An integrative view of the role of prefrontal cortex in consciousness.

The involvement of the prefrontal cortex (PFC) in consciousness is an ongoing focus of intense investigation. An important question is whether representations of conscious contents and experiences in the PFC are confounded by post-perceptual processes related to cognitive functions. Here, I review recent findings suggesting that neuronal representations of consciously perceived contents-in the absence of post-perceptual processes-can indeed be observed in the PFC. Slower ongoing fluctuations in the electrophysiological state of the PFC seem to control the stability and updates of these prefrontal representations of conscious awareness. In addition to conscious perception, the PFC has been shown to play a critical role in controlling the levels of consciousness as observed during anesthesia, while prefrontal lesions can result in severe loss of perceptual awareness. Together, the convergence of these processes in the PFC suggests its integrative role in consciousness and highlights the complex nature of consciousness itself.

Spontaneously emerging internal models of visual sequences combine abstract and event-specific information in the prefrontal cortex.

When exposed to sensory sequences, do macaque monkeys spontaneously form abstract internal models that generalize to novel experiences? Here, we show that neuronal populations in macaque ventrolateral prefrontal cortex jointly encode visual sequences by separate codes for the specific pictures presented and for their abstract sequential structure. We recorded prefrontal neurons while macaque monkeys passively viewed visual sequences and sequence mismatches in the local-global paradigm. Even without any overt task or response requirements, prefrontal populations spontaneously form representations of sequence structure, serial order, and image identity within distinct but superimposed neuronal subspaces. Representations of sequence structure rapidly update following single exposure to a mismatch sequence, while distinct populations represent mismatches for sequences of different complexity. Finally, those representations generalize across sequences following the same repetition structure but comprising different images. These results suggest that prefrontal populations spontaneously encode rich internal models of visual sequences reflecting both content-specific and abstract information.

Uncovering the organization of neural circuits with Generalized Phase Locking Analysis.

Despite the considerable progress of in vivo neural recording techniques, inferring the biophysical mechanisms underlying large scale coordination of brain activity from neural data remains challenging. One obstacle is the difficulty to link high dimensional functional connectivity measures to mechanistic models of network activity. We address this issue by investigating spike-field coupling (SFC) measurements, which quantify the synchronization between, on the one hand, the action potentials produced by neurons, and on the other hand mesoscopic "field" signals, reflecting subthreshold activities at possibly multiple recording sites. As the number of recording sites gets large, the amount of pairwise SFC measurements becomes overwhelmingly challenging to interpret. We develop Generalized Phase Locking Analysis (GPLA) as an interpretable dimensionality reduction of this multivariate SFC. GPLA describes the dominant coupling between field activity and neural ensembles across space and frequencies. We show that GPLA features are biophysically interpretable when used in conjunction with appropriate network models, such that we can identify the influence of underlying circuit properties on these features. We demonstrate the statistical benefits and interpretability of this approach in various computational models and Utah array recordings. The results suggest that GPLA, used jointly with biophysical modeling, can help uncover the contribution of recurrent microcircuits to the spatio-temporal dynamics observed in multi-channel experimental recordings.

Bistability of prefrontal states gates access to consciousness.

Access of sensory information to consciousness has been linked to the ignition of content-specific representations in association cortices. How does ignition interact with intrinsic cortical state fluctuations to give rise to conscious perception? We addressed this question in the prefrontal cortex (PFC) by combining multi-electrode recordings with a binocular rivalry (BR) paradigm inducing spontaneously driven changes in the content of consciousness, inferred from the reflexive optokinetic nystagmus (OKN) pattern. We find that fluctuations between low-frequency (LF, 1-9 Hz) and beta (∼20-40 Hz) local field potentials (LFPs) reflect competition between spontaneous updates and stability of conscious contents, respectively. Both LF and beta events were locally modulated. The phase of the former locked differentially to the competing populations just before a spontaneous transition while the latter synchronized the neuronal ensemble coding the consciously perceived content. These results suggest that prefrontal state fluctuations gate conscious perception by mediating internal states that facilitate perceptual update and stability.

