: Visual cortical prostheses (VCP) could potentially benefit a majority of the blind population. Feasibility testing of these VCP opens new avenues to characterize stimulation of visual cortex in blind subjects. OBJECTIVE/HYPOTHESIS: To determine if sequential stimulation of visual cortex produces a perception bias in phosphene brightness. METHODS: We stimulated three blind subjects implanted with the Orion array with sequences of two and three electrodes and asked them to determine the brighter phosphene, using interval forced-choice paradigms. We selected a set of reference electrodes as the constant stimuli across sequences and compared across three different amplitude levels keeping all other stimulation parameters fixed across electrodes. RESULTS: For two subjects, we measured a significant increase in the probability of perceiving a lower-level amplitude just as bright or brighter than a higher-level amplitude when stimulated later in the sequence (p < 0.001, Wilcoxon rank sum test). The probability of reference electrodes selected as brighter was also higher during the second phase, across most amplitude comparisons. For the third subject, there were measurable but not significant changes, where the first stimuli were perceived as brighter. The effects were consistent within subjects in the three-electrode sequences, where the probability of the reference electrode selected as brighter was correlated to when it was presented in the sequence. CONCLUSIONS: We showed evidence of temporal interactions in non-overlapping sequences of electrodes, where the direction of the effect was subject specific but consistent across a variety of electrode locations and current amplitude levels.

Biased Orientation and Color Tuning of the Human Visual Gamma Rhythm.

Narrowband γ oscillations (NBG: ∼20-60 Hz) in visual cortex reflect rhythmic fluctuations in population activity generated by underlying circuits tuned for stimulus location, orientation, and color. A variety of theories posit a specific role for NBG in encoding and communicating this information within visual cortex. However, recent findings suggest a more nuanced role for NBG, given its dependence on certain stimulus feature configurations, such as coherent-oriented edges and specific hues. Motivated by these factors, we sought to quantify the independent and joint tuning properties of NBG to oriented and color stimuli using intracranial recordings from the human visual cortex (male and female). NBG was shown to display a cardinal orientation bias (horizontal) and also an end- and mid-spectral color bias (red/blue and green). When jointly probed, the cardinal bias for orientation was attenuated and an end-spectral preference for red and blue predominated. This loss of mid-spectral tuning occurred even for recording sites showing large responses to uniform green stimuli. Our results demonstrate the close, yet complex, link between the population dynamics driving NBG oscillations and known feature selectivity biases for orientation and color within visual cortex. Such a bias in stimulus tuning imposes new constraints on the functional significance of the visual γ rhythm. More generally, these biases in population electrophysiology will need to be considered in experiments using orientation or color features to examine the role of visual cortex in other domains, such as working memory and decision-making.SIGNIFICANCE STATEMENT Oscillations in electrophysiological activity occur in visual cortex in response to stimuli that strongly drive the orientation or color selectivity of visual neurons. The significance of this induced "γ rhythm" to brain function remains unclear. Answering this question requires understanding how and why some stimuli can reliably generate oscillatory γ activity while others do not. We examined how different orientations and colors independently and jointly modulate γ oscillations in the human brain. Our data show that γ oscillations are greatest for certain orientations and colors that reflect known response biases in visual cortex. Such findings complicate the functional significance of γ oscillations but open new avenues for linking circuits to population dynamics in visual cortex.

Raising the stakes for cortical visual prostheses.

In this issue of the JCI, the dream of restoring useful vision to blind individuals with neurotechnology moves one step closer to realization. Fernández et al. implanted an electrode array with 96 penetrating electrodes in the visual cortex of a blind patient who had been without light perception for 16 years due to optic neuropathy. Remarkably, the patient was able to perceive visual patterns created by passing current through array electrodes. The use of a penetrating electrode array meant that action potentials from single neurons could be recorded to study the neural response to stimulation. Compared with electrodes resting on the cortical surface, penetrating electrodes require one-tenth the current to create a visual percept. However, patterned electrical stimulation often fails to produce the expected percept for penetrating and surface electrode arrays, highlighting the need for further research to untangle the relationship between stimulus and perception.

Multi-electrode stimulation evokes consistent spatial patterns of phosphenes and improves phosphene mapping in blind subjects.

