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.

Mesoscopic calcium imaging in a head-unrestrained male non-human primate using a lensless microscope.

Mesoscopic calcium imaging enables studies of cell-type specific neural activity over large areas. A growing body of literature suggests that neural activity can be different when animals are free to move compared to when they are restrained. Unfortunately, existing systems for imaging calcium dynamics over large areas in non-human primates (NHPs) are table-top devices that require restraint of the animal's head. Here, we demonstrate an imaging device capable of imaging mesoscale calcium activity in a head-unrestrained male non-human primate. We successfully miniaturize our system by replacing lenses with an optical mask and computational algorithms. The resulting lensless microscope can fit comfortably on an NHP, allowing its head to move freely while imaging. We are able to measure orientation columns maps over a 20 mm2 field-of-view in a head-unrestrained macaque. Our work establishes mesoscopic imaging using a lensless microscope as a powerful approach for studying neural activity under more naturalistic conditions.

Invited Session IV: Studies of the visual cortex with sub-millimeter resolution: Toward an all-optical bi-directional interrogation of topographic population codes in primate cortex.

The representation of visual stimuli in primate V1 is widely distributed and topographic. This raises the possibility that in some visual tasks, downstream areas that decode V1 signals in order to mediate perception could combine V1 signals at a relevant topographic scale-e.g., at the scale of orientation columns. If this were the case, then the fundamental unit of information would be individual columns rather than single neurons, and to account for the subject's behavior in a perceptual task, it would be necessary and sufficient to consider the summed activity of the thousands of neurons within each column. In this presentation I will discuss our initial attempts to test this topographic-code hypothesis using our optical-genetic toolbox for "reading" and "writing" neural population codes at the spatial scales of topographic maps in V1 of behaving macaques.

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.

Exact analysis of the subthreshold variability for conductance-based neuronal models with synchronous synaptic inputs.

The spiking activity of neocortical neurons exhibits a striking level of variability, even when these networks are driven by identical stimuli. The approximately Poisson firing of neurons has led to the hypothesis that these neural networks operate in the asynchronous state. In the asynchronous state neurons fire independently from one another, so that the probability that a neuron experience synchronous synaptic inputs is exceedingly low. While the models of asynchronous neurons lead to observed spiking variability, it is not clear whether the asynchronous state can also account for the level of subthreshold membrane potential variability. We propose a new analytical framework to rigorously quantify the subthreshold variability of a single conductance-based neuron in response to synaptic inputs with prescribed degrees of synchrony. Technically we leverage the theory of exchangeability to model input synchrony via jump-process-based synaptic drives; we then perform a moment analysis of the stationary response of a neuronal model with all-or-none conductances that neglects post-spiking reset. As a result, we produce exact, interpretable closed forms for the first two stationary moments of the membrane voltage, with explicit dependence on the input synaptic numbers, strengths, and synchrony. For biophysically relevant parameters, we find that the asynchronous regime only yields realistic subthreshold variability (voltage variance ≅ 4-9mV 2 ) when driven by a restricted number of large synapses, compatible with strong thalamic drive. By contrast, we find that achieving realistic subthreshold variability with dense cortico-cortical inputs requires including weak but nonzero input synchrony, consistent with measured pairwise spiking correlations. We also show that without synchrony, the neural variability averages out to zero for all scaling limits with vanishing synaptic weights, independent of any balanced state hypothesis. This result challenges the theoretical basis for mean-field theories of the asynchronous state.

Exact analysis of the subthreshold variability for conductance-based neuronal models with synchronous synaptic inputs.

The spiking activity of neocortical neurons exhibits a striking level of variability, even when these networks are driven by identical stimuli. The approximately Poisson firing of neurons has led to the hypothesis that these neural networks operate in the asynchronous state. In the asynchronous state neurons fire independently from one another, so that the probability that a neuron experience synchronous synaptic inputs is exceedingly low. While the models of asynchronous neurons lead to observed spiking variability, it is not clear whether the asynchronous state can also account for the level of subthreshold membrane potential variability. We propose a new analytical framework to rigorously quantify the subthreshold variability of a single conductance-based neuron in response to synaptic inputs with prescribed degrees of synchrony. Technically we leverage the theory of exchangeability to model input synchrony via jump-process-based synaptic drives; we then perform a moment analysis of the stationary response of a neuronal model with all-or-none conductances that neglects post-spiking reset. As a result, we produce exact, interpretable closed forms for the first two stationary moments of the membrane voltage, with explicit dependence on the input synaptic numbers, strengths, and synchrony. For biophysically relevant parameters, we find that the asynchronous regime only yields realistic subthreshold variability (voltage variance ≃4-9mV2) when driven by a restricted number of large synapses, compatible with strong thalamic drive. By contrast, we find that achieving realistic subthreshold variability with dense cortico-cortical inputs requires including weak but nonzero input synchrony, consistent with measured pairwise spiking correlations. We also show that without synchrony, the neural variability averages out to zero for all scaling limits with vanishing synaptic weights, independent of any balanced state hypothesis. This result challenges the theoretical basis for mean-field theories of the asynchronous state.

