Data-driven multiscale model of macaque auditory thalamocortical circuits reproduces in vivo dynamics.

We developed a detailed model of macaque auditory thalamocortical circuits, including primary auditory cortex (A1), medial geniculate body (MGB), and thalamic reticular nucleus, utilizing the NEURON simulator and NetPyNE tool. The A1 model simulates a cortical column with over 12,000 neurons and 25 million synapses, incorporating data on cell-type-specific neuron densities, morphology, and connectivity across six cortical layers. It is reciprocally connected to the MGB thalamus, which includes interneurons and core and matrix-layer-specific projections to A1. The model simulates multiscale measures, including physiological firing rates, local field potentials (LFPs), current source densities (CSDs), and electroencephalography (EEG) signals. Laminar CSD patterns, during spontaneous activity and in response to broadband noise stimulus trains, mirror experimental findings. Physiological oscillations emerge spontaneously across frequency bands comparable to those recorded in vivo. We elucidate population-specific contributions to observed oscillation events and relate them to firing and presynaptic input patterns. The model offers a quantitative theoretical framework to integrate and interpret experimental data and predict its underlying cellular and circuit mechanisms.

Saccadic inhibition during free viewing in macaque monkeys.

Through the process of saccadic inhibition, visual events briefly suppress eye movements including microsaccades. In humans, saccadic inhibition has been shown to occur in response to the presentation of parafoveal or peripheral visual distractors during fixation and target-directed saccades and to physical changes of behaviorally relevant visual objects. In monkeys performing tasks that controlled eye movements, saccadic inhibition of microsaccades and target-directed saccades has been shown. Using eye data from three previously published studies, we investigated how saccade rate changed while monkeys were presented with visual stimuli under conditions with loose or no viewing demands. In two conditions, animals passively sat while an LED lamp flashed or screen-wide images appeared in front of them. In the third condition, images were repeated semiperiodically while animals had to maintain their gaze within a wide rectangular area and detect oddballs. Despite animals not being required to maintain fixation or make saccades to particular targets, the onset of visual events led to a temporary reduction of saccade rate across all conditions. Interestingly, saccadic inhibition was found at image offsets as well. These results show that saccadic inhibition occurs in monkeys during free viewing.NEW & NOTEWORTHY We investigated the time courses of saccade rate following visual stimuli during three conditions of free viewing in macaque monkeys. Under all conditions, saccade rate decreased transiently after the onset of visual stimuli. These results suggest that saccadic inhibition occurs during free viewing.

Detecting Spontaneous Neural Oscillation Events in Primate Auditory Cortex.

Electrophysiological oscillations in the brain have been shown to occur as multicycle events, with onset and offset dependent on behavioral and cognitive state. To provide a baseline for state-related and task-related events, we quantified oscillation features in resting-state recordings. We developed an open-source wavelet-based tool to detect and characterize such oscillation events (OEvents) and exemplify the use of this tool in both simulations and two invasively-recorded electrophysiology datasets: one from human, and one from nonhuman primate (NHP) auditory system. After removing incidentally occurring event-related potentials (ERPs), we used OEvents to quantify oscillation features. We identified ∼2 million oscillation events, classified within traditional frequency bands: δ, θ, α, ß, low γ, γ, and high γ. Oscillation events of 1-44 cycles could be identified in at least one frequency band 90% of the time in human and NHP recordings. Individual oscillation events were characterized by nonconstant frequency and amplitude. This result necessarily contrasts with prior studies which assumed frequency constancy, but is consistent with evidence from event-associated oscillations. We measured oscillation event duration, frequency span, and waveform shape. Oscillations tended to exhibit multiple cycles per event, verifiable by comparing filtered to unfiltered waveforms. In addition to the clear intraevent rhythmicity, there was also evidence of interevent rhythmicity within bands, demonstrated by finding that coefficient of variation of interval distributions and Fano factor (FF) measures differed significantly from a Poisson distribution assumption. Overall, our study provides an easy-to-use tool to study oscillation events at the single-trial level or in ongoing recordings, and demonstrates that rhythmic, multicycle oscillation events dominate auditory cortical dynamics.

Cross Laminar Traveling Components of Field Potentials due to Volume Conduction of Non-Traveling Neuronal Activity in Macaque Sensory Cortices.

