Convergent effects of different anesthetics are due to changes in phase alignment of cortical oscillations.

Many different anesthetics cause loss of responsiveness despite having diverse underlying molecular and circuit actions. To explore the convergent effects of these drugs, we examined how ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, and dexmedetomidine, an α2 adrenergic receptor agonist, affected neural oscillations in the prefrontal cortex of nonhuman primates. Previous work has shown that anesthesia increases phase locking of low-frequency local field potential activity across cortex. We observed similar increases with anesthetic doses of ketamine and dexmedetomidine in the ventrolateral and dorsolateral prefrontal cortex, within and across hemispheres. However, the nature of the phase locking varied between regions. We found that oscillatory activity in different prefrontal subregions within each hemisphere became more anti-phase with both drugs. Local analyses within a region suggested that this finding could be explained by broad cortical distance-based effects, such as a large traveling wave. By contrast, homologous areas across hemispheres increased their phase alignment. Our results suggest that the drugs induce strong patterns of cortical phase alignment that are markedly different from those in the awake state, and that these patterns may be a common feature driving loss of responsiveness from different anesthetic drugs.

Propofol-mediated Unconsciousness Disrupts Progression of Sensory Signals through the Cortical Hierarchy.

A critical component of anesthesia is the loss of sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of nonhuman primates before and during propofol-mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-related synchronization between brain areas in the local field potential of Awake animals. By contrast, propofol-mediated unconsciousness eliminated stimulus-related synchrony and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in Awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol's effect on sensory processing is not just because of asynchronous Down states. Rather, both Down states and Up states reflect disrupted dynamics.

Propofol Mediated Unconsciousness Disrupts Progression of Sensory Signals through the Cortical Hierarchy.

A critical component of anesthesia is the loss sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential (LFP) and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of non-human primates before and during propofol mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-induced coherence between brain areas in the LFP of awake animals. By contrast, propofol mediated unconsciousness eliminated stimulus-induced coherence and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol's effect on sensory processing is not just due to asynchronous down states. Rather, both Down states and Up states reflect disrupted dynamics.

Working memory control dynamics follow principles of spatial computing.

Working memory (WM) allows us to remember and selectively control a limited set of items. Neural evidence suggests it is achieved by interactions between bursts of beta and gamma oscillations. However, it is not clear how oscillations, reflecting coherent activity of millions of neurons, can selectively control individual WM items. Here we propose the novel concept of spatial computing where beta and gamma interactions cause item-specific activity to flow spatially across the network during a task. This way, control-related information such as item order is stored in the spatial activity independent of the detailed recurrent connectivity supporting the item-specific activity itself. The spatial flow is in turn reflected in low-dimensional activity shared by many neurons. We verify these predictions by analyzing local field potentials and neuronal spiking. We hypothesize that spatial computing can facilitate generalization and zero-shot learning by utilizing spatial component as an additional information encoding dimension.

Robust and brain-like working memory through short-term synaptic plasticity.

Working memory has long been thought to arise from sustained spiking/attractor dynamics. However, recent work has suggested that short-term synaptic plasticity (STSP) may help maintain attractor states over gaps in time with little or no spiking. To determine if STSP endows additional functional advantages, we trained artificial recurrent neural networks (RNNs) with and without STSP to perform an object working memory task. We found that RNNs with and without STSP were able to maintain memories despite distractors presented in the middle of the memory delay. However, RNNs with STSP showed activity that was similar to that seen in the cortex of a non-human primate (NHP) performing the same task. By contrast, RNNs without STSP showed activity that was less brain-like. Further, RNNs with STSP were more robust to network degradation than RNNs without STSP. These results show that STSP can not only help maintain working memories, it also makes neural networks more robust and brain-like.

Reduced variability of bursting activity during working memory.

Working memories have long been thought to be maintained by persistent spiking. However, mounting evidence from multiple-electrode recording (and single-trial analyses) shows that the underlying spiking is better characterized by intermittent bursts of activity. A counterargument suggested this intermittent activity is at odds with observations that spike-time variability reduces during task performance. However, this counterargument rests on assumptions, such as randomness in the timing of the bursts, which may not be correct. Thus, we analyzed spiking and LFPs from monkeys' prefrontal cortex (PFC) to determine if task-related reductions in variability can co-exist with intermittent spiking. We found that it does because both spiking and associated gamma bursts were task-modulated, not random. In fact, the task-related reduction in spike variability could largely be explained by a related reduction in gamma burst variability. Our results provide further support for the intermittent activity models of working memory as well as novel mechanistic insights into how spike variability is reduced during cognitive tasks.

Propofol Anesthesia Alters Cortical Traveling Waves.

