Control of working memory by phase-amplitude coupling of human hippocampal neurons.

Retaining information in working memory is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference1,2. However, how cognitive control regulates working memory storage is unclear. Here we show that interactions of frontal control and hippocampal persistent activity are coordinated by theta-gamma phase-amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in their working memory. In the hippocampus, TG-PAC was indicative of working memory load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. The spike timing of these PAC neurons was coordinated with frontal theta activity when cognitive control demand was high. By introducing noise correlations with persistently active neurons in the hippocampus, PAC neurons shaped the geometry of the population code. This led to higher-fidelity representations of working memory content that were associated with improved behaviour. Our results support a multicomponent architecture of working memory1,2, with frontal control managing maintenance of working memory content in storage-related areas3-5. Within this framework, hippocampal TG-PAC integrates cognitive control and working memory storage across brain areas, thereby suggesting a potential mechanism for top-down control over sensory-driven processes.

Neurophysiological mechanisms of error monitoring in human and non-human primates.

Performance monitoring is an important executive function that allows us to gain insight into our own behaviour. This remarkable ability relies on the frontal cortex, and its impairment is an aspect of many psychiatric diseases. In recent years, recordings from the macaque and human medial frontal cortex have offered a detailed understanding of the neurophysiological substrate that underlies performance monitoring. Here we review the discovery of single-neuron correlates of error monitoring, a key aspect of performance monitoring, in both species. These neurons are the generators of the error-related negativity, which is a non-invasive biomarker that indexes error detection. We evaluate a set of tasks that allows the synergistic elucidation of the mechanisms of cognitive control across the two species, consider differences in brain anatomy and testing conditions across species, and describe the clinical relevance of these findings for understanding psychopathology. Last, we integrate the body of experimental facts into a theoretical framework that offers a new perspective on how error signals are computed in both species and makes novel, testable predictions.

Encoding of Predictive Associations in Human Prefrontal and Medial Temporal Neurons During Pavlovian Appetitive Conditioning.

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here, we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus, and amygdala while patients of both sexes performed an appetitive Pavlovian conditioning task probing both stimulus-value and stimulus-stimulus associations. Ventromedial prefrontal cortex encoded predictive value along with the amygdala, and also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial frontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.

The Architecture of Human Memory: Insights from Human Single-Neuron Recordings.

Deciphering the mechanisms of human memory is a central goal of neuroscience, both from the point of view of the fundamental biology of memory and for its translational relevance. Here, we review some contributions that recordings from neurons in humans implanted with electrodes for clinical purposes have made toward this goal. Recordings from the medial temporal lobe, including the hippocampus, reveal the existence of two classes of cells: those encoding highly selective and invariant representations of abstract concepts, and memory-selective cells whose activity is related to familiarity and episodic retrieval. Insights derived from observing these cells in behaving humans include that semantic representations are activated before episodic representations, that memory content and memory strength are segregated, and that the activity of both types of cells is related to subjective awareness as expected from a substrate for declarative memory. Visually selective cells can remain persistently active for several seconds, thereby revealing a cellular substrate for working memory in humans. An overarching insight is that the neural code of human memory is interpretable at the single-neuron level. Jointly, intracranial recording studies are starting to reveal aspects of the building blocks of human memory at the single-cell level. This work establishes a bridge to cellular-level work in animals on the one hand, and the extensive literature on noninvasive imaging in humans on the other hand. More broadly, this work is a step toward a detailed mechanistic understanding of human memory that is needed to develop therapies for human memory disorders.

Properties and hemispheric differences of theta oscillations in the human hippocampus.