An adversarial collaboration protocol for testing contrasting predictions of global neuronal workspace and integrated information theory.

The relationship between conscious experience and brain activity has intrigued scientists and philosophers for centuries. In the last decades, several theories have suggested different accounts for these relationships. These theories have developed in parallel, with little to no cross-talk among them. To advance research on consciousness, we established an adversarial collaboration between proponents of two of the major theories in the field, Global Neuronal Workspace and Integrated Information Theory. Together, we devised and preregistered two experiments that test contrasting predictions of these theories concerning the location and timing of correlates of visual consciousness, which have been endorsed by the theories' proponents. Predicted outcomes should either support, refute, or challenge these theories. Six theory-impartial laboratories will follow the study protocol specified here, using three complementary methods: Functional Magnetic Resonance Imaging (fMRI), Magneto-Electroencephalography (M-EEG), and intracranial electroencephalography (iEEG). The study protocol will include built-in replications, both between labs and within datasets. Through this ambitious undertaking, we hope to provide decisive evidence in favor or against the two theories and clarify the footprints of conscious visual perception in the human brain, while also providing an innovative model of large-scale, collaborative, and open science practice.

Decoding internally generated transitions of conscious contents in the prefrontal cortex without subjective reports.

A major debate about the neural correlates of conscious perception concerns its cortical organization, namely, whether it includes the prefrontal cortex (PFC), which mediates executive functions, or it is constrained within posterior cortices. It has been suggested that PFC activity during paradigms investigating conscious perception is conflated with post-perceptual processes associated with reporting the contents of consciousness or feedforward signals originating from exogenous stimulus manipulations and relayed via posterior cortical areas. We addressed this debate by simultaneously probing neuronal populations in the rhesus macaque (Macaca mulatta) PFC during a no-report paradigm, capable of instigating internally generated transitions in conscious perception, without changes in visual stimulation. We find that feature-selective prefrontal neurons are modulated concomitantly with subjective perception and perceptual suppression of their preferred stimulus during both externally induced and internally generated changes in conscious perception. Importantly, this enables reliable single-trial, population decoding of conscious contents. Control experiments confirm significant decoding of stimulus contents, even when oculomotor responses, used for inferring perception, are suppressed. These findings suggest that internally generated changes in the contents of conscious visual perception are reliably reflected within the activity of prefrontal populations in the absence of volitional reports or changes in sensory input.

Decoding rapidly presented visual stimuli from prefrontal ensembles without report nor post-perceptual processing.

The role of the primate prefrontal cortex (PFC) in conscious perception is debated. The global neuronal workspace theory of consciousness predicts that PFC neurons should contain a detailed code of the current conscious contents. Previous research showed that PFC is indeed activated in paradigms of conscious visual perception, including no-report paradigms where no voluntary behavioral report of the percept is given, thus avoiding a conflation of signals related to visual consciousness with signals related to the report. Still, it has been argued that prefrontal modulation could reflect post-perceptual processes that may be present even in the absence of report, such as thinking about the perceived stimulus, therefore reflecting a consequence rather than a direct correlate of conscious experience. Here, we investigate these issues by recording neuronal ensemble activity from the macaque ventrolateral PFC during briefly presented visual stimuli, either in isolated trials in which stimuli were clearly perceived or in sequences of rapid serial visual presentation (RSVP) in which perception and post-perceptual processing were challenged. We report that the identity of each stimulus could be decoded from PFC population activity even in the RSVP condition. The first visual signals could be detected at 60 ms after stimulus onset and information was maximal at 150 ms. However, in the RSVP condition, 200 ms after the onset of a stimulus, the decoding accuracy quickly dropped to chance level and the next stimulus started to be decodable. Interestingly, decoding in the ventrolateral PFC was stronger compared to posterior parietal cortex for both isolated and RSVP stimuli. These results indicate that neuronal populations in the macaque PFC reliably encode visual stimuli even under conditions that have been shown to challenge conscious perception and/or substantially reduce the probability of post-perceptual processing in humans. We discuss whether the observed activation reflects conscious access, phenomenal consciousness, or merely a preconscious bottom-up wave.