Oscillatory dynamics in cortex seem to organize into traveling waves that serve a variety of functions. Recent studies show that propofol, a widely used anesthetic, dramatically alters cortical oscillations by increasing slow-delta oscillatory power and coherence. It is not known how this affects traveling waves. We compared traveling waves across the cortex of non-human primates before, during, and after propofol-induced loss of consciousness (LOC). After LOC, traveling waves in the slow-delta (∼1 Hz) range increased, grew more organized, and traveled in different directions relative to the awake state. Higher frequency (8-30 Hz) traveling waves, by contrast, decreased, lost structure, and switched to directions where the slow-delta waves were less frequent. The results suggest that LOC may be due, in part, to increases in the strength and direction of slow-delta traveling waves that, in turn, alter and disrupt traveling waves in the higher frequencies associated with cognition.

Traveling waves in the prefrontal cortex during working memory.

Neural oscillations are evident across cortex but their spatial structure is not well- explored. Are oscillations stationary or do they form "traveling waves", i.e., spatially organized patterns whose peaks and troughs move sequentially across cortex? Here, we show that oscillations in the prefrontal cortex (PFC) organized as traveling waves in the theta (4-8Hz), alpha (8-12Hz) and beta (12-30Hz) bands. Some traveling waves were planar but most rotated. The waves were modulated during performance of a working memory task. During baseline conditions, waves flowed bidirectionally along a specific axis of orientation. Waves in different frequency bands could travel in different directions. During task performance, there was an increase in waves in one direction over the other, especially in the beta band.

Neural effects of propofol-induced unconsciousness and its reversal using thalamic stimulation.

The specific circuit mechanisms through which anesthetics induce unconsciousness have not been completely characterized. We recorded neural activity from the frontal, parietal, and temporal cortices and thalamus while maintaining unconsciousness in non-human primates (NHPs) with the anesthetic propofol. Unconsciousness was marked by slow frequency (~1 Hz) oscillations in local field potentials, entrainment of local spiking to Up states alternating with Down states of little or no spiking activity, and decreased coherence in frequencies above 4 Hz. Thalamic stimulation 'awakened' anesthetized NHPs and reversed the electrophysiologic features of unconsciousness. Unconsciousness is linked to cortical and thalamic slow frequency synchrony coupled with decreased spiking, and loss of higher-frequency dynamics. This may disrupt cortical communication/integration.

Interhemispheric transfer of working memories.

Visual working memory (WM) storage is largely independent between the left and right visual hemifields/cerebral hemispheres, yet somehow WM feels seamless. We studied how WM is integrated across hemifields by recording neural activity bilaterally from lateral prefrontal cortex. An instructed saccade during the WM delay shifted the remembered location from one hemifield to the other. Before the shift, spike rates and oscillatory power showed clear signatures of memory laterality. After the shift, the lateralization inverted, consistent with transfer of the memory trace from one hemisphere to the other. Transferred traces initially used different neural ensembles from feedforward-induced ones, but they converged at the end of the delay. Around the time of transfer, synchrony between the two prefrontal hemispheres peaked in theta and beta frequencies, with a directionality consistent with memory trace transfer. This illustrates how dynamics between the two cortical hemispheres can stitch together WM traces across visual hemifields.

Conjunctive representation of what and when in monkey hippocampus and lateral prefrontal cortex during an associative memory task.

Adaptive memory requires the organism to form associations that bridge between events separated in time. Many studies show interactions between hippocampus (HPC) and prefrontal cortex (PFC) during formation of such associations. We analyze neural recording from monkey HPC and PFC during a memory task that requires the monkey to associate stimuli separated by about a second in time. After the first stimulus was presented, large numbers of units in both HPC and PFC fired in sequence. Many units fired only when a particular stimulus was presented at a particular time in the past. These results indicate that both HPC and PFC maintain a temporal record of events that could be used to form associations across time. This temporal record of the past is a key component of the temporal coding hypothesis, a hypothesis in psychology that memory not only encodes what happened, but when it happened.

Task-evoked activity quenches neural correlations and variability across cortical areas.

Many large-scale functional connectivity studies have emphasized the importance of communication through increased inter-region correlations during task states. In contrast, local circuit studies have demonstrated that task states primarily reduce correlations among pairs of neurons, likely enhancing their information coding by suppressing shared spontaneous activity. Here we sought to adjudicate between these conflicting perspectives, assessing whether co-active brain regions during task states tend to increase or decrease their correlations. We found that variability and correlations primarily decrease across a variety of cortical regions in two highly distinct data sets: non-human primate spiking data and human functional magnetic resonance imaging data. Moreover, this observed variability and correlation reduction was accompanied by an overall increase in dimensionality (reflecting less information redundancy) during task states, suggesting that decreased correlations increased information coding capacity. We further found in both spiking and neural mass computational models that task-evoked activity increased the stability around a stable attractor, globally quenching neural variability and correlations. Together, our results provide an integrative mechanistic account that encompasses measures of large-scale neural activity, variability, and correlations during resting and task states.