The left and right primate hippocampi (LH and RH) are thought to support distinct functions, but little is known about differences between the hemispheres at the neuronal level. We recorded single-neuron and local field potentials from the human hippocampus in epilepsy patients implanted with depth electrodes. We detected theta-frequency bouts of oscillatory activity while patients performed a visual recognition memory task. Theta appeared in bouts of 3.16 cycles, with sawtooth-shaped oscillations that had a prolonged downswing period. Outside the seizure onset zone, the average frequency of theta bouts was higher in the RH compared to the LH (6.0 vs. 5.3 Hz). LH theta bouts had lower amplitudes and a higher prevalence compared to the RH (26% vs. 21% of total time). Additionally, the RH contained a population of thin spiking visually tuned neurons that were not present in the LH. These data show that human theta appears in short oscillatory bouts whose properties vary between hemispheres, thereby revealing neurophysiological properties of the hippocampus that differ between the hemispheres.

Extent of Single-Neuron Activity Modulation by Hippocampal Interictal Discharges Predicts Declarative Memory Disruption in Humans.

Memory deficits are common in epilepsy patients. In these patients, the interictal EEG commonly shows interictal epileptiform discharges (IEDs). While IEDs are associated with transient cognitive impairments, it remains poorly understood why this is. We investigated the effects of human (male and female) hippocampal IEDs on single-neuron activity during a memory task in patients with medically refractory epilepsy undergoing depth electrode monitoring. We quantified the effects of hippocampal IEDs on single-neuron activity and the impact of this modulation on subjectively declared memory strength. Across all recorded neurons, the activity of 50 of 728 neurons were significantly modulated by IEDs, with the strongest modulation in the medial temporal lobe (33 of 416) and in particular the right hippocampus (12 of 58). Putative inhibitory neurons, as identified by their extracellular signature, were more likely to be modulated by IEDs than putative excitatory neurons (19 of 157 vs 31 of 571). Behaviorally, the occurrence of hippocampal IEDs was accompanied by a disruption of recognition of familiar images only if they occurred up to 2 s before stimulus onset. In contrast, IEDs did not impair encoding or recognition of novel images, indicating high temporal and task specificity of the effects of IEDs. The degree of modulation of individual neurons by an IED correlated with the declared confidence of a retrieval trial, with higher firing rates indicative of reduced confidence. Together, these data link the transient modulation of individual neurons by IEDs to specific declarative memory deficits in specific cell types, thereby revealing a mechanism by which IEDs disrupt medial temporal lobe-dependent declarative memory retrieval processes.SIGNIFICANCE STATEMENT Interictal epileptiform discharges (IEDs) are thought to be a cause of memory deficits in chronic epilepsy patients, but the underlying mechanisms are not understood. Utilizing single-neuron recordings in epilepsy patients, we found that hippocampal IEDs transiently change firing of hippocampal neurons and disrupted selectively the retrieval, but not encoding, of declarative memories. The extent of the modulation of the individual firing of hippocampal neurons by an IED predicted the extent of reduction of subjective retrieval confidence. Together, these data reveal a specific kind of transient cognitive impairment caused by IEDs and link this impairment to the modulation of the activity of individual neurons. Understanding the mechanisms by which IEDs impact memory is critical for understanding memory impairments in epilepsy patients.

Value-Related Neuronal Responses in the Human Amygdala during Observational Learning.

The amygdala plays an important role in many aspects of social cognition and reward learning. Here, we aimed to determine whether human amygdala neurons are involved in the computations necessary to implement learning through observation. We performed single-neuron recordings from the amygdalae of human neurosurgical patients (male and female) while they learned about the value of stimuli through observing the outcomes experienced by another agent interacting with those stimuli. We used a detailed computational modeling approach to describe patients' behavior in the task. We found a significant proportion of amygdala neurons whose activity correlated with both expected rewards for oneself and others, and in tracking outcome values received by oneself or other agents. Additionally, a population decoding analysis suggests the presence of information for both observed and experiential outcomes in the amygdala. Encoding and decoding analyses suggested observational value coding in amygdala neurons occurred in a different subset of neurons than experiential value coding. Collectively, these findings support a key role for the human amygdala in the computations underlying the capacity for learning through observation.SIGNIFICANCE STATEMENT Single-neuron studies of the human brain provide a unique window into the computational mechanisms of cognition. In this study, epilepsy patients implanted intracranially with hybrid depth electrodes performed an observational learning (OL) task. We measured single-neuron activity in the amygdala and found a representation for observational rewards as well as observational expected reward values. Additionally, distinct subsets of amygdala neurons represented self-experienced and observational values. This study provides a rare glimpse into the role of human amygdala neurons in social cognition.