Similar neural and perceptual masking effects of low-power optogenetic stimulation in primate V1.

Can direct stimulation of primate V1 substitute for a visual stimulus and mimic its perceptual effect? To address this question, we developed an optical-genetic toolkit to 'read' neural population responses using widefield calcium imaging, while simultaneously using optogenetics to 'write' neural responses into V1 of behaving macaques. We focused on the phenomenon of visual masking, where detection of a dim target is significantly reduced by a co-localized medium-brightness mask (Cornsweet and Pinsker, 1965; Whittle and Swanston, 1974). Using our toolkit, we tested whether V1 optogenetic stimulation can recapitulate the perceptual masking effect of a visual mask. We find that, similar to a visual mask, low-power optostimulation can significantly reduce visual detection sensitivity, that a sublinear interaction between visual- and optogenetic-evoked V1 responses could account for this perceptual effect, and that these neural and behavioral effects are spatially selective. Our toolkit and results open the door for further exploration of perceptual substitutions by direct stimulation of sensory cortex.

Dendritic calcium signals in rhesus macaque motor cortex drive an optical brain-computer interface.

Calcium imaging is a powerful tool for recording from large populations of neurons in vivo. Imaging in rhesus macaque motor cortex can enable the discovery of fundamental principles of motor cortical function and can inform the design of next generation brain-computer interfaces (BCIs). Surface two-photon imaging, however, cannot presently access somatic calcium signals of neurons from all layers of macaque motor cortex due to photon scattering. Here, we demonstrate an implant and imaging system capable of chronic, motion-stabilized two-photon imaging of neuronal calcium signals from macaques engaged in a motor task. By imaging apical dendrites, we achieved optical access to large populations of deep and superficial cortical neurons across dorsal premotor (PMd) and gyral primary motor (M1) cortices. Dendritic signals from individual neurons displayed tuning for different directions of arm movement. Combining several technical advances, we developed an optical BCI (oBCI) driven by these dendritic signalswhich successfully decoded movement direction online. By fusing two-photon functional imaging with CLARITY volumetric imaging, we verified that many imaged dendrites which contributed to oBCI decoding originated from layer 5 output neurons, including a putative Betz cell. This approach establishes new opportunities for studying motor control and designing BCIs via two photon imaging.

Similar masking effects of natural backgrounds on detection performances in humans, macaques, and macaque-V1 population responses.

Visual systems evolve to process the stimuli that arise in the organism's natural environment, and hence, to fully understand the neural computations in the visual system, it is important to measure behavioral and neural responses to natural visual stimuli. Here, we measured psychometric and neurometric functions in the macaque monkey for detection of a windowed sine-wave target in uniform backgrounds and in natural backgrounds of various contrasts. The neurometric functions were obtained by near-optimal decoding of voltage-sensitive-dye-imaging (VSDI) responses at the retinotopic scale in primary visual cortex (V1). The results were compared with previous human psychophysical measurements made under the same conditions. We found that human and macaque behavioral thresholds followed the generalized Weber's law as function of contrast, and that both the slopes and the intercepts of the threshold as a function of background contrast match each other up to a single scale factor. We also found that the neurometric thresholds followed the generalized Weber's law with slopes and intercepts matching the behavioral slopes and intercepts up to a single scale factor. We conclude that human and macaque ability to detect targets in natural backgrounds are affected in the same way by background contrast, that these effects are consistent with population decoding at the retinotopic scale by down-stream circuits, and that the macaque monkey is an appropriate animal model for gaining an understanding of the neural mechanisms in humans for detecting targets in natural backgrounds. Finally, we discuss limitations of the current study and potential next steps.NEW & NOTEWORTHY We measured macaque detection performance in natural images and compared their performance to the detection sensitivity of neurophysiological responses recorded in the primary visual cortex (V1), and to the performance of human subjects. We found that 1) human and macaque behavioral performances are in quantitative agreement and 2) are consistent with near-optimal decoding of V1 population responses.

Voltage-Gated Intrinsic Conductances Shape the Input-Output Relationship of Cortical Neurons in Behaving Primate V1.