Field potentials (FPs) reflect neuronal activities in the brain, and often exhibit traveling peaks across recording sites. While traveling FPs are interpreted as propagation of neuronal activity, not all studies directly reveal such propagating patterns of neuronal activation. Neuronal activity is associated with transmembrane currents that form dipoles and produce negative and positive fields. Thereby, FP components reverse polarity between those fields and have minimal amplitudes at the center of dipoles. Although their amplitudes could be smaller, FPs are never flat even around these reversals. What occurs around the reversal has not been addressed explicitly, although those are rationally in the middle of active neurons. We show that sensory FPs around the reversal appeared with peaks traveling across cortical laminae in macaque sensory cortices. Interestingly, analyses of current source density did not depict traveling patterns but lamina-delimited current sinks and sources. We simulated FPs produced by volume conduction of a simplified 2 dipoles' model mimicking sensory cortical laminar current source density components. While FPs generated by single dipoles followed the temporal patterns of the dipole moments without traveling peaks, FPs generated by concurrently active dipole moments appeared with traveling components in the vicinity of dipoles by superimposition of individually non-traveling FPs generated by single dipoles. These results indicate that not all traveling FP are generated by traveling neuronal activity, and that recording positions need to be taken into account to describe FP peak components around active neuronal populations.SIGNIFICANCE STATEMENT Field potentials (FPs) generated by neuronal activity in the brain occur with fields of opposite polarity. Likewise, in the cerebral cortices, they have mirror-imaged waveforms in upper and lower layers. We show that FPs appear like traveling across the cortical layers. Interestingly, the traveling FPs occur without traveling components of current source density, which represents transmembrane currents associated with neuronal activity. These seemingly odd findings are explained using current source density models of multiple dipoles. Concurrently active, non-traveling dipoles produce FPs as mixtures of FPs produced by individual dipoles, and result in traveling FP waveforms as the mixing ratio depends on the distances from those dipoles. The results suggest that not all traveling FP components are associated with propagating neuronal activity.

The Role of Motor and Environmental Visual Rhythms in Structuring Auditory Cortical Excitability.

Previous studies indicate that motor sampling patterns modulate neuronal excitability in sensory brain regions by entraining brain rhythms, a process termed motor-initiated entrainment. In addition, rhythms of the external environment are also capable of entraining brain rhythms. Our first goal was to investigate the properties of motor-initiated entrainment in the auditory system using a prominent visual motor sampling pattern in primates, saccades. Second, we wanted to determine whether/how motor-initiated entrainment interacts with visual environmental entrainment. We examined laminar profiles of neuronal ensemble activity in primary auditory cortex and found that whereas motor-initiated entrainment has a suppressive effect, visual environmental entrainment has an enhancive effect. We also found that these processes are temporally coupled, and their temporal relationship ensures that their effect on excitability is complementary rather than interfering. Altogether, our results demonstrate that motor and sensory systems continuously interact in orchestrating the brain's context for the optimal sampling of our multisensory environment.

Dissociation of broadband high-frequency activity and neuronal firing in the neocortex.

Broadband high-frequency activity (BHA; 70 to 150 Hz), also known as "high gamma," a key analytic signal in human intracranial (electrocorticographic) recordings, is often assumed to reflect local neural firing [multiunit activity (MUA)]. As the precise physiological substrates of BHA are unknown, this assumption remains controversial. Our analysis of laminar multielectrode data from V1 and A1 in monkeys outlines two components of stimulus-evoked BHA distributed across the cortical layers: an "early-deep" and "late-superficial" response. Early-deep BHA has a clear spatial and temporal overlap with MUA. Late-superficial BHA was more prominent and accounted for more of the BHA signal measured near the cortical pial surface. However, its association with local MUA is weak and often undetectable, consistent with the view that it reflects dendritic processes separable from local neuronal firing.

The Thalamocortical Circuit of Auditory Mismatch Negativity.

BACKGROUND: Mismatch negativity (MMN) is an extensively validated biomarker of cognitive function across both normative and clinical populations and has previously been localized to supratemporal auditory cortex. MMN is thought to represent a comparison of the features of the present stimulus versus a mnemonic template formed by the prior stimuli. METHODS: We used concurrent thalamic and primary auditory cortical (A1) laminar recordings in 7 macaques to evaluate the relative contributions of core (lemniscal) and matrix (nonlemniscal) thalamic afferents to MMN generation. RESULTS: We demonstrated that deviance-related activity is observed mainly in matrix regions of auditory thalamus, MMN generators are most prominent in layer 1 of cortex as opposed to sensory responses that activate layer 4 first and sequentially all cortical layers, and MMN is elicited independent of the frequency tuning of A1 neuronal ensembles. Consistent with prior reports, MMN-related thalamocortical activity was strongly inhibited by ketamine. CONCLUSIONS: Taken together, our results demonstrate distinct matrix versus core thalamocortical circuitry underlying the generation of a higher-order brain response (MMN) versus sensory responses.