Single-neuron correlate of epilepsy-related cognitive deficits in visual recognition memory in right mesial temporal lobe.

OBJECTIVE: Impaired memory is a common comorbidity of refractory temporal lobe epilepsy (TLE) and often perceived by patients as more problematic than the seizures themselves. The objective of this study is to understand what the relationship of these behavioral impairments is to the underlying pathophysiology, as there are currently no treatments for these deficits, and it remains unknown what circuits are affected. METHODS: We recorded single neurons in the medial temporal lobes (MTLs) of 62 patients (37 with refractory TLE) who performed a visual recognition memory task to characterize the relationship between behavior, tuning, and anatomical location of memory selective and visually selective neurons. RESULTS: Subjects with a seizure onset zone (SOZ) in the right but not left MTL demonstrated impaired ability to recollect as indicated by the degree of asymmetry of the receiver operating characteristic curve. Of the 1973 recorded neurons, 159 were memory selective (MS) and 366 were visually selective (VS) category cells. The responses of MS neurons located within right but not left MTL SOZs were impaired during high-confidence retrieval trials, mirroring the behavioral deficit seen both in our task and in standardized neuropsychological tests. In contrast, responses of VS neurons were unimpaired in both left and right MTL SOZs. Our findings show that neuronal dysfunction within SOZs in the MTL was specific to a functional cell type and behavior, whereas other cell types respond normally even within the SOZ. We show behavioral metrics that detect right MTL SOZ-related deficits and identify a neuronal correlate of this impairment. SIGNIFICANCE: Together, these findings show that single-cell responses can be used to assess the causal effects of local circuit disruption by an SOZ in the MTL, and establish a neural correlate of cognitive impairment due to epilepsy that can be used as a biomarker to assess the efficacy of novel treatments.

Abstract goal representation in visual search by neurons in the human pre-supplementary motor area.

The medial frontal cortex is important for goal-directed behaviours such as visual search. The pre-supplementary motor area (pre-SMA) plays a critical role in linking higher-level goals to actions, but little is known about the responses of individual cells in this area in humans. Pre-SMA dysfunction is thought to be a critical factor in the cognitive deficits that are observed in diseases such as Parkinson's disease and schizophrenia, making it important to develop a better mechanistic understanding of the pre-SMA's role in cognition. We simultaneously recorded single neurons in the human pre-SMA and eye movements while subjects performed goal-directed visual search tasks. We characterized two groups of neurons in the pre-SMA. First, 40% of neurons changed their firing rate whenever a fixation landed on the search target. These neurons responded to targets in an abstract manner across several conditions and tasks. Responses were invariant to motor output (i.e. button press or not), and to different ways of defining the search target (by instruction or pop-out). Second, ∼50% of neurons changed their response as a function of fixation order. Together, our results show that human pre-SMA neurons carry abstract signals during visual search that indicate whether a goal was reached in an action- and cue-independent manner. This suggests that the pre-SMA contributes to goal-directed behaviour by flexibly signalling goal detection and time elapsed since start of the search, and this process occurs regardless of task. These observations provide insights into how pre-SMA dysfunction might impact cognitive function.

Human Episodic Memory Retrieval Is Accompanied by a Neural Contiguity Effect.