Neurons are input-output (I/O) devices-they receive synaptic inputs from other neurons, integrate those inputs with their intrinsic properties, and generate action potentials as outputs. To understand this fundamental process, we studied the interaction between synaptic inputs and intrinsic properties using whole-cell recordings from V1 neurons of awake, fixating macaque monkeys. Our measurements during spontaneous activity and visual stimulation reveal an intrinsic voltage-gated conductance that profoundly alters the integrative properties and visual responses of cortical neurons. This voltage-gated conductance increases neuronal gain and selectivity with subthreshold depolarization and linearizes the relationship between synaptic input and neural output. This intrinsic conductance is found in layer 2/3 V1 neurons of awake macaques, anesthetized mice, and acute brain slices. These results demonstrate that intrinsic conductances play an essential role in shaping the I/O relationship of cortical neurons and must be taken into account in future models of cortical computations.

Functional Access to Neuron Subclasses in Rodent and Primate Forebrain.

Viral vectors enable foreign proteins to be expressed in brains of non-genetic species, including non-human primates. However, viruses targeting specific neuron classes have proved elusive. Here we describe viral promoters and strategies for accessing GABAergic interneurons and their molecularly defined subsets in the rodent and primate. Using a set intersection approach, which relies on two co-active promoters, we can restrict heterologous protein expression to cortical and hippocampal somatostatin-positive and parvalbumin-positive interneurons. With an orthogonal set difference method, we can enrich for subclasses of neuropeptide-Y-positive GABAergic interneurons by effectively subtracting the expression pattern of one promoter from that of another. These methods harness the complexity of gene expression patterns in the brain and significantly expand the number of genetically tractable neuron classes across mammals.

Scale-Invariant Visual Capabilities Explained by Topographic Representations of Luminance and Texture in Primate V1.

Humans have remarkable scale-invariant visual capabilities. For example, our orientation discrimination sensitivity is largely constant over more than two orders of magnitude of variations in stimulus spatial frequency (SF). Orientation-selective V1 neurons are likely to contribute to orientation discrimination. However, because at any V1 location neurons have a limited range of receptive field (RF) sizes, we predict that at low SFs V1 neurons will carry little orientation information. If this were the case, what could account for the high behavioral sensitivity at low SFs? Using optical imaging in behaving macaques, we show that, as predicted, V1 orientation-tuned responses drop rapidly with decreasing SF. However, we reveal a surprising coarse-scale signal that corresponds to the projection of the luminance layout of low-SF stimuli to V1's retinotopic map. This homeomorphic and distributed representation, which carries high-quality orientation information, is likely to contribute to our striking scale-invariant visual capabilities.

Nonlinear Lateral Interactions in V1 Population Responses Explained by a Contrast Gain Control Model.

How do cortical responses to local image elements combine to form a spatial pattern of population activity in primate V1? Here, we used voltage-sensitive dye imaging, which measures summed membrane potential activity, to examine the rules that govern lateral interactions between the representations of two small local-oriented elements in macaque (Macaca mulatta) V1. We find strong subadditive and mostly orientation-independent interactions for nearby elements [2-4 mm interelement cortical distance (IED)] that gradually become linear at larger separations (>6 mm IED). These results are consistent with a population gain control model describing nonlinear V1 population responses to single oriented elements. However, because of the membrane potential-to-spiking accelerating nonlinearity, the model predicts supra-additive lateral interactions of spiking responses for intermediate separations at a range of locations between the two elements, consistent with some prior facilitatory effects observed in electrophysiology and psychophysics. Overall, our results suggest that population-level lateral interactions in V1 are primarily explained by a simple orientation-independent contrast gain control mechanism.SIGNIFICANCE STATEMENT Interactions between representations of simple visual elements such as oriented edges in primary visual cortex (V1) are thought to contribute to our ability to easily integrate contours and segment surfaces, but the mechanisms that govern these interactions are primarily unknown. Our study provides novel evidence that lateral interactions at the population level are governed by a simple contrast gain-control mechanism, and we show how this divisive gain-control mechanism can give rise to apparently facilitatory spiking responses.

Linking V1 Activity to Behavior.

A long-term goal of visual neuroscience is to develop and test quantitative models that account for the moment-by-moment relationship between neural responses in early visual cortex and human performance in natural visual tasks. This review focuses on efforts to address this goal by measuring and perturbing the activity of primary visual cortex (V1) neurons while nonhuman primates perform demanding, well-controlled visual tasks. We start by describing a conceptual approach-the decoder linking model (DLM) framework-in which candidate decoding models take neural responses as input and generate predicted behavior as output. The ultimate goal in this framework is to find the actual decoder-the model that best predicts behavior from neural responses. We discuss key relevant properties of primate V1 and review current literature from the DLM perspective. We conclude by discussing major technological and theoretical advances that are likely to accelerate our understanding of the link between V1 activity and behavior.