BACKGROUND: Visual cortical prostheses (VCPs) have the potential to restore visual function to patients with acquired blindness. Successful implementation of VCPs requires the ability to reliably map the location of the phosphene produced by stimulation of each implanted electrode. OBJECTIVE: To evaluate the efficacy of different approaches to phosphene mapping and propose simple improvements to mapping strategy. METHODS: We stimulated electrodes implanted in the visual cortex of five blind and fifteen sighted patients. We tested two fixation strategies, unimanual fixation, where subjects placed a single index finger on a tactile fixation point and bimanual fixation, where subjects overlaid their right index finger over their left on the tactile point. In addition, we compared absolute mapping in which a single electrode was stimulated on each trial, and relative mapping with sequences containing stimulation of three to five phosphenes on each trial. Trial-to-trial variability present in relative mapping sequences was quantified. RESULTS: Phosphene mapping was less precise in blind subjects than in sighted subjects (2DRMS, 16 ± 2.9° vs. 1.9 ± 0.93°; t (18) = 18, p = <0.001). Within blind subjects, bimanual fixation resulted in more consistent phosphene localization than unimanual fixation (BS1: 4.0 ± 2.6° vs. 19 ± 4.7°, t (79) = 24, p < 0.001; BS2 4.1 ± 2.0° vs. 12 ± 2.7°, t (65) = 19, p < 0.001). Multi-point relative mapping had similar baseline precision to absolute mapping (BS1: 4.7 ± 2.6° vs. 3.9 ± 2.0°; BS2: 4.1 ± 2.0° vs. 3.2 ± 1.1°) but improved significantly when trial-to-trial translational variability was removed. Although multi-point mapping methods did reveal more of the functional organization expected in early visual cortex, subjects tended to artificially regularize the spacing between phosphenes. We attempt to address this issue by fitting a standard logarithmic map to relative multi-point sequences. CONCLUSIONS: Relative mapping methods, combined with bimanual fixation, resulted in the most precise estimates of phosphene organization. These techniques, combined with use of a standard logarithmic model of visual cortex, may provide a practical way to improve the implementation of a VCP.

Dynamic Stimulation of Visual Cortex Produces Form Vision in Sighted and Blind Humans.

A visual cortical prosthesis (VCP) has long been proposed as a strategy for restoring useful vision to the blind, under the assumption that visual percepts of small spots of light produced with electrical stimulation of visual cortex (phosphenes) will combine into coherent percepts of visual forms, like pixels on a video screen. We tested an alternative strategy in which shapes were traced on the surface of visual cortex by stimulating electrodes in dynamic sequence. In both sighted and blind participants, dynamic stimulation enabled accurate recognition of letter shapes predicted by the brain's spatial map of the visual world. Forms were presented and recognized rapidly by blind participants, up to 86 forms per minute. These findings demonstrate that a brain prosthetic can produce coherent percepts of visual forms.

Seeing Visual Gamma Oscillations in a New Light.

Gamma oscillations have been argued to support visual perception by synchronizing the processing and transfer of information within and across areas of visual cortex. Here, we highlight recent findings implicating the influence of color on visual gamma oscillations and how these observations may relate to local cortical tuning and organization.

Functionally Distinct Gamma Range Activity Revealed by Stimulus Tuning in Human Visual Cortex.

Neocortical gamma activity has long been hypothesized as a mechanism for synchronizing brain regions to support visual perception and cognition more broadly. Although early studies focused on narrowband gamma oscillations (∼20-60 Hz), recent work has emphasized a more broadband "high-gamma" response (∼70-150+ Hz). These responses are often conceptually or analytically treated as synonymous markers of gamma activity. Using high-density intracranial recordings from the human visual cortex, we challenge this view by showing distinct spectral, temporal, and functional properties of narrow and broadband gamma. Across four experiments, narrowband gamma was strongly selective for gratings and long-wavelength colors, displaying a delayed response onset, sustained temporal profile, and contrast-dependent peak frequency. In addition, induced narrowband gamma oscillations lacked phase consistency across stimulus repetitions and displayed highly focal inter-site synchronization. In contrast, broadband gamma was consistently observed for all presented stimuli, displaying a rapid response onset, transient temporal profile, and invariant spectral properties. We exploited stimulus tuning to highlight the functional dissociation of these distinct signals, reconciling prior inconsistencies across species and stimuli regarding the ubiquity of visual gamma oscillations during natural vision. The occurrence of visual narrowband gamma oscillations, unlike broadband high gamma, appears contingent on specific structural and chromatic stimulus attributes intersecting with the receptive field. Together, these findings have important implications for the study, analysis, and functional interpretation of neocortical gamma-range activity.