Cognitive psychologists have long hypothesized that experiences are encoded in a temporal context that changes gradually over time. When an episodic memory is retrieved, the state of context is recovered-a jump back in time. We recorded from single units in the medial temporal lobe of epilepsy patients performing an item recognition task. The population vector changed gradually over minutes during presentation of the list. When a probe from the list was remembered with high confidence, the population vector reinstated the temporal context of the original presentation of that probe during study, a neural contiguity effect that provides a possible mechanism for behavioral contiguity effects. This pattern was only observed for well remembered probes; old probes that were not well remembered showed an anti-contiguity effect. These results constitute the first direct evidence that recovery of an episodic memory in humans is associated with retrieval of a gradually changing state of temporal context, a neural "jump back in time" that parallels the act of remembering.SIGNIFICANCE STATEMENT Episodic memory is the ability to relive a specific experience from one's life. For decades, researchers have hypothesized that, unlike other forms of memory that can be described as simple associations between stimuli, episodic memory depends on the recovery of a neural representation of spatiotemporal context. During study of a sequence of stimuli, the brain state of epilepsy patients changed slowly over at least a minute. When the participant remembered a particular event from the list, this gradually changing state was recovered. This provides direct confirmation of the prediction from computational models of episodic memory. The resolution of this point means that the study of episodic memory can focus on the mechanisms by which this representation of spatiotemporal context is maintained and sometimes recovered.

Working Memory Load-related Theta Power Decreases in Dorsolateral Prefrontal Cortex Predict Individual Differences in Performance.

Holding information in working memory (WM) is an active and effortful process that is accompanied by sustained load-dependent changes in oscillatory brain activity. These proportional power increases are often reported in EEG studies recording theta over frontal midline sites. Intracranial recordings, however, yield mixed results, depending on the brain area being recorded from. We recorded intracranial EEG with depth electrodes in 13 patients with epilepsy who were performing a Sternberg WM task. Here, we investigated patterns of theta power changes as a function of memory load during maintenance in three areas critical for WM: dorsolateral prefrontal cortex (DLPFC), dorsal ACC (dACC), and hippocampus. Theta frequency power in both hippocampus and dACC increased during maintenance. In contrast, theta frequency power in the DLPFC decreased during maintenance, and this decrease was proportional to memory load. Only the power decreases in DLPFC, but not the power increases in hippocampus and dACC, were predictive of behavior in a given trial. The extent of the load-related theta power decreases in the DLPFC in a given participant predicted a participant's RTs, revealing that DLPFC theta explains individual differences in WM ability between participants. Together, these data reveal a pattern of theta power decreases in the DLPFC that is predictive of behavior and that is opposite of that in other brain areas. This result suggests that theta band power changes serve different cognitive functions in different brain areas and specifically that theta power decreases in DLPFC have an important role in maintenance of information.

Solving Constraint-Satisfaction Problems with Distributed Neocortical-Like Neuronal Networks.

Finding actions that satisfy the constraints imposed by both external inputs and internal representations is central to decision making. We demonstrate that some important classes of constraint satisfaction problems (CSPs) can be solved by networks composed of homogeneous cooperative-competitive modules that have connectivity similar to motifs observed in the superficial layers of neocortex. The winner-take-all modules are sparsely coupled by programming neurons that embed the constraints onto the otherwise homogeneous modular computational substrate. We show rules that embed any instance of the CSP's planar four-color graph coloring, maximum independent set, and sudoku on this substrate and provide mathematical proofs that guarantee these graph coloring problems will convergence to a solution. The network is composed of nonsaturating linear threshold neurons. Their lack of right saturation allows the overall network to explore the problem space driven through the unstable dynamics generated by recurrent excitation. The direction of exploration is steered by the constraint neurons. While many problems can be solved using only linear inhibitory constraints, network performance on hard problems benefits significantly when these negative constraints are implemented by nonlinear multiplicative inhibition. Overall, our results demonstrate the importance of instability rather than stability in network computation and offer insight into the computational role of dual inhibitory mechanisms in neural circuits.

Safety and Utility of Hybrid Depth Electrodes for Seizure Localization and Single-Unit Neuronal Recording.

