A ubiquitous spectrolaminar motif of local field potential power across the primate cortex.

The mammalian cerebral cortex is anatomically organized into a six-layer motif. It is currently unknown whether a corresponding laminar motif of neuronal activity patterns exists across the cortex. Here we report such a motif in the power of local field potentials (LFPs). Using laminar probes, we recorded LFPs from 14 cortical areas across the cortical hierarchy in five macaque monkeys. The laminar locations of recordings were histologically identified by electrolytic lesions. Across all areas, we found a ubiquitous spectrolaminar pattern characterized by an increasing deep-to-superficial layer gradient of high-frequency power peaking in layers 2/3 and an increasing superficial-to-deep gradient of alpha-beta power peaking in layers 5/6. Laminar recordings from additional species showed that the spectrolaminar pattern is highly preserved among primates-macaque, marmoset and human-but more dissimilar in mouse. Our results suggest the existence of a canonical layer-based and frequency-based mechanism for cortical computation.

A role for ocular dominance in binocular integration.

Neurons in the primate primary visual cortex (V1) combine left- and right-eye information to form a binocular output. Controversy surrounds whether ocular dominance, the preference of these neurons for one eye over the other, is functionally relevant. Here, we demonstrate that ocular dominance impacts gain control during binocular combination. We recorded V1 spiking activity while monkeys passively viewed grating stimuli. Gratings were either presented to one eye (monocular), both eyes with the same contrasts (binocular balanced), or both eyes with different contrasts (binocular imbalanced). We found that contrast placed in a neuron's dominant eye was weighted more strongly than contrast placed in a neuron's non-dominant eye. This asymmetry covaried with neurons' ocular dominance. We then tested whether accounting for ocular dominance within divisive normalization improves the fit to neural data. We found that ocular dominance significantly improved model performance, with interocular normalization providing the best fits. These findings suggest that V1 ocular dominance is relevant for response normalization during binocular stimulation.

Feedforward attentional selection in sensory cortex.

Salient objects grab attention because they stand out from their surroundings. Whether this phenomenon is accomplished by bottom-up sensory processing or requires top-down guidance is debated. We tested these alternative hypotheses by measuring how early and in which cortical layer(s) neural spiking distinguished a target from a distractor. We measured synaptic and spiking activity across cortical columns in mid-level area V4 of male macaque monkeys performing visual search for a color singleton. A neural signature of attentional capture was observed in the earliest response in the input layer 4. The magnitude of this response predicted response time and accuracy. Errant behavior followed errant selection. Because this response preceded top-down influences and arose in the cortical layer not targeted by top-down connections, these findings demonstrate that feedforward activation of sensory cortex can underlie attentional priority.

Does V1 response suppression initiate binocular rivalry?

During binocular rivalry (BR) only one eye's view is perceived. Neural underpinnings of BR are debated. Recent studies suggest that primary visual cortex (V1) initiates BR. One trigger might be response suppression across most V1 neurons at the onset of BR. Here, we utilize a variant of BR called binocular rivalry flash suppression (BRFS) to test this hypothesis. BRFS is identical to BR, except stimuli are shown with a ∼1s delay. If V1 response suppression was required to initiate BR, it should occur during BRFS as well. To test this, we compared V1 spiking in two macaques observing BRFS. We found that BRFS resulted in response facilitation rather than response suppression across V1 neurons. However, BRFS still reduces responses in a subset of V1 neurons due to the adaptive effects of asynchronous stimulus presentation. We argue that this selective response suppression could serve as an alternate initiator of BR.

Rapid adaptation of primate LGN neurons to drifting grating stimulation.