Electrical Stimulation of Visual Cortex: Relevance for the Development of Visual Cortical Prosthetics.

Electrical stimulation of the cerebral cortex is a powerful tool for exploring cortical function. Stimulation of early visual cortical areas is easily detected by subjects and produces simple visual percepts known as phosphenes. A device implanted in visual cortex that generates patterns of phosphenes could be used as a substitute for natural vision in blind patients. We review the possibilities and limitations of such a device, termed a visual cortical prosthetic. Currently, we can predict the location and size of phosphenes produced by stimulation of single electrodes. A functional prosthetic, however, must produce spatial temporal patterns of activity that will result in the perception of complex visual objects. Although stimulation of later visual cortical areas alone usually does not lead to a visual percept, it can alter visual perception and the performance of visual behaviors, and training subjects to use signals injected into these areas may be possible.

Saturation in Phosphene Size with Increasing Current Levels Delivered to Human Visual Cortex.

Electrically stimulating early visual cortex results in a visual percept known as a phosphene. Although phosphenes can be evoked by a wide range of electrode sizes and current amplitudes, they are invariably described as small. To better understand this observation, we electrically stimulated 93 electrodes implanted in the visual cortex of 13 human subjects who reported phosphene size while stimulation current was varied. Phosphene size increased as the stimulation current was initially raised above threshold, but then rapidly reached saturation. Phosphene size also depended on the location of the stimulated site, with size increasing with distance from the foveal representation. We developed a model relating phosphene size to the amount of activated cortex and its location within the retinotopic map. First, a sigmoidal curve was used to predict the amount of activated cortex at a given current. Second, the amount of active cortex was converted to degrees of visual angle by multiplying by the inverse cortical magnification factor for that retinotopic location. This simple model accurately predicted phosphene size for a broad range of stimulation currents and cortical locations. The unexpected saturation in phosphene sizes suggests that the functional architecture of cerebral cortex may impose fundamental restrictions on the spread of artificially evoked activity and this may be an important consideration in the design of cortical prosthetic devices.SIGNIFICANCE STATEMENT Understanding the neural basis for phosphenes, the visual percepts created by electrical stimulation of visual cortex, is fundamental to the development of a visual cortical prosthetic. Our experiments in human subjects implanted with electrodes over visual cortex show that it is the activity of a large population of cells spread out across several millimeters of tissue that supports the perception of a phosphene. In addition, we describe an important feature of the production of phosphenes by electrical stimulation: phosphene size saturates at a relatively low current level. This finding implies that, with current methods, visual prosthetics will have a limited dynamic range available to control the production of spatial forms and that more advanced stimulation methods may be required.

Optogenetic assessment of horizontal interactions in primary visual cortex.

Columnar organization of orientation selectivity and clustered horizontal connections linking orientation columns are two of the distinctive organizational features of primary visual cortex in many mammalian species. However, the functional role of these connections has been harder to characterize. Here we examine the extent and nature of horizontal interactions in V1 of the tree shrew using optical imaging of intrinsic signals, optogenetic stimulation, and multi-unit recording. Surprisingly, we find the effects of optogenetic stimulation depend primarily on distance and not on the specific orientation domains or axes in the cortex, which are stimulated. In addition, across a wide range of variation in both visual and optogenetic stimulation we find linear addition of the two inputs. These results emphasize that the cortex provides a rich substrate for functional interactions that are not limited to the orientation-specific interactions predicted by the monosynaptic distribution of horizontal connections.

Effects of stimulus direction on the correlation between behavior and single units in area MT during a motion detection task.