A Geometric Characterization of Population Coding in the Prefrontal Cortex and Hippocampus during a Paired-Associate Learning Task.

Large-scale neuronal recording techniques have enabled discoveries of population-level mechanisms for neural computation. However, it is not clear how these mechanisms form by trial-and-error learning. In this article, we present an initial effort to characterize the population activity in monkey prefrontal cortex (PFC) and hippocampus (HPC) during the learning phase of a paired-associate task. To analyze the population data, we introduce the normalized distance, a dimensionless metric that describes the encoding of cognitive variables from the geometrical relationship among neural trajectories in state space. It is found that PFC exhibits a more sustained encoding of the visual stimuli, whereas HPC only transiently encodes the identity of the associate stimuli. Surprisingly, after learning, the neural activity is not reorganized to reflect the task structure, raising the possibility that learning is accompanied by some "silent" mechanism that does not explicitly change the neural representations. We did find partial evidence on the learning-dependent changes for some of the task variables. This study shows the feasibility of using normalized distance as a metric to characterize and compare population-level encoding of task variables and suggests further directions to explore learning-dependent changes in the neural circuits.

TORUS GRAPHS FOR MULTIVARIATE PHASE COUPLING ANALYSIS.

Angular measurements are often modeled as circular random variables, where there are natural circular analogues of moments, including correlation. Because a product of circles is a torus, a d-dimensional vector of circular random variables lies on a d-dimensional torus. For such vectors we present here a class of graphical models, which we call torus graphs, based on the full exponential family with pairwise interactions. The topological distinction between a torus and Euclidean space has several important consequences. Our development was motivated by the problem of identifying phase coupling among oscillatory signals recorded from multiple electrodes in the brain: oscillatory phases across electrodes might tend to advance or recede together, indicating coordination across brain areas. The data analyzed here consisted of 24 phase angles measured repeatedly across 840 experimental trials (replications) during a memory task, where the electrodes were in 4 distinct brain regions, all known to be active while memories are being stored or retrieved. In realistic numerical simulations, we found that a standard pairwise assessment, known as phase locking value, is unable to describe multivariate phase interactions, but that torus graphs can accurately identify conditional associations. Torus graphs generalize several more restrictive approaches that have appeared in various scientific literatures, and produced intuitive results in the data we analyzed. Torus graphs thus unify multivariate analysis of circular data and present fertile territory for future research.

Gradual progression from sensory to task-related processing in cerebral cortex.

Somewhere along the cortical hierarchy, behaviorally relevant information is distilled from raw sensory inputs. We examined how this transformation progresses along multiple levels of the hierarchy by comparing neural representations in visual, temporal, parietal, and frontal cortices in monkeys categorizing across three visual domains (shape, motion direction, and color). Representations in visual areas middle temporal (MT) and V4 were tightly linked to external sensory inputs. In contrast, lateral prefrontal cortex (PFC) largely represented the abstracted behavioral relevance of stimuli (task rule, motion category, and color category). Intermediate-level areas, including posterior inferotemporal (PIT), lateral intraparietal (LIP), and frontal eye fields (FEF), exhibited mixed representations. While the distribution of sensory information across areas aligned well with classical functional divisions (MT carried stronger motion information, and V4 and PIT carried stronger color and shape information), categorical abstraction did not, suggesting these areas may participate in different networks for stimulus-driven and cognitive functions. Paralleling these representational differences, the dimensionality of neural population activity decreased progressively from sensory to intermediate to frontal cortex. This shows how raw sensory representations are transformed into behaviorally relevant abstractions and suggests that the dimensionality of neural activity in higher cortical regions may be specific to their current task.

Detecting multivariate cross-correlation between brain regions.