The visual system needs to dynamically adapt to changing environments. Much is known about the adaptive effects of constant stimulation over prolonged periods. However, there are open questions regarding adaptation to stimuli that are changing over time, interrupted, or repeated. Feature-specific adaptation to repeating stimuli has been shown to occur as early as primary visual cortex (V1), but there is also evidence for more generalized, fatigue-like adaptation that might occur at an earlier stage of processing. Here, we show adaptation in the lateral geniculate nucleus (LGN) of awake, fixating monkeys following brief (1 s) exposure to repeated cycles of a 4-Hz drifting grating. We examined the relative change of each neuron's response across successive (repeated) grating cycles. We found that neurons from all cell classes (parvocellular, magnocellular, and koniocellular) showed significant adaptation. However, only magnocellular neurons showed adaptation when responses were averaged to a population response. In contrast to firing rates, response variability was largely unaffected. Finally, adaptation was comparable between monocular and binocular stimulation, suggesting that rapid LGN adaptation is monocular in nature.NEW & NOTEWORTHY Neural adaptation can be defined as reduction of spiking responses following repeated or prolonged stimulation. Adaptation helps adjust neural responsiveness to avoid saturation and has been suggested to improve perceptual selectivity, information transmission, and predictive coding. Here, we report rapid adaptation to repeated cycles of gratings drifting over the receptive field of neurons at the earliest site of postretinal processing, the lateral geniculate nucleus of the thalamus.

Near-field potentials index local neural computations more accurately than population spiking.

Local field potentials (LFP) are low-frequency extracellular voltage fluctuations thought to primarily arise from synaptic activity. However, unlike highly localized neuronal spiking, LFP is spatially less specific. LFP measured at one location is not entirely generated there due to far-field contributions that are passively conducted across volumes of neural tissue. We sought to quantify how much information within the locally generated, near-field low-frequency activity (nfLFP) is masked by volume-conducted far-field signals. To do so, we measured laminar neural activity in primary visual cortex (V1) of monkeys viewing sequences of multifeatured stimuli. We compared information content of regular LFP and nfLFP that was mathematically stripped of volume-conducted far-field contributions. Information content was estimated by decoding stimulus properties from neural responses via spatiotemporal multivariate pattern analysis. Volume-conducted information differed from locally generated information in two important ways: (1) for stimulus features relevant to V1 processing (orientation and eye-of-origin), nfLFP contained more information. (2) in contrast, the volume-conducted signal was more informative regarding temporal context (relative stimulus position in a sequence), a signal likely to be coming from elsewhere. Moreover, LFP and nfLFP differed both spectrally as well as spatially, urging caution regarding the interpretations of individual frequency bands and/or laminar patterns of LFP. Most importantly, we found that population spiking of local neurons was less informative than either the LFP or nfLFP, with nfLFP containing most of the relevant information regarding local stimulus processing. These findings suggest that the optimal way to read out local computational processing from neural activity is to decode the local contributions to LFP, with significant information loss hampering both regular LFP and local spiking. Author's Contributions: Conceptualization, D.A.T., J.A.W, and A.M.; Data Collection, J.A.W., M.A.C., K.D.; Formal Analysis, D.A.T. and J.A.W.; Data Visualization, D.A.T. and J.A.W.; Original Draft, D.A.T., J.A.W., and A.M.; Revisions and Final Draft, D.A.T., J.A.W., M.A.C., K.D., M.T.W., A.M.B., and A.M. Competing Interests: The authors declare no conflicts of interest.

Shared Neural Activity But Distinct Neural Dynamics for Cognitive Control in Monkey Prefrontal and Parietal Cortex.

To better understand how prefrontal networks mediate forms of cognitive control disrupted in schizophrenia, we translated a variant of the AX continuous performance task that measures specific deficits in the human disease to 2 male monkeys and recorded neurons in PFC and parietal cortex during task performance. In the task, contextual information instructed by cue stimuli determines the response required to a subsequent probe stimulus. We found parietal neurons encoding the behavioral context instructed by cues that exhibited nearly identical activity to their prefrontal counterparts (Blackman et al., 2016). This neural population switched their preference for stimuli over the course of the trial depending on whether the stimuli signaled the need to engage cognitive control to override a prepotent response. Cues evoked visual responses that appeared in parietal neurons first, whereas population activity encoding contextual information instructed by cues was stronger and more persistent in PFC. Increasing cognitive control demand biased the representation of contextual information toward the PFC and augmented the temporal correlation of task-defined information encoded by neurons in the two areas. Oscillatory dynamics in local field potentials differed between cortical areas and carried as much information about task conditions as spike rates. We found that, at the single-neuron level, patterns of activity evoked by the task were nearly identical between the two cortical areas. Nonetheless, distinct population dynamics in PFC and parietal cortex were evident. suggesting differential contributions to cognitive control.SIGNIFICANCE STATEMENT We recorded neural activity in PFC and parietal cortex of monkeys performing a task that measures cognitive control deficits in schizophrenia. This allowed us to characterize computations performed by neurons in the two areas to support forms of cognitive control disrupted in the disease. Subpopulations of neurons in the two areas exhibited parallel modulations in firing rate; and as a result, all patterns of task-evoked activity were distributed between PFC and parietal cortex. This included the presence in both cortical areas of neurons reflecting proactive and reactive cognitive control dissociated from stimuli or responses in the task. However, differences in the timing, strength, synchrony, and correlation of information encoded by neural activity were evident, indicating differential contributions to cognitive control.