Trial-to-trial variations in the firing rates of neurons in the middle temporal visual area (MT) are correlated with the behavior of macaque monkeys performing motion detection and motion discrimination tasks. Here we examine how these correlations depend on the direction of motion used for a detection task relative to the preferred direction of the neuron under study. There was a robust correlation between the firing rate of MT neurons and the animal's detection of motion when the direction of that motion was within ∼ 45° of the preferred direction of the neuron. This correlation was undetectable using motions that were ∼ 90° away from the preferred direction, and an inverse correlation between activity and behavior was found for motion in the null direction. Correlation between reaction times and single-cell activity in MT followed a similar pattern. Although motion detection could have been based solely on the activity of neurons preferring the expected direction, these results suggest that it depends on the relative activity of neurons preferring opposite directions of motion. They furthermore show that the subset of neurons used to guide behavior can vary from trial to trial based on task requirements.

Statistical structure of lateral connections in the primary visual cortex.

BACKGROUND: The statistical structure of the visual world offers many useful clues for understanding how biological visual systems may understand natural scenes. One particularly important early process in visual object recognition is that of grouping together edges which belong to the same contour. The layout of edges in natural scenes have strong statistical structure. One such statistical property is that edges tend to lie on a common circle, and this 'co-circularity' can predict human performance at contour grouping. We therefore tested the hypothesis that long-range excitatory lateral connections in the primary visual cortex, which are believed to be involved in contour grouping, display a similar co-circular structure. RESULTS: By analyzing data from tree shrews, where information on both lateral connectivity and the overall structure of the orientation map was available, we found a surprising diversity in the relevant statistical structure of the connections. In particular, the extent to which co-circularity was displayed varied significantly. CONCLUSIONS: Overall, these data suggest the intriguing possibility that V1 may contain both co-circular and anti-cocircular connections.

V1 neurons: in tune with the neighbors.

In this issue of Neuron, Nauhaus et al. use a combination of optical imaging and multiple electrode recording to demonstrate that the orientation tuning of single cells in primary visual cortex is reliably related to the local structure of the orientation preference map in both cats and monkeys.

Local cortical function after uncomplicated subdural electrode implantation. Laboratory investigation.

OBJECTIVES: Although subdural electrodes are routinely used to map regional brain function, it is unknown if the presence of these implants hinders local cortical function. The authors used psychophysical methods to measure the effect of uncomplicated electrode implantation on local cortical function. METHODS: Local field potentials were used to map receptive fields (RFs) for subdural electrodes that were unilaterally implanted on early visual cortex in 4 patients. After electrode implantation, patients did a task that required them to detect an orientation change in a flashing visual stimulus that was presented either inside the mapped RF or outside the RF in the diametrically opposite portion of the other hemifield. The size of the orientation change was varied to span a wide range of behavioral performance. Psychometric curves were generated by fitting behavioral responses to a logistic function. The threshold was defined as the point at which the fitted function crossed 50% detection. RESULTS: Data were well fit by the logistic function in all 4 patients for both RF and non-RF conditions. None of the volunteers tested showed a statistically significant difference in detection threshold, reaction time, or in the slope of the psychometric function for stimuli presented inside or outside the RF. CONCLUSIONS: Subdural electrodes implanted for extraoperative monitoring do not impair psychophysical performance for a task based on stimuli lying within the RF for recording electrodes. This finding suggests that these electrodes can be used reliably for accurate assessment of regional neurological function.

Spatial attention does not strongly modulate neuronal responses in early human visual cortex.

Attention can dramatically enhance behavioral performance based on a visual stimulus, but the degree to which attention modulates activity in early visual cortex is unclear. Whereas single-unit studies of spatial attention in monkeys have repeatedly revealed relatively modest attentional modulations in V1, human functional magnetic resonance imaging studies demonstrate a large attentional enhancement of the blood oxygen level-dependent (BOLD) signal in V1. To explore this discrepancy, we used intracranial electrodes to directly measure the effect of spatial attention on the responses of neurons near the human occipital pole. We found that spatial attention does not robustly modulate stimulus-driven local field potentials in early human visual cortex, but instead produces modest modulations that are consistent with those seen in monkey neurophysiology experiments. This finding suggests that the neuronal activity that underlies visual attention in humans is similar to that found in other primates and that behavioral state may alter the linear relationship between neuronal activity and BOLD.

Receptive fields in human visual cortex mapped with surface electrodes.

