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.

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.

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.

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.

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.

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.

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.

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.

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.

Prefrontal Cortex Networks Shift from External to Internal Modes during Learning.

UNLABELLED: As we learn about items in our environment, their neural representations become increasingly enriched with our acquired knowledge. But there is little understanding of how network dynamics and neural processing related to external information changes as it becomes laden with "internal" memories. We sampled spiking and local field potential activity simultaneously from multiple sites in the lateral prefrontal cortex (PFC) and the hippocampus (HPC)-regions critical for sensory associations-of monkeys performing an object paired-associate learning task. We found that in the PFC, evoked potentials to, and neural information about, external sensory stimulation decreased while induced beta-band (∼11-27 Hz) oscillatory power and synchrony associated with "top-down" or internal processing increased. By contrast, the HPC showed little evidence of learning-related changes in either spiking activity or network dynamics. The results suggest that during associative learning, PFC networks shift their resources from external to internal processing. SIGNIFICANCE STATEMENT: As we learn about items in our environment, their representations in our brain become increasingly enriched with our acquired "top-down" knowledge. We found that in the prefrontal cortex, but not the hippocampus, processing of external sensory inputs decreased while internal network dynamics related to top-down processing increased. The results suggest that during learning, prefrontal cortex networks shift their resources from external (sensory) to internal (memory) processing.

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.

Curvature processing dynamics in macaque area V4.

We have previously analyzed shape processing dynamics in macaque monkey posterior inferotemporal cortex (PIT). We described how early PIT responses to individual contour fragments evolve into tuning for multifragment shape configurations. Here, we analyzed curvature processing dynamics in area V4, which provides feedforward inputs to PIT. We contrasted 2 hypotheses: 1) that V4 curvature tuning evolves from tuning for simpler elements, analogous to PIT shape synthesis and 2) that V4 curvature tuning emerges immediately, based on purely feedforward mechanisms. Our results clearly supported the first hypothesis. Early V4 responses carried information about individual contour orientations. Tuning for multiorientation (curved) contours developed gradually over ∼50 ms. Together, the current and previous results suggest a partial sequence for shape synthesis in ventral pathway cortex. We propose that early orientation signals are synthesized into curved contour fragment representations in V4 and that these signals are transmitted to PIT, where they are then synthesized into multifragment shape representations. The observed dynamics might additionally or alternatively reflect influences from earlier (V1, V2) and later (central and anterior IT) processing stages in the ventral pathway. In either case, the dynamics of contour information in V4 and PIT appear to reflect a sequential hierarchical process of shape synthesis.

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 anesthesia destabilizes neural dynamics across cortex.

Every day, hundreds of thousands of people undergo general anesthesia. One hypothesis is that anesthesia disrupts dynamic stability-the ability of the brain to balance excitability with the need to be stable and controllable. To test this hypothesis, we developed a method for quantifying changes in population-level dynamic stability in complex systems: delayed linear analysis for stability estimation (DeLASE). Propofol was used to transition animals between the awake state and anesthetized unconsciousness. DeLASE was applied to macaque cortex local field potentials (LFPs). We found that neural dynamics were more unstable in unconsciousness compared with the awake state. Cortical trajectories mirrored predictions from destabilized linear systems. We mimicked the effect of propofol in simulated neural networks by increasing inhibitory tone. This in turn destabilized the networks, as observed in the neural data. Our results suggest that anesthesia disrupts dynamical stability that is required for consciousness.

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.

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.

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.

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.

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.

Dynamic shape synthesis in posterior inferotemporal cortex.

How does the brain synthesize low-level neural signals for simple shape parts into coherent representations of complete objects? Here, we present evidence for a dynamic process of object part integration in macaque posterior inferotemporal cortex (IT). Immediately after stimulus onset, neural responses carried information about individual object parts (simple contour fragments) only. Subsequently, information about specific multipart configurations emerged, building gradually over the course of approximately 60 ms, producing a sparser and more explicit representation of object shape. We show that this gradual transformation can be explained by a recurrent network process that effectively compares parts signals across neurons to generate inferences about multipart shape configurations.