Resolving the mesoscopic missing link: Biophysical modeling of EEG from cortical columns in primates.

Event-related potentials (ERP) are among the most widely measured indices for studying human cognition. While their timing and magnitude provide valuable insights, their usefulness is limited by our understanding of their neural generators at the circuit level. Inverse source localization offers insights into such generators, but their solutions are not unique. To address this problem, scientists have assumed the source space generating such signals comprises a set of discrete equivalent current dipoles, representing the activity of small cortical regions. Based on this notion, theoretical studies have employed forward modeling of scalp potentials to understand how changes in circuit-level dynamics translate into macroscopic ERPs. However, experimental validation is lacking because it requires in vivo measurements of intracranial brain sources. Laminar local field potentials (LFP) offer a mechanism for estimating intracranial current sources. Yet, a theoretical link between LFPs and intracranial brain sources is missing. Here, we present a forward modeling approach for estimating mesoscopic intracranial brain sources from LFPs and predict their contribution to macroscopic ERPs. We evaluate the accuracy of this LFP-based representation of brain sources utilizing synthetic laminar neurophysiological measurements and then demonstrate the power of the approach in vivo to clarify the source of a representative cognitive ERP component. To that end, LFP was measured across the cortical layers of visual area V4 in macaque monkeys performing an attention demanding task. We show that area V4 generates dipoles through layer-specific transsynaptic currents that biophysically recapitulate the ERP component through the detailed forward modeling. The constraints imposed on EEG production by this method also revealed an important dissociation between computational and biophysical contributors. As such, this approach represents an important bridge between laminar microcircuitry, through the mesoscopic activity of cortical columns to the patterns of EEG we measure at the scalp.

Stimulating both eyes with matching stimuli enhances V1 responses.

Neurons in the primary visual cortex (V1) of primates play a key role in combining monocular inputs to form a binocular response. Although much has been gleaned from studying how V1 responds to discrepant (dichoptic) images, equally important is to understand how V1 responds to concordant (dioptic) images in the two eyes. Here, we investigated the extent to which concordant, balanced, zero-disparity binocular stimulation modifies V1 responses to varying stimulus contrast using intracranial multielectrode arrays. On average, binocular stimuli evoked stronger V1 activity than their monocular counterparts. This binocular facilitation scaled most proportionately with contrast during the initial transient. As V1 responses evolved, additional contrast-mediated dynamics emerged. Specifically, responses exhibited longer maintenance of facilitation for lower contrast and binocular suppression at high contrast. These results suggest that V1 processes concordant stimulation of both eyes in at least two sequential steps: initial response enhancement followed by contrast-dependent control of excitation.

Laminar microcircuitry of visual cortex producing attention-associated electric fields.

Cognitive operations are widely studied by measuring electric fields through EEG and ECoG. However, despite their widespread use, the neural circuitry giving rise to these signals remains unknown because the functional architecture of cortical columns producing attention-associated electric fields has not been explored. Here, we detail the laminar cortical circuitry underlying an attention-associated electric field measured over posterior regions of the brain in humans and monkeys. First, we identified visual cortical area V4 as one plausible contributor to this attention-associated electric field through inverse modeling of cranial EEG in macaque monkeys performing a visual attention task. Next, we performed laminar neurophysiological recordings on the prelunate gyrus and identified the electric-field-producing dipoles as synaptic activity in distinct cortical layers of area V4. Specifically, activation in the extragranular layers of cortex resulted in the generation of the attention-associated dipole. Feature selectivity of a given cortical column determined the overall contribution to this electric field. Columns selective for the attended feature contributed more to the electric field than columns selective for a different feature. Last, the laminar profile of synaptic activity generated by V4 was sufficient to produce an attention-associated signal measurable outside of the column. These findings suggest that the top-down recipient cortical layers produce an attention-associated electric field that can be measured extracortically with the relative contribution of each column depending upon the underlying functional architecture.