BACKGROUND: Invasive electrode monitoring provides more precise localization of epileptogenic foci in patients with medically refractory epilepsy. The use of hybrid depth electrodes that include microwires for simultaneous single-neuron monitoring is becoming more widespread. OBJECTIVE: To determine the safety and utility of hybrid depth electrodes for intracranial monitoring of medically refractory epilepsy. METHODS: We reviewed the medical charts of 53 cases of medically refractory epilepsy operated on from 2006 to 2017, where both non-hybrid and hybrid microwire depth electrodes were used for intracranial monitoring. We assessed the localization accuracy and complications that arose to assess the relative safety and utility of hybrid depth electrodes compared with standard electrodes. RESULTS: A total of 555 electrodes were implanted in 52 patients. The overall per-electrode complication rate was 2.3%, with a per-case complication rate of 20.8%. There were no infections or deaths. Serious or hemorrhagic complications occurred in 2 patients (0.4% per-electrode risk). Complications did not correlate with the use of any particular electrode type, and hybrids were equally as reliable as standard electrodes in localizing seizure onset zones. CONCLUSIONS: Hybrid depth electrodes appear to be as safe and effective as standard depth electrodes for intracranial monitoring and provide unique opportunities to study the human brain at single-neuron resolution.

Neurons in the human amygdala selective for perceived emotion.

The human amygdala plays a key role in recognizing facial emotions and neurons in the monkey and human amygdala respond to the emotional expression of faces. However, it remains unknown whether these responses are driven primarily by properties of the stimulus or by the perceptual judgments of the perceiver. We investigated these questions by recording from over 200 single neurons in the amygdalae of 7 neurosurgical patients with implanted depth electrodes. We presented degraded fear and happy faces and asked subjects to discriminate their emotion by button press. During trials where subjects responded correctly, we found neurons that distinguished fear vs. happy emotions as expressed by the displayed faces. During incorrect trials, these neurons indicated the patients' subjective judgment. Additional analysis revealed that, on average, all neuronal responses were modulated most by increases or decreases in response to happy faces, and driven predominantly by judgments about the eye region of the face stimuli. Following the same analyses, we showed that hippocampal neurons, unlike amygdala neurons, only encoded emotions but not subjective judgment. Our results suggest that the amygdala specifically encodes the subjective judgment of emotional faces, but that it plays less of a role in simply encoding aspects of the image array. The conscious percept of the emotion shown in a face may thus arise from interactions between the amygdala and its connections within a distributed cortical network, a scheme also consistent with the long response latencies observed in human amygdala recordings.

Computation in dynamically bounded asymmetric systems.

Previous explanations of computations performed by recurrent networks have focused on symmetrically connected saturating neurons and their convergence toward attractors. Here we analyze the behavior of asymmetrical connected networks of linear threshold neurons, whose positive response is unbounded. We show that, for a wide range of parameters, this asymmetry brings interesting and computationally useful dynamical properties. When driven by input, the network explores potential solutions through highly unstable 'expansion' dynamics. This expansion is steered and constrained by negative divergence of the dynamics, which ensures that the dimensionality of the solution space continues to reduce until an acceptable solution manifold is reached. Then the system contracts stably on this manifold towards its final solution trajectory. The unstable positive feedback and cross inhibition that underlie expansion and divergence are common motifs in molecular and neuronal networks. Therefore we propose that very simple organizational constraints that combine these motifs can lead to spontaneous computation and so to the spontaneous modification of entropy that is characteristic of living systems.

Human memory strength is predicted by theta-frequency phase-locking of single neurons.

Learning from novel experiences is a major task of the central nervous system. In mammals, the medial temporal lobe is crucial for this rapid form of learning. The modification of synapses and neuronal circuits through plasticity is thought to underlie memory formation. The induction of synaptic plasticity is favoured by coordinated action-potential timing across populations of neurons. Such coordinated activity of neural populations can give rise to oscillations of different frequencies, recorded in local field potentials. Brain oscillations in the theta frequency range (3-8 Hz) are often associated with the favourable induction of synaptic plasticity as well as behavioural memory. Here we report the activity of single neurons recorded together with the local field potential in humans engaged in a learning task. We show that successful memory formation in humans is predicted by a tight coordination of spike timing with the local theta oscillation. More stereotyped spiking predicts better memory, as indicated by higher retrieval confidence reported by subjects. These findings provide a link between the known modulation of theta oscillations by many memory-modulating behaviours and circuit mechanisms of plasticity.