Dynamic Modulation of Cortical Excitability during Visual Active Sensing.

Visual physiology is traditionally investigated by presenting stimuli with gaze held constant. However, during active viewing of a scene, information is actively acquired using systematic patterns of fixations and saccades. Prior studies suggest that during such active viewing, both nonretinal, saccade-related signals and "extra-classical" receptive field inputs modulate visual processing. This study used a set of active viewing tasks that allowed us to compare visual responses with and without direct foveal input, thus isolating the contextual eye movement-related influences. Studying nonhuman primates, we find strong contextual modulation in primary visual cortex (V1): excitability and response amplification immediately after fixation onset, transiting to suppression leading up to the next saccade. Time-frequency decomposition suggests that this amplification and suppression cycle stems from a phase reset of ongoing neuronal oscillatory activity. The impact of saccade-related contextual modulation on stimulus processing makes active visual sensing fundamentally different from the more passive processes investigated in traditional paradigms.

Top-down, contextual entrainment of neuronal oscillations in the auditory thalamocortical circuit.

Prior studies have shown that repetitive presentation of acoustic stimuli results in an alignment of ongoing neuronal oscillations to the sequence rhythm via oscillatory entrainment by external cues. Our study aimed to explore the neural correlates of the perceptual parsing and grouping of complex repeating auditory patterns that occur based solely on statistical regularities, or context. Human psychophysical studies suggest that the recognition of novel auditory patterns amid a continuous auditory stimulus sequence occurs automatically halfway through the first repetition. We hypothesized that once repeating patterns were detected by the brain, internal rhythms would become entrained, demarcating the temporal structure of these repetitions despite lacking external cues defining pattern on- or offsets. To examine the neural correlates of pattern perception, neuroelectric activity of primary auditory cortex (A1) and thalamic nuclei was recorded while nonhuman primates passively listened to streams of rapidly presented pure tones and bandpass noise bursts. At arbitrary intervals, random acoustic patterns composed of 11 stimuli were repeated five times without any perturbance of the constant stimulus flow. We found significant delta entrainment by these patterns in the A1, medial geniculate body, and medial pulvinar. In A1 and pulvinar, we observed a statistically significant, pattern structure-aligned modulation of neuronal firing that occurred earliest in the pulvinar, supporting the idea that grouping and detecting complex auditory patterns is a top-down, context-driven process. Besides electrophysiological measures, a pattern-related modulation of pupil diameter verified that, like humans, nonhuman primates consciously detect complex repetitive patterns that lack physical boundaries.

Global dynamics of selective attention and its lapses in primary auditory cortex.

Previous research demonstrated that while selectively attending to relevant aspects of the external world, the brain extracts pertinent information by aligning its neuronal oscillations to key time points of stimuli or their sampling by sensory organs. This alignment mechanism is termed oscillatory entrainment. We investigated the global, long-timescale dynamics of this mechanism in the primary auditory cortex of nonhuman primates, and hypothesized that lapses of entrainment would correspond to lapses of attention. By examining electrophysiological and behavioral measures, we observed that besides the lack of entrainment by external stimuli, attentional lapses were also characterized by high-amplitude alpha oscillations, with alpha frequency structuring of neuronal ensemble and single-unit operations. Entrainment and alpha-oscillation-dominated periods were strongly anticorrelated and fluctuated rhythmically at an ultra-slow rate. Our results indicate that these two distinct brain states represent externally versus internally oriented computational resources engaged by large-scale task-positive and task-negative functional networks.

Pondering the Pulvinar.

While the function of the pulvinar remains one of the least explored among the thalamic nuclei despite occupying the most thalamic volume in primates, it has long been suspected to play a crucial role in attentive stimulus processing. In this issue of Neuron, Zhou et al. (2016) use simultaneous pulvinar-visual cortex recordings and pulvinar inactivation to provide evidence that the pulvinar is essential for intact stimulus processing, maintenance of neuronal oscillatory dynamics, and mediating the effects of attention.