Pop-out search instigates beta-gated feature selectivity enhancement across V4 layers.

Visual search is a workhorse for investigating how attention interacts with processing of sensory information. Attentional selection has been linked to altered cortical sensory responses and feature preferences (i.e., tuning). However, attentional modulation of feature selectivity during search is largely unexplored. Here we map the spatiotemporal profile of feature selectivity during singleton search. Monkeys performed a search where a pop-out feature determined the target of attention. We recorded laminar neural responses from visual area V4. We first identified "feature columns" which showed preference for individual colors. In the unattended condition, feature columns were significantly more selective in superficial relative to middle and deep layers. Attending a stimulus increased selectivity in all layers but not equally. Feature selectivity increased most in the deep layers, leading to higher selectivity in extragranular layers as compared to the middle layer. This attention-induced enhancement was rhythmically gated in phase with the beta-band local field potential. Beta power dominated both extragranular laminar compartments, but current source density analysis pointed to an origin in superficial layers, specifically. While beta-band power was present regardless of attentional state, feature selectivity was only gated by beta in the attended condition. Neither the beta oscillation nor its gating of feature selectivity varied with microsaccade production. Importantly, beta modulation of neural activity predicted response times, suggesting a direct link between attentional gating and behavioral output. Together, these findings suggest beta-range synaptic activation in V4's superficial layers rhythmically gates attentional enhancement of feature tuning in a way that affects the speed of attentional selection.

Binocular Suppression in the Macaque Lateral Geniculate Nucleus Reveals Early Competitive Interactions between the Eyes.

The lateral geniculate nucleus (LGN) of the dorsal thalamus is the primary recipient of the two eyes' outputs. Most LGN neurons are monocular in that they are activated by visual stimulation through only one (dominant) eye. However, there are both intrinsic connections and inputs from binocular structures to the LGN that could provide these neurons with signals originating from the other (non-dominant) eye. Indeed, previous work introducing luminance differences across the eyes or using a single-contrast stimulus showed binocular modulation for single unit activity in anesthetized macaques and multiunit activity in awake macaques. Here, we sought to determine the influence of contrast viewed by both the non-dominant and dominant eyes on LGN single-unit responses in awake macaques. To do this, we adjusted each eye's signal strength by independently varying the contrast of stimuli presented to the two eyes. Specifically, we recorded LGN single unit spiking activity in two awake macaques while they viewed drifting gratings of varying contrast. We found that LGN neurons of all types [parvocellular (P), magnocellular (M), and koniocellular (K)] were significantly suppressed when stimuli were presented at low contrast to the dominant eye and at high contrast to the non-dominant eye. Further, the inputs of the two eyes showed antagonistic interaction, whereby the magnitude of binocular suppression diminished with high contrast in the dominant eye, or low contrast in the non-dominant eye. These results suggest that the LGN represents a site of precortical binocular processing involved in resolving discrepant contrast differences between the eyes.

Neural mechanism of priming in visual search.

Selective attention affords scrutinizing items in our environment. However, attentional selection changes over time and across space. Empirically, repetition of visual search conditions changes attentional processing. Priming of pop-out is a vivid example. Repeatedly searching for the same pop-out search feature is accomplished with faster response times and fewer errors. We review the psychophysical background of priming of pop-out, focusing on the hypothesis that it arises through changes in visual selective attention. We also describe research done with macaque monkeys to understand the neural mechanisms supporting visual selective attention and priming of pop-out, and survey research on priming of pop-out using noninvasive brain measures with humans. We conclude by hypothesizing three alternative neural mechanisms and highlighting open questions.

Stimulus Feature-Specific Information Flow Along the Columnar Cortical Microcircuit Revealed by Multivariate Laminar Spiking Analysis.