Synthesizing cognition in neuromorphic electronic systems.

The quest to implement intelligent processing in electronic neuromorphic systems lacks methods for achieving reliable behavioral dynamics on substrates of inherently imprecise and noisy neurons. Here we report a solution to this problem that involves first mapping an unreliable hardware layer of spiking silicon neurons into an abstract computational layer composed of generic reliable subnetworks of model neurons and then composing the target behavioral dynamics as a "soft state machine" running on these reliable subnets. In the first step, the neural networks of the abstract layer are realized on the hardware substrate by mapping the neuron circuit bias voltages to the model parameters. This mapping is obtained by an automatic method in which the electronic circuit biases are calibrated against the model parameters by a series of population activity measurements. The abstract computational layer is formed by configuring neural networks as generic soft winner-take-all subnetworks that provide reliable processing by virtue of their active gain, signal restoration, and multistability. The necessary states and transitions of the desired high-level behavior are then easily embedded in the computational layer by introducing only sparse connections between some neurons of the various subnets. We demonstrate this synthesis method for a neuromorphic sensory agent that performs real-time context-dependent classification of motion patterns observed by a silicon retina.

Social Status as a Latent Variable in the Amygdala of Observers of Social Interactions.

Successful integration into a hierarchical social group requires knowledge of the status of each individual and of the rules that govern social interactions within the group. In species that lack morphological indicators of status, social status can be inferred by observing the signals exchanged between individuals. We simulated social interactions between macaques by juxtaposing videos of aggressive and appeasing displays where two individuals appeared in each other's line of sight and their displays were timed to suggest the reciprocation of dominant and subordinate signals. Viewers of these videos successfully inferred the social status of the interacting characters. Dominant individuals attracted more social attention from viewers even when they were not engaged in social displays. Neurons in the viewers' amygdala signaled the status of both the attended (fixated) and the unattended individuals suggesting that in third party observers of social interactions, the amygdala signals jointly the status of interacting parties. Highlights: Monkeys infer the social status of conspecifics from videos of simulated dyadic interactionsDuring fixations neural populations signal the social status of the attended individualsNeurons in the amygdala jointly encode the status of interacting individuals. In brief: Third party-viewers of pairwise dominant-subordinate interactions infer social status from the observed behaviors. Neurons in the amygdala are tuned to the inferred dominant/subordinate status of both individuals.

Single-neuron spiking variability in hippocampus dynamically tracks sensory content during memory formation in humans.

During memory formation, the hippocampus is presumed to represent the content of stimuli, but how it does so is unknown. Using computational modelling and human single-neuron recordings, we show that the more precisely hippocampal spiking variability tracks the composite features of each individual stimulus, the better those stimuli are later remembered. We propose that moment-to-moment spiking variability may provide a new window into how the hippocampus constructs memories from the building blocks of our sensory world.

Persistent activity during working memory maintenance predicts long-term memory formation in the human hippocampus.

Working Memory (WM) and Long-Term Memory (LTM) are often viewed as separate cognitive systems. Little is known about how these systems interact when forming memories. We recorded single neurons in the human medial temporal lobe while patients maintained novel items in WM and a subsequent recognition memory test for the same items. In the hippocampus but not the amygdala, the level of WM content-selective persist activity during WM maintenance was predictive of whether the item was later recognized with high confidence or forgotten. In contrast, visually evoked activity in the same cells was not predictive of LTM formation. During LTM retrieval, memory-selective neurons responded more strongly to familiar stimuli for which persistent activity was high while they were maintained in WM. Our study suggests that hippocampal persistent activity of the same cell supports both WM maintenance and LTM encoding, thereby revealing a common single-neuron component of these two memory systems.