The problem of identifying functional connectivity from multiple time series data recorded in each of two or more brain areas arises in many neuroscientific investigations. For a single stationary time series in each of two brain areas statistical tools such as cross-correlation and Granger causality may be applied. On the other hand, to examine multivariate interactions at a single time point, canonical correlation, which finds the linear combinations of signals that maximize the correlation, may be used. We report here a new method that produces interpretations much like these standard techniques and, in addition, 1) extends the idea of canonical correlation to 3-way arrays (with dimensionality number of signals by number of time points by number of trials), 2) allows for nonstationarity, 3) also allows for nonlinearity, 4) scales well as the number of signals increases, and 5) captures predictive relationships, as is done with Granger causality. We demonstrate the effectiveness of the method through simulation studies and illustrate by analyzing local field potentials recorded from a behaving primate. NEW & NOTEWORTHY Multiple signals recorded from each of multiple brain regions may contain information about cross-region interactions. This article provides a method for visualizing the complicated interdependencies contained in these signals and assessing them statistically. The method combines signals optimally but allows the resulting measure of dependence to change, both within and between regions, as the responses evolve dynamically across time. We demonstrate the effectiveness of the method through numerical simulations and by uncovering a novel connectivity pattern between hippocampus and prefrontal cortex during a declarative memory task.

Gamma and beta bursts during working memory readout suggest roles in its volitional control.

Working memory (WM) activity is not as stationary or sustained as previously thought. There are brief bursts of gamma (~50-120 Hz) and beta (~20-35 Hz) oscillations, the former linked to stimulus information in spiking. We examined these dynamics in relation to readout and control mechanisms of WM. Monkeys held sequences of two objects in WM to match to subsequent sequences. Changes in beta and gamma bursting suggested their distinct roles. In anticipation of having to use an object for the match decision, there was an increase in gamma and spiking information about that object and reduced beta bursting. This readout signal was only seen before relevant test objects, and was related to premotor activity. When the objects were no longer needed, beta increased and gamma decreased together with object spiking information. Deviations from these dynamics predicted behavioral errors. Thus, beta could regulate gamma and the information in WM.

A Meta-Analysis Suggests Different Neural Correlates for Implicit and Explicit Learning.

A meta-analysis of non-human primates performing three different tasks (Object-Match, Category-Match, and Category-Saccade associations) revealed signatures of explicit and implicit learning. Performance improved equally following correct and error trials in the Match (explicit) tasks, but it improved more after correct trials in the Saccade (implicit) task, a signature of explicit versus implicit learning. Likewise, error-related negativity, a marker for error processing, was greater in the Match (explicit) tasks. All tasks showed an increase in alpha/beta (10-30 Hz) synchrony after correct choices. However, only the implicit task showed an increase in theta (3-7 Hz) synchrony after correct choices that decreased with learning. In contrast, in the explicit tasks, alpha/beta synchrony increased with learning and decreased thereafter. Our results suggest that explicit versus implicit learning engages different neural mechanisms that rely on different patterns of oscillatory synchrony.

On memories, neural ensembles and mental flexibility.

Memories are assumed to be represented by groups of co-activated neurons, called neural ensembles. Describing ensembles is a challenge: complexity of the underlying micro-circuitry is immense. Current approaches use a piecemeal fashion, focusing on single neurons and employing local measures like pairwise correlations. We introduce an alternative approach that identifies ensembles and describes the effective connectivity between them in a holistic fashion. It also links the oscillatory frequencies observed in ensembles with the spatial scales at which activity is expressed. Using unsupervised learning, biophysical modeling and graph theory, we analyze multi-electrode LFPs from frontal cortex during a spatial delayed response task. We find distinct ensembles for different cues and more parsimonious connectivity for cues on the horizontal axis, which may explain the oblique effect in psychophysics. Our approach paves the way for biophysical models with learned parameters that can guide future Brain Computer Interface development.

Decoding of intended saccade direction in an oculomotor brain-computer interface.

OBJECTIVE: To date, invasive brain-computer interface (BCI) research has largely focused on replacing lost limb functions using signals from the hand/arm areas of motor cortex. However, the oculomotor system may be better suited to BCI applications involving rapid serial selection from spatial targets, such as choosing from a set of possible words displayed on a computer screen in an augmentative and alternative communication (AAC) application. Here we aimed to demonstrate the feasibility of a BCI utilizing the oculomotor system. APPROACH: We developed a chronic intracortical BCI in monkeys to decode intended saccadic eye movement direction using activity from multiple frontal cortical areas. MAIN RESULTS: Intended saccade direction could be decoded in real time with high accuracy, particularly at contralateral locations. Accurate decoding was evident even at the beginning of the BCI session; no extensive BCI experience was necessary. High-frequency (80-500 Hz) local field potential magnitude provided the best performance, even over spiking activity, thus simplifying future BCI applications. Most of the information came from the frontal and supplementary eye fields, with relatively little contribution from dorsolateral prefrontal cortex. SIGNIFICANCE: Our results support the feasibility of high-accuracy intracortical oculomotor BCIs that require little or no practice to operate and may be ideally suited for 'point and click' computer operation as used in most current AAC systems.