Parallel and functionally segregated processing of task phase and conscious content in the prefrontal cortex.

The role of lateral prefrontal cortex (LPFC) in mediating conscious perception has been recently questioned due to potential confounds resulting from the parallel operation of task related processes. We have previously demonstrated encoding of contents of visual consciousness in LPFC neurons during a no-report task involving perceptual suppression. Here, we report a separate LPFC population that exhibits task-phase related activity during the same task. The activity profile of these neurons could be captured as canonical response patterns (CRPs), with their peak amplitudes sequentially distributed across different task phases. Perceptually suppressed visual input had a negligible impact on sequential firing and functional connectivity structure. Importantly, task-phase related neurons were functionally segregated from the neuronal population, which encoded conscious perception. These results suggest that neurons exhibiting task-phase related activity operate in the LPFC concurrently with, but segregated from neurons representing conscious content during a no-report task involving perceptual suppression.

Nonmonotonic spatial structure of interneuronal correlations in prefrontal microcircuits.

Correlated fluctuations of single neuron discharges, on a mesoscopic scale, decrease as a function of lateral distance in early sensory cortices, reflecting a rapid spatial decay of lateral connection probability and excitation. However, spatial periodicities in horizontal connectivity and associational input as well as an enhanced probability of lateral excitatory connections in the association cortex could theoretically result in nonmonotonic correlation structures. Here, we show such a spatially nonmonotonic correlation structure, characterized by significantly positive long-range correlations, in the inferior convexity of the macaque prefrontal cortex. This functional connectivity kernel was more pronounced during wakefulness than anesthesia and could be largely attributed to the spatial pattern of correlated variability between functionally similar neurons during structured visual stimulation. These results suggest that the spatial decay of lateral functional connectivity is not a common organizational principle of neocortical microcircuits. A nonmonotonic correlation structure could reflect a critical topological feature of prefrontal microcircuits, facilitating their role in integrative processes.

Discrepancies between Multi-Electrode LFP and CSD Phase-Patterns: A Forward Modeling Study.

Multi-electrode recordings of local field potentials (LFPs) provide the opportunity to investigate the spatiotemporal organization of neural activity on the scale of several millimeters. In particular, the phases of oscillatory LFPs allow studying the coordination of neural oscillations in time and space and to tie it to cognitive processing. Given the computational roles of LFP phases, it is important to know how they relate to the phases of the underlying current source densities (CSDs) that generate them. Although CSDs and LFPs are distinct physical quantities, they are often (implicitly) identified when interpreting experimental observations. That this identification is problematic is clear from the fact that LFP phases change when switching to different electrode montages, while the underlying CSD phases remain unchanged. In this study we use a volume-conductor model to characterize discrepancies between LFP and CSD phase-patterns, to identify the contributing factors, and to assess the effect of different electrode montages. Although we focus on cortical LFPs recorded with two-dimensional (Utah) arrays, our findings are also relevant for other electrode configurations. We found that the main factors that determine the discrepancy between CSD and LFP phase-patterns are the frequency of the neural oscillations and the extent to which the laminar CSD profile is balanced. Furthermore, the presence of laminar phase-differences in cortical oscillations, as commonly observed in experiments, precludes identifying LFP phases with those of the CSD oscillations at a given cortical depth. This observation potentially complicates the interpretation of spike-LFP coherence and spike-triggered LFP averages. With respect to reference strategies, we found that the average-reference montage leads to larger discrepancies between LFP and CSD phases as compared with the referential montage, while the Laplacian montage reduces these discrepancies. We therefore advice to conduct analysis of two-dimensional LFP recordings using the Laplacian montage.

A novel model of early experiences involving neonatal learning of a T-maze using maternal contact as a reward or its denial as an event of mild emotional adversity.