Most of the mammalian neocortex is comprised of a highly similar anatomical structure, consisting of a granular cell layer between superficial and deep layers. Even so, different cortical areas process different information. Taken together, this suggests that cortex features a canonical functional microcircuit that supports region-specific information processing. For example, the primate primary visual cortex (V1) combines the two eyes' signals, extracts stimulus orientation, and integrates contextual information such as visual stimulation history. These processes co-occur during the same laminar stimulation sequence that is triggered by the onset of visual stimuli. Yet, we still know little regarding the laminar processing differences that are specific to each of these types of stimulus information. Univariate analysis techniques have provided great insight by examining one electrode at a time or by studying average responses across multiple electrodes. Here we focus on multivariate statistics to examine response patterns across electrodes instead. Specifically, we applied multivariate pattern analysis (MVPA) to linear multielectrode array recordings of laminar spiking responses to decode information regarding the eye-of-origin, stimulus orientation, and stimulus repetition. MVPA differs from conventional univariate approaches in that it examines patterns of neural activity across simultaneously recorded electrode sites. We were curious whether this added dimensionality could reveal neural processes on the population level that are challenging to detect when measuring brain activity without the context of neighboring recording sites. We found that eye-of-origin information was decodable for the entire duration of stimulus presentation, but diminished in the deepest layers of V1. Conversely, orientation information was transient and equally pronounced along all layers. More importantly, using time-resolved MVPA, we were able to evaluate laminar response properties beyond those yielded by univariate analyses. Specifically, we performed a time generalization analysis by training a classifier at one point of the neural response and testing its performance throughout the remaining period of stimulation. Using this technique, we demonstrate repeating (reverberating) patterns of neural activity that have not previously been observed using standard univariate approaches.

Priming of Attentional Selection in Macaque Visual Cortex: Feature-Based Facilitation and Location-Based Inhibition of Return.

Visual search performance varies with stimulus and response history. Priming of pop-out refers to increased accuracy and reduced response time with repeated presentation of particular singleton and distractor features (e.g., a red target among green distractor stimuli), which are abruptly impaired when singleton and distractor features swap (e.g., green target among red distractors). Meanwhile, inhibition of return refers to the slowing of response time when target location repeats. Neurophysiological correlates of both these phenomena have been reported in the frontal eye field (FEF), an area in the frontal lobe contributing to attentional selection and eye movement planning. To understand the mechanistic origin of these adaptive behaviors, we investigated visual cortical area V4, an area providing input to and receiving feedback from FEF, during feature-based priming of pop-out and location-based inhibition of return. Performing a color pop-out task, monkeys exhibited pronounced priming of pop-out and inhibition of return. Neural spiking from V4 revealed earlier target selection associated with priming of pop-out and delayed selection associated with inhibition of return. These results demonstrate substantial involvement of extrastriate visual cortex in behavioral priming and inhibition of return.

Performance Monitoring during Visual Priming.

Repetitive performance of single-feature (efficient or pop-out) visual search improves RTs and accuracy. This phenomenon, known as priming of pop-out, has been demonstrated in both humans and macaque monkeys. We investigated the relationship between performance monitoring and priming of pop-out. Neuronal activity in the supplementary eye field (SEF) contributes to performance monitoring and to the generation of performance monitoring signals in the EEG. To determine whether priming depends on performance monitoring, we investigated spiking activity in SEF as well as the concurrent EEG of two monkeys performing a priming of pop-out task. We found that SEF spiking did not modulate with priming. Surprisingly, concurrent EEG did covary with priming. Together, these results suggest that performance monitoring contributes to priming of pop-out. However, this performance monitoring seems not mediated by SEF. This dissociation suggests that EEG indices of performance monitoring arise from multiple, functionally distinct neural generators.

Temporal dynamics of binocular integration in primary visual cortex.

Whenever we open our eyes, our brain quickly integrates the two eyes' perspectives into a combined view. This process of binocular integration happens so rapidly that even incompatible stimuli are briefly fused before one eye's view is suppressed in favor of the other (binocular rivalry). The neuronal basis for this brief period of fusion during incompatible binocular stimulation is unclear. Neuroanatomically, the eyes provide two largely separate streams of information that are integrated into a binocular response by the primary visual cortex (V1). However, the temporal dynamics underlying the formation of this binocular response are largely unknown. To address this question, we examined the temporal profile of binocular responses in V1 of fixating monkeys. We found that V1 processes binocular stimuli in a dynamic sequence that comprises at least two distinct temporal phases. An initial transient phase is characterized by enhanced spiking responses for both compatible and incompatible binocular stimuli compared to monocular stimulation. This transient is followed by a sustained response that differed markedly between congruent and incongruent binocular stimulation. Specifically, incompatible binocular stimulation resulted in overall response reduction relative to monocular stimulation (binocular suppression). In contrast, responses to compatible stimuli were either suppressed or enhanced (binocular facilitation) depending on the neurons' ocularity (selectivity for one eye over the other) and laminar location. These results suggest that binocular integration in V1 occurs in at least two sequential steps that comprise initial additive combination of the two eyes' signals followed by widespread differentiation between binocular concordance and discordance.