Most of our understanding of the functional organization of human visual cortex comes from lesion and functional imaging studies and by extrapolation from results obtained by neuroanatomical and neurophysiological studies in nonhuman primates. Although some single-unit and field potential recordings have been made in human visual cortex, none has provided quantitative characterization of spatial receptive fields (RFs) of individual sites. Here we use subdural electrodes implanted for clinical purposes to quantitatively measure response properties in different regions of human visual cortex. We find significant differences in RF size, response latency, and response magnitude for sites in early visual areas, versus sites in later stages of both the dorsal and ventral streams. In addition, we use this technique to estimate the cortical magnification factor in early human visual cortex. The spatial and temporal resolution of cortical surface recordings suggest that this technique is well suited to examine further issues in visual processing in humans.

Functional organization of visual cortex in the prosimian bush baby revealed by optical imaging of intrinsic signals.

Cells in primary visual cortex (V1) of primates and carnivores respond most strongly to a visual stimulus presented to one eye, in a particular visual field location, and at a particular orientation. Each of these stimulus attributes is mapped across the cortical surface, and, in macaque monkeys and cats, strong geometrical relationships exist between these feature maps. In macaque V1 and V2, correlations between feature maps and cytochrome oxidase (CO)-rich modules have also been observed. To see if such relationships reflect a conserved principle of V1 functional architecture among primate species, we examined these maps in the prosimian bush baby, a species that has been proposed to represent the ancestral primate organization. We found that the layout of individual feature maps in bush baby V1 is similar to that of other primates, but we found an entirely different organization of orientation preference in bush baby V2 compared with that reported in simian primates. Another striking distinction between bush baby and simian species is that we observed no strong relationships among maps of orientation, ocular dominance, and CO blobs in V1. Thus our findings suggest that precise relationships between feature maps are not a common element of the functional organization in all primates and that such relationships are not necessary for achieving basic coverage of stimulus feature combinations. In addition, our results suggest that specific relationships between feature maps in V1, and the subdivision of V2 into functional compartments, may have arisen comparatively late in the evolution of primates.

A morphological basis for orientation tuning in primary visual cortex.

Feedforward connections are thought to be important in the generation of orientation-selective responses in visual cortex by establishing a bias in the sampling of information from regions of visual space that lie along a neuron's axis of preferred orientation. It remains unclear, however, which structural elements-dendrites or axons-are ultimately responsible for conveying this sampling bias. To explore this question, we have examined the spatial arrangement of feedforward axonal connections that link non-oriented neurons in layer 4 and orientation-selective neurons in layer 2/3 of visual cortex in the tree shrew. Target sites of labeled boutons in layer 2/3 resulting from focal injections of biocytin in layer 4 show an orientation-specific axial bias that is sufficient to confer orientation tuning to layer 2/3 neurons. We conclude that the anisotropic arrangement of axon terminals is the principal source of the orientation bias contributed by feedforward connections.

Functional organization of visual cortex in the owl monkey.

In this study, we compared the organization of orientation preference in visual areas V1, V2, and V3. Within these visual areas, we also quantified the relationship between orientation preference and cytochrome oxidase (CO) staining patterns. V1 maps of orientation preference contained both pinwheels and linear zones. The location of CO blobs did not relate in a systematic way to maps of orientation; although, as in other primates, there were approximately twice as many pinwheels as CO blobs. V2 contained bands of high and low orientation selectivity. The bands of high orientation selectivity were organized into pinwheels and linear zones, but iso-orientation domains were twice as large as those in V1. Quantitative comparisons between bands containing high or low orientation selectivity and CO dark and light bands suggested that at least four functional compartments exist in V2, CO dense bands with either high or low orientation selectivity, and CO light bands with either high or low selectivity. We also demonstrated that two functional compartments exist in V3, with zones of high orientation selectivity corresponding to CO dense areas and zones of low orientation selectivity corresponding to CO pale areas. Together with previous findings, these results suggest that the modular organization of V1 is similar across primates and indeed across most mammals. V2 organization in owl monkeys also appears similar to that of other simians but different from that of prosimians and other mammals. Finally, V3 of owl monkeys shows a compartmental organization for orientation selectivity that remains to be demonstrated in other primates.