We developed a novel animal model of early life experiences in which rat pups are trained during postnatal days (PND) 10-13 in a T-maze with maternal contact as a reward (RER group) or its denial (DER group) as a mildly aversive event. Both groups of animals learn the T-maze, albeit the RER do so more efficiently. Training results in activation of the basal ganglia in the RER and of the hippocampus and prefrontal cortex in the DER. Moreover, on PND10 DER training leads to increased corticosterone levels and activation of the amygdala. In adulthood, male DER animals show better mnemonic abilities in the Morris water maze while the RER exhibit enhanced fear memory. Furthermore, DER animals have a hypofunctioning serotonergic system and express depressive-like behavior and increased aggression. However, they have increased hippocampal glucocorticoid receptors, indicative of efficient hypothalamic-pituitary-adrenal axis function, and an adaptive pattern of stress-induced corticosterone response. The DER experience with its relatively negative emotional valence results in a complex behavioral phenotype, which cannot be considered simply as adaptive or maladaptive.

Subjective visual perception: from local processing to emergent phenomena of brain activity.

The combination of electrophysiological recordings with ambiguous visual stimulation made possible the detection of neurons that represent the content of subjective visual perception and perceptual suppression in multiple cortical and subcortical brain regions. These neuronal populations, commonly referred to as the neural correlates of consciousness, are more likely to be found in the temporal and prefrontal cortices as well as the pulvinar, indicating that the content of perceptual awareness is represented with higher fidelity in higher-order association areas of the cortical and thalamic hierarchy, reflecting the outcome of competitive interactions between conflicting sensory information resolved in earlier stages. However, despite the significant insights into conscious perception gained through monitoring the activities of single neurons and small, local populations, the immense functional complexity of the brain arising from correlations in the activity of its constituent parts suggests that local, microscopic activity could only partially reveal the mechanisms involved in perceptual awareness. Rather, the dynamics of functional connectivity patterns on a mesoscopic and macroscopic level could be critical for conscious perception. Understanding these emergent spatio-temporal patterns could be informative not only for the stability of subjective perception but also for spontaneous perceptual transitions suggested to depend either on the dynamics of antagonistic ensembles or on global intrinsic activity fluctuations that may act upon explicit neural representations of sensory stimuli and induce perceptual reorganization. Here, we review the most recent results from local activity recordings and discuss the potential role of effective, correlated interactions during perceptual awareness.

Effects of an Early Experience Involving Training in a T-Maze Under either Denial or Receipt of Expected Reward through Maternal Contact.

The mother is the most salient stimulus for the developing pups and a number of early experience models employ manipulation of the mother-infant interaction. We have developed a new model which in addition to changes in maternal behavior includes a learning component on the part of the pups. More specifically, pups were trained in a T-maze and either received (RER rats) or were denied (DER) the reward of maternal contact, during postnatal days 10-13. Pups of both experimental groups learn the T-maze, but the RER do so more efficiently utilizing a procedural-type of learning and memory with activation of the dorsal basal ganglia. On the other hand, the DER experience leads to activation of the hippocampus, prefrontal cortex, and amygdala in the pups. In adulthood, male DER animals exhibit better mnemonic abilities in the Morris water maze and higher activation of the hippocampus, while they have decreased brain serotonergic activity, exhibit a depressive-like phenotype and proactive aggressive behavior in the resident-intruder test. While male RER animals assume a reactive coping style in this test, and showed increased freezing during both contextual and cued memory recall following fear conditioning.

Desynchronization and rebound of beta oscillations during conscious and unconscious local neuronal processing in the macaque lateral prefrontal cortex.