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.

Long-range traveling waves of activity triggered by local dichoptic stimulation in V1 of behaving monkeys.

Traveling waves of cortical activity, in which local stimulation triggers lateral spread of activity to distal locations, have been hypothesized to play an important role in cortical function. However, there is conflicting physiological evidence for the existence of spreading traveling waves of neural activity triggered locally. Dichoptic stimulation, in which the two eyes view dissimilar monocular patterns, can lead to dynamic wave-like fluctuations in visual perception and therefore, provides a promising means for identifying and studying cortical traveling waves. Here, we used voltage-sensitive dye imaging to test for the existence of traveling waves of activity in the primary visual cortex of awake, fixating monkeys viewing dichoptic stimuli. We find clear traveling waves that are initiated by brief, localized contrast increments in one of the monocular patterns and then, propagate at speeds of ∼ 30 mm/s. These results demonstrate that under an appropriate visual context, circuitry in visual cortex in alert animals is capable of supporting long-range traveling waves triggered by local stimulation.

Sensory stimulation shifts visual cortex from synchronous to asynchronous states.

In the mammalian cerebral cortex, neural responses are highly variable during spontaneous activity and sensory stimulation. To explain this variability, the cortex of alert animals has been proposed to be in an asynchronous high-conductance state in which irregular spiking arises from the convergence of large numbers of uncorrelated excitatory and inhibitory inputs onto individual neurons. Signatures of this state are that a neuron's membrane potential (Vm) hovers just below spike threshold, and its aggregate synaptic input is nearly Gaussian, arising from many uncorrelated inputs. Alternatively, irregular spiking could arise from infrequent correlated input events that elicit large fluctuations in Vm (refs 5, 6). To distinguish between these hypotheses, we developed a technique to perform whole-cell Vm measurements from the cortex of behaving monkeys, focusing on primary visual cortex (V1) of monkeys performing a visual fixation task. Here we show that, contrary to the predictions of an asynchronous state, mean Vm during fixation was far from threshold (14 mV) and spiking was triggered by occasional large spontaneous fluctuations. Distributions of Vm values were skewed beyond that expected for a range of Gaussian input, but were consistent with synaptic input arising from infrequent correlated events. Furthermore, spontaneous fluctuations in Vm were correlated with the surrounding network activity, as reflected in simultaneously recorded nearby local field potential. Visual stimulation, however, led to responses more consistent with an asynchronous state: mean Vm approached threshold, fluctuations became more Gaussian, and correlations between single neurons and the surrounding network were disrupted. These observations show that sensory drive can shift a common cortical circuitry from a synchronous to an asynchronous state.

An illusion predicted by V1 population activity implicates cortical topography in shape perception.

Mammalian primary visual cortex (V1) is topographically organized such that the pattern of neural activation in V1 reflects the location and spatial extent of visual elements in the retinal image, but it is unclear whether this organization contributes to visual perception. We combined computational modeling, voltage-sensitive dye imaging (VSDI) in behaving monkeys and behavioral measurements in humans to investigate whether the large-scale topography of V1 population responses influences shape judgments. Specifically, we used a computational model to design visual stimuli that had the same physical shape, but were predicted to elicit variable V1 response spread. We confirmed these predictions with VSDI. Finally, we designed a behavioral task in which human observers judged the shapes of these stimuli and found that their judgments were systematically distorted by the spread of V1 activity. This illusion suggests that the topographic pattern of neural population responses in visual cortex contributes to visual perception.

Attentional modulations related to spatial gating but not to allocation of limited resources in primate V1.

Attention can modulate neural responses in sensory cortical areas and improve behavioral performance in perceptual tasks. However, the nature and purpose of these modulations remain under debate. Here we used voltage-sensitive dye imaging (VSDI) to measure V1 population responses while monkeys performed a difficult detection task under focal or distributed attention. We found that V1 responses at attended locations are significantly elevated relative to actively ignored or irrelevant locations, consistent with the hypothesis that an important goal of attention in V1 is to highlight task-relevant information. Surprisingly, these modulations were indistinguishable under focal and distributed attention, suggesting a minor or no role for attention as a mechanism for allocating limited representational resources in V1. The response elevation at attended locations is additive, is widespread, and starts shortly before stimulus onset. This elevation could contribute to spatial gating by biasing competition in subsequent processing stages in favor of attended stimuli.