Laminar Profile and Physiology of the α Rhythm in Primary Visual, Auditory, and Somatosensory Regions of Neocortex.

The functional significance of the α rhythm is widely debated. It has been proposed that α reflects sensory inhibition and/or a temporal sampling or "parsing" mechanism. There is also continuing disagreement over the more fundamental questions of which cortical layers generate α rhythms and whether the generation of α is equivalent across sensory systems. To address these latter questions, we analyzed laminar profiles of local field potentials (LFPs) and concomitant multiunit activity (MUA) from macaque V1, S1, and A1 during both spontaneous activity and sensory stimulation. Current source density (CSD) analysis of laminar LFP profiles revealed α current generators in the supragranular, granular, and infragranular layers. MUA phase-locked to local current source/sink configurations confirmed that α rhythms index local neuronal excitability fluctuations. CSD-defined α generators were strongest in the supragranular layers, whereas LFP α power was greatest in the infragranular layers, consistent with some of the previous reports. The discrepancy between LFP and CSD findings appears to be attributable to contamination of the infragranular LFP signal by activity that is volume-conducted from the stronger supragranular α generators. The presence of α generators across cortical depth in V1, S1, and A1 suggests the involvement of α in feedforward as well as feedback processes and is consistent with the view that α rhythms, perhaps in addition to a role in sensory inhibition, may parse sensory input streams in a way that facilitates communication across cortical areas. SIGNIFICANCE STATEMENT: The α rhythm is thought to reflect sensory inhibition and/or a temporal parsing mechanism. Here, we address two outstanding issues: (1) whether α is a general mechanism across sensory systems and (2) which cortical layers generate α oscillations. Using intracranial recordings from macaque V1, S1, and A1, we show α band activity with a similar spectral and laminar profile in each of these sensory areas. Furthermore, α generators were present in each of the cortical layers, with a strong source in superficial layers. We argue that previous findings, locating α generators exclusively in the deeper layers, were biased because of use of less locally specific local field potential measurements. The laminar distribution of α band activity appears more complex than generally assumed.

Layer specific sharpening of frequency tuning by selective attention in primary auditory cortex.

Recent electrophysiological and neuroimaging studies provide converging evidence that attending to sounds increases the response selectivity of neuronal ensembles even at the first cortical stage of auditory stimulus processing in primary auditory cortex (A1). This is achieved by enhancement of responses in the regions that process attended frequency content, and by suppression of responses in the surrounding regions. The goals of our study were to define the extent to which A1 neuronal ensembles are involved in this process, determine its effect on the frequency tuning of A1 neuronal ensembles, and examine the involvement of the different cortical layers. To accomplish these, we analyzed laminar profiles of synaptic activity and action potentials recorded in A1 of macaques performing a rhythmic intermodal selective attention task. We found that the frequency tuning of neuronal ensembles was sharpened due to both increased gain at the preferentially processed or best frequency and increased response suppression at all other frequencies when auditory stimuli were attended. Our results suggest that these effects are due to a frequency-specific counterphase entrainment of ongoing delta oscillations, which predictively orchestrates opposite sign excitability changes across all of A1. This results in a net suppressive effect due to the large proportion of neuronal ensembles that do not specifically process the attended frequency content. Furthermore, analysis of laminar activation profiles revealed that although attention-related suppressive effects predominate the responses of supragranular neuronal ensembles, response enhancement is dominant in the granular and infragranular layers, providing evidence for layer-specific cortical operations in attentive stimulus processing.

The leading sense: supramodal control of neurophysiological context by attention.

Attending to a stimulus enhances its neuronal representation, even at the level of primary sensory cortex. Cross-modal modulation can similarly enhance a neuronal representation, and this process can also operate at the primary cortical level. Phase reset of ongoing neuronal oscillatory activity has been shown to be an important element of the underlying modulation of local cortical excitability in both cases. We investigated the influence of attention on oscillatory phase reset in primary auditory and visual cortices of macaques performing an intermodal selective attention task. In addition to responses "driven" by preferred modality stimuli, we noted that both preferred and nonpreferred modality stimuli could "modulate" local cortical excitability by phase reset of ongoing oscillatory activity, and that this effect was linked to their being attended. These findings outline a supramodal mechanism by which attention can control neurophysiological context, thus determining the representation of specific sensory content in primary sensory cortex.