Who am I really? The ephemerality of the self-schema following vmPFC damage.

We studied the role of the ventromedial prefrontal cortex (vmPFC) in supporting the self-schema, by asking vmPFC patients, along with healthy and brain-damaged controls, to judge the degree to which they (or another person) were likely to engage in a series of activities, and how confident they were in their responses. Critically, participants provided their judgments on two separate occasions, a week apart. Our underlying assumption was that a strong self-schema would lead to confident and stable self-related judgments. We observed that control groups exhibited higher across-session consistency for self-related compared to other-related judgments, while this self-advantage was absent in vmPFC patients. In addition, regression analyses showed that in control groups the level of confidence associated with a specific (self- or other-related) judgment predicted the stability of that judgment across sessions. In contrast, vmPFC patients' confidence and rating consistency were aligned only for other-related judgments. By contrast, self-related judgments changed across sessions regardless of the confidence level with which they were initially endorsed. These findings indicate that the vmPFC is crucial to maintaining the self-schema and supporting the reliable retrieval of self-related information.

Rapid encoding of task regularities in the human hippocampus guides sensorimotor timing.

The brain encodes the statistical regularities of the environment in a task-specific yet flexible and generalizable format. Here, we seek to understand this process by bridging two parallel lines of research, one centered on sensorimotor timing, and the other on cognitive mapping in the hippocampal system. By combining functional magnetic resonance imaging (fMRI) with a fast-paced time-to-contact (TTC) estimation task, we found that the hippocampus signaled behavioral feedback received in each trial as well as performance improvements across trials along with reward-processing regions. Critically, it signaled performance improvements independent from the tested intervals, and its activity accounted for the trial-wise regression-to-the-mean biases in TTC estimation. This is in line with the idea that the hippocampus supports the rapid encoding of temporal context even on short time scales in a behavior-dependent manner. Our results emphasize the central role of the hippocampus in statistical learning and position it at the core of a brain-wide network updating sensorimotor representations in real time for flexible behavior.

Transforming social perspectives with cognitive maps.

Growing evidence suggests that cognitive maps represent relations between social knowledge similar to how spatial locations are represented in an environment. Notably, the extant human medial temporal lobe literature assumes associations between social stimuli follow a linear associative mapping from an egocentric viewpoint to a cognitive map. Yet, this form of associative social memory does not account for a core phenomenon of social interactions in which social knowledge learned via comparisons to the self, other individuals or social networks are assimilated within a single frame of reference. We argue that hippocampal-entorhinal coordinate transformations, known to integrate egocentric and allocentric spatial cues, inform social perspective switching between the self and others. We present evidence that the hippocampal formation helps inform social interactions by relating self vs other social attribute comparisons to society in general, which can afford rapid and flexible assimilation of knowledge about the relationship between the self and social networks of varying proximities. We conclude by discussing the ramifications of cognitive maps in aiding this social perspective transformation process in states of health and disease.

An immersive first-person navigation task for abstract knowledge acquisition.

Advances in virtual reality (VR) technology have greatly benefited spatial navigation research. By presenting space in a controlled manner, changing aspects of the environment one at a time or manipulating the gain from different sensory inputs, the mechanisms underlying spatial behaviour can be investigated. In parallel, a growing body of evidence suggests that the processes involved in spatial navigation extend to non-spatial domains. Here, we leverage VR technology advances to test whether participants can navigate abstract knowledge. We designed a two-dimensional quantity space-presented using a head-mounted display-to test if participants can navigate abstract knowledge using a first-person perspective navigation paradigm. To investigate the effect of physical movement, we divided participants into two groups: one walking and rotating on a motion platform, the other group using a gamepad to move through the abstract space. We found that both groups learned to navigate using a first-person perspective and formed accurate representations of the abstract space. Interestingly, navigation in the quantity space resembled behavioural patterns observed in navigation studies using environments with natural visuospatial cues. Notably, both groups demonstrated similar patterns of learning. Taken together, these results imply that both self-movement and remote exploration can be used to learn the relational mapping between abstract stimuli.

Impaired theta phase coupling underlies frontotemporal dysconnectivity in schizophrenia.

Frontotemporal dysconnectivity is a key pathology in schizophrenia. The specific nature of this dysconnectivity is unknown, but animal models imply dysfunctional theta phase coupling between hippocampus and medial prefrontal cortex (mPFC). We tested this hypothesis by examining neural dynamics in 18 participants with a schizophrenia diagnosis, both medicated and unmedicated; and 26 age, sex and IQ matched control subjects. All participants completed two tasks known to elicit hippocampal-prefrontal theta coupling: a spatial memory task (during magnetoencephalography) and a memory integration task. In addition, an overlapping group of 33 schizophrenia and 29 control subjects underwent PET to measure the availability of GABAARs expressing the α5 subunit (concentrated on hippocampal somatostatin interneurons). We demonstrate-in the spatial memory task, during memory recall-that theta power increases in left medial temporal lobe (mTL) are impaired in schizophrenia, as is theta phase coupling between mPFC and mTL. Importantly, the latter cannot be explained by theta power changes, head movement, antipsychotics, cannabis use, or IQ, and is not found in other frequency bands. Moreover, mPFC-mTL theta coupling correlated strongly with performance in controls, but not in subjects with schizophrenia, who were mildly impaired at the spatial memory task and no better than chance on the memory integration task. Finally, mTL regions showing reduced phase coupling in schizophrenia magnetoencephalography participants overlapped substantially with areas of diminished α5-GABAAR availability in the wider schizophrenia PET sample. These results indicate that mPFC-mTL dysconnectivity in schizophrenia is due to a loss of theta phase coupling, and imply α5-GABAARs (and the cells that express them) have a role in this process.

Human hippocampal theta oscillations reflect sequential dependencies during spatial planning.

Movement-related theta oscillations in rodent hippocampus coordinate 'forward sweeps' of location-specific neural activity that could be used to evaluate spatial trajectories online. This raises the possibility that increases in human hippocampal theta power accompany the evaluation of upcoming spatial choices. To test this hypothesis, we measured neural oscillations during a spatial planning task that closely resembles a perceptual decision-making paradigm. In this task, participants searched visually for the shortest path between a start and goal location in novel mazes that contained multiple choice points, and were subsequently asked to make a spatial decision at one of those choice points. We observed ~4-8 Hz hippocampal/medial temporal lobe theta power increases specific to sequential planning that were negatively correlated with subsequent decision speed, where decision speed was inversely correlated with choice accuracy. These results implicate the hippocampal theta rhythm in decision tree search during planning in novel environments.

Entorhinal transformations in abstract frames of reference.

Knowing how another's preferences relate to our own is a central aspect of everyday decision-making, yet how the brain performs this transformation is unclear. Here, we ask whether the putative role of the hippocampal-entorhinal system in transforming relative and absolute spatial coordinates during navigation extends to transformations in abstract decision spaces. During functional magnetic resonance imaging (fMRI), subjects learned a stranger's preference for an everyday activity-relative to one of three personally known individuals-and subsequently decided how the stranger's preference relates to the other two individuals' preferences. We observed entorhinal/subicular responses to the absolute distance between the ratings of the stranger and the familiar choice options. Notably, entorhinal/subicular signals were sensitive to which familiar individuals were being compared to the stranger. In contrast, striatal signals increased when accurately determining the ordinal position of choice options in relation to the stranger. Paralleling its role in navigation, these data implicate the entorhinal/subicular region in assimilating relatively coded knowledge within abstract metric spaces.

Planning and navigation as active inference.

This paper introduces an active inference formulation of planning and navigation. It illustrates how the exploitation-exploration dilemma is dissolved by acting to minimise uncertainty (i.e. expected surprise or free energy). We use simulations of a maze problem to illustrate how agents can solve quite complicated problems using context sensitive prior preferences to form subgoals. Our focus is on how epistemic behaviour-driven by novelty and the imperative to reduce uncertainty about the world-contextualises pragmatic or goal-directed behaviour. Using simulations, we illustrate the underlying process theory with synthetic behavioural and electrophysiological responses during exploration of a maze and subsequent navigation to a target location. An interesting phenomenon that emerged from the simulations was a putative distinction between 'place cells'-that fire when a subgoal is reached-and 'path cells'-that fire until a subgoal is reached.

The Role of Mental Maps in Decision-Making.

A growing body of work is investigating the use of mental maps during decision-making. Here we discuss how decision-making organizes experiences according to an internal model of the current task, thereby structuring memory. Likewise, we consider how the structure of mental maps contributes to decision-making.

The Neural Representation of Prospective Choice during Spatial Planning and Decisions.

We are remarkably adept at inferring the consequences of our actions, yet the neuronal mechanisms that allow us to plan a sequence of novel choices remain unclear. We used functional magnetic resonance imaging (fMRI) to investigate how the human brain plans the shortest path to a goal in novel mazes with one (shallow maze) or two (deep maze) choice points. We observed two distinct anterior prefrontal responses to demanding choices at the second choice point: one in rostrodorsal medial prefrontal cortex (rd-mPFC)/superior frontal gyrus (SFG) that was also sensitive to (deactivated by) demanding initial choices and another in lateral frontopolar cortex (lFPC), which was only engaged by demanding choices at the second choice point. Furthermore, we identified hippocampal responses during planning that correlated with subsequent choice accuracy and response time, particularly in mazes affording sequential choices. Psychophysiological interaction (PPI) analyses showed that coupling between the hippocampus and rd-mPFC increases during sequential (deep versus shallow) planning and is higher before correct versus incorrect choices. In short, using a naturalistic spatial planning paradigm, we reveal how the human brain represents sequential choices during planning without extensive training. Our data highlight a network centred on the cortical midline and hippocampus that allows us to make prospective choices while maintaining initial choices during planning in novel environments.

Medial Prefrontal-Medial Temporal Theta Phase Coupling in Dynamic Spatial Imagery.

Hippocampal-medial prefrontal interactions are thought to play a crucial role in mental simulation. Notably, the frontal midline/medial pFC (mPFC) theta rhythm in humans has been linked to introspective thought and working memory. In parallel, theta rhythms have been proposed to coordinate processing in the medial temporal cortex, retrosplenial cortex (RSc), and parietal cortex during the movement of viewpoint in imagery, extending their association with physical movement in rodent models. Here, we used noninvasive whole-head MEG to investigate theta oscillatory power and phase-locking during the 18-sec postencoding delay period of a spatial working memory task, in which participants imagined previously learned object sequences either on a blank background (object maintenance), from a first-person viewpoint in a scene (static imagery), or moving along a path past the objects (dynamic imagery). We found increases in 4- to 7-Hz theta power in mPFC when comparing the delay period with a preencoding baseline. We then examined whether the mPFC theta rhythm was phase-coupled with ongoing theta oscillations elsewhere in the brain. The same mPFC region showed significantly higher theta phase coupling with the posterior medial temporal lobe/RSc for dynamic imagery versus either object maintenance or static imagery. mPFC theta phase coupling was not observed with any other brain region. These results implicate oscillatory coupling between mPFC and medial temporal lobe/RSc theta rhythms in the dynamic mental exploration of imagined scenes.

Hippocampal Sharp-Wave Ripples Influence Selective Activation of the Default Mode Network.

The default mode network (DMN) is a commonly observed resting-state network (RSN) that includes medial temporal, parietal, and prefrontal regions involved in episodic memory [1-3]. The behavioral relevance of endogenous DMN activity remains elusive, despite an emerging literature correlating resting fMRI fluctuations with memory performance [4, 5]-particularly in DMN regions [6-8]. Mechanistic support for the DMN's role in memory consolidation might come from investigation of large deflections (sharp-waves) in the hippocampal local field potential that co-occur with high-frequency (>80 Hz) oscillations called ripples-both during sleep [9, 10] and awake deliberative periods [11-13]. Ripples are ideally suited for memory consolidation [14, 15], since the reactivation of hippocampal place cell ensembles occurs during ripples [16-