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.

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.

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.

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.

Dual mechanism of neuronal ensemble inhibition in primary auditory cortex.

Inhibition plays an essential role in shaping and refining the brain's representation of sensory stimulus attributes. In primary auditory cortex (A1), so-called "sideband" inhibition helps to sharpen the tuning of local neuronal responses. Several distinct types of anatomical circuitry could underlie sideband inhibition, including direct thalamocortical (TC) afferents, as well as indirect intracortical mechanisms. The goal of the present study was to characterize sideband inhibition in A1 and to determine its mechanism by analyzing laminar profiles of neuronal ensemble activity. Our results indicate that both lemniscal and nonlemniscal TC afferents play a role in inhibitory responses via feedforward inhibition and oscillatory phase reset, respectively. We propose that the dynamic modulation of excitability in A1 due to the phase reset of ongoing oscillations may alter the tuning of local neuronal ensembles and can be regarded as a flexible overlay on the more obligatory system of lemniscal feedforward type responses.

Changing plans: neural correlates of executive control in monkey and human frontal cortex.

Changing plans depends on executive control, the orchestration of behavior based on knowledge of both goal and context. Dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) cortices are clearly involved in these processes. Intracranial recordings in these regions were obtained from a monkey performing an executive control-challenging task that is widely used in clinic and laboratory to assess the integrity of cognitive function, the AX version of the continuous performance task (AX-CPT), and directly compared to scalp-recorded evoked potentials in humans. In this task the subject presses a button when detecting a frequent cue-target probe sequence in a stream of letters presented on a computer screen, and withholds response following incorrect sequences. Thus correct performance requires correct encoding of cue and probe instruction and inhibitory control. Intracranial recordings showed that DLPFC in the monkey was primarily activated by conditions that required inhibition of imminent action, as had been shown in human event-related potential (ERP) recordings. Different subregions of monkey ACC were activated primarily by either initiating or inhibiting action, whereas human ERP had shown ACC activation in both situations. We suggest that simultaneous activation of both types of subregions in conflict conditions may account the ubiquitous ACC activation observed with fMRI and ERP in those conditions.

Timing and laminar profile of eye-position effects on auditory responses in primate auditory cortex.

We examined effects of eye position on auditory cortical responses in macaques. Laminar current-source density (CSD) and multiunit activity (MUA) profiles were sampled with linear array multielectrodes. Eye position significantly modulated auditory-evoked CSD amplitude in 24/29 penetrations (83%), across A1 and belt regions; 4/24 cases also showed significant MUA AM. Eye-position effects occurred mainly in the supragranular laminae and lagged the co-located auditory response by, on average, 38 ms. Effects in A1 and belt regions were indistinguishable in amplitude, laminar profile, and latency. The timing and laminar profile of the eye-position effects suggest that they are not combined with auditory signals at a subcortical stage of the lemniscal auditory pathways and simply "fed-forward" into cortex. Rather, these effects may be conveyed to auditory cortex by feedback projections from parietal or frontal cortices, or alternatively, they may be conveyed by nonclassical feedforward projections through auditory koniocellular (calbindin positive) neurons.

Anatomical mechanisms and functional implications of multisensory convergence in early cortical processing.

Recent findings in both monkeys and humans indicate that multisensory convergence occurs in low-level cortical structures generally believed to be unisensory in function. In an in-depth treatment of this theme, this paper reviews anatomical and physiological findings relating to the convergence of visual, somatosensory and auditory signals at early stages of auditory cortical processing. We discuss the potential anatomical sources of the input, and the types of known projections, and attempt to integrate this information with the current hierarchical model of auditory processing. Finally, we consider the functional implications of multisensory integration in early sensory processing.