Accumulating evidence indicates that control mechanisms are not tightly bound to conscious perception since both conscious and unconscious information can trigger control processes, probably through the activation of higher-order association areas like the prefrontal cortex. Studying the modulation of control-related prefrontal signals in a microscopic, neuronal level during conscious and unconscious neuronal processing, and under control-free conditions could provide an elementary understanding of these interactions. Here we performed extracellular electrophysiological recordings in the macaque lateral prefrontal cortex (LPFC) during monocular physical alternation (PA) and binocular flash suppression (BFS) and studied the local scale relationship between beta (15-30 Hz) oscillations, a rhythmic signal believed to reflect the current sensory, motor, or cognitive state (status-quo), and conscious or unconscious neuronal processing. First, we show that beta oscillations are observed in the LPFC during resting state. Both PA and BFS had a strong impact on the power of this spontaneous rhythm with the modulation pattern of beta power being identical across these two conditions. Specifically, both perceptual dominance and suppression of local neuronal populations in BFS were accompanied by a transient beta desynchronization followed by beta activity rebound, a pattern also observed when perception occurred without any underlying visual competition in PA. These results indicate that under control-free conditions, at least one rhythmic signal known to reflect control processes in the LPFC (i.e., beta oscillations) is not obstructed by local neuronal, and accordingly perceptual, suppression, thus being independent from temporally co-existing conscious and unconscious local neuronal representations. Future studies could reveal the additive effects of motor or cognitive control demands on prefrontal beta oscillations during conscious and unconscious processing.

Development of tube tetrodes and a multi-tetrode drive for deep structure electrophysiological recordings in the macaque brain.

Understanding the principles that underlie information processing by neuronal networks requires simultaneous recordings from large populations of well isolated single units. Twisted wire tetrodes (TWTs), typically made by winding together four ultrathin wires (diameter: 12-25 µm), are ideally suited for such population recordings. They are advantageous over single electrodes; both with respect to quality of isolation as well as the number of single units isolated and have therefore been used extensively for superficial cortical recordings. However, their limited tensile strength poses a difficulty to their use for recordings in deep brain areas. We therefore developed a method to overcome this limitation and utilize tetrodes for electrophysiological recordings in the inferotemporal cortex of rhesus macaque. We fabricated a novel, stiff tetrode called the tube tetrode (TuTe) and developed a multi-tetrode driving system for advancing up to 5 TuTes through a ball and socket chamber to precise locations in the temporal lobe of a rhesus macaque. The signal quality acquired with TuTes was comparable to conventional TWTs and allowed excellent isolation of multiple single units. We describe here a simple method for constructing TuTes, which requires only standard laboratory equipment. Further, our TuTes can be easily adapted to work with other microdrives commonly used for electrophysiological investigation in the macaque brain and produce minimal damage to the cortex along its path because of their ultrathin diameter. The tetrode development described here could allow studying neuronal populations in deep lying brain structures previously difficult to reach with the current technology.

A common neurodynamical mechanism could mediate externally induced and intrinsically generated transitions in visual awareness.

The neural correlates of conscious visual perception are commonly studied in paradigms of perceptual multistability that allow multiple perceptual interpretations during unchanged sensory stimulation. What is the source of this multistability in the content of perception? From a theoretical perspective, a fine balance between deterministic and stochastic forces has been suggested to underlie the spontaneous, intrinsically driven perceptual transitions observed during multistable perception. Deterministic forces are represented by adaptation of feature-selective neuronal populations encoding the competing percepts while stochastic forces are modeled as noise-driven processes. Here, we used a unified neuronal competition model to study the dynamics of adaptation and noise processes in binocular flash suppression (BFS), a form of externally induced perceptual suppression, and compare it with the dynamics of intrinsically driven alternations in binocular rivalry (BR). For the first time, we use electrophysiological, biologically relevant data to constrain a model of perceptual rivalry. Specifically, we show that the mean population discharge pattern of a perceptually modulated neuronal population detected in electrophysiological recordings in the lateral prefrontal cortex (LPFC) during BFS, constrains the dynamical range of externally induced perceptual transitions to a region around the bifurcation separating a noise-driven attractor regime from an adaptation-driven oscillatory regime. Most interestingly, the dynamical range of intrinsically driven perceptual transitions during BR is located in the noise-driven attractor regime, where it overlaps with BFS. Our results suggest that the neurodynamical mechanisms of externally induced and spontaneously generated perceptual alternations overlap in a narrow, noise-driven region just before a bifurcation where the system becomes adaptation-driven.