V1 microcircuit dynamics: altered signal propagation suggests intracortical origins for adaptation in response to visual repetition.

Repetitive visual stimulation profoundly changes sensory processing in the primary visual cortex (V1). We show how the associated adaptive changes are linked to an altered flow of synaptic activation across the V1 laminar microcircuit. Using repeated visual stimulation, we recorded layer-specific responses in V1 of two fixating monkeys. We found that repetition-related spiking suppression was most pronounced outside granular V1 layers that receive the main retinogeniculate input. This repetition-related response suppression was robust to alternating stimuli between the eyes, in line with the notion that repetition-related adaptation is predominantly of cortical origin. Most importantly, current source density (CSD) analysis, which provides an estimate of local net depolarization, revealed that synaptic processing during repeated stimulation was most profoundly affected within supragranular layers, which harbor the bulk of cortico-cortical connections. Direct comparison of the temporal evolution of laminar CSD and spiking activity showed that stimulus repetition first affected supragranular synaptic currents, which translated into a reduction of stimulus-evoked spiking across layers. Together, these results suggest that repetition induces an altered state of intracortical processing that underpins visual adaptation. NEW & NOTEWORTHY Our survival depends on our brains rapidly adapting to ever changing environments. A well-studied form of adaptation occurs whenever we encounter the same or similar stimuli repeatedly. We show that this repetition-related adaptation is supported by systematic changes in the flow of sensory activation across the laminar cortical microcircuitry of primary visual cortex. These results demonstrate how adaptation impacts neuronal interactions across cortical circuits.

Binocular Modulation of Monocular V1 Neurons.

In humans and other primates, sensory signals from each eye remain separated until they arrive in the primary visual cortex (V1), but their exact meeting point is unknown. In V1, some neurons respond to stimulation of only one eye (monocular neurons), while most neurons respond to stimulation of either eye (binocular neurons). The main input layers of V1 contain most of the monocular neurons while binocular neurons dominate the layers above and below. This observation has given rise to the idea that the two eyes' signals remain separate until they converge outside V1's input layers. Here, we show that, despite responding to only one eye, monocular neurons in all layers, including the input layers, of V1 discriminate between stimulation of their driving eye alone and stimulation of both eyes. Some monocular V1 neurons' responses were significantly enhanced, or facilitated, when both eyes were stimulated. Binocular facilitation within V1's input layers tended to occur at the onset of the visual response, which could be explained by converging thalamocortical inputs. However, most V1 monocular neurons were significantly reduced, or suppressed, to binocular stimulation. In contrast to facilitation, binocular suppression occurred several milliseconds following the onset of the visual response, suggesting that the bulk of binocular modulation involves cortical inhibition. These findings, combined, suggest that binocular signals arise at an earlier processing stage than previously appreciated, as even so-called monocular neurons in V1's input layers encode what is shown to both eyes.

Spiking Suppression Precedes Cued Attentional Enhancement of Neural Responses in Primary Visual Cortex.

Attending to a visual stimulus increases its detectability, even if gaze is directed elsewhere. This covert attentional selection is known to enhance spiking across many brain areas, including the primary visual cortex (V1). Here we investigate the temporal dynamics of attention-related spiking changes in V1 of macaques performing a task that separates attentional selection from the onset of visual stimulation. We found that preceding attentional enhancement there was a sharp, transient decline in spiking following presentation of an attention-guiding cue. This disruption of V1 spiking was not observed in a task-naïve subject that passively observed the same stimulus sequence, suggesting that sensory activation is insufficient to cause suppression. Following this suppression, attended stimuli evoked more spiking than unattended stimuli, matching previous reports of attention-related activity in V1. Laminar analyses revealed a distinct pattern of activation in feedback-associated layers during both the cue-induced suppression and subsequent attentional enhancement. These findings suggest that top-down modulation of V1 spiking can be bidirectional and result in either suppression or enhancement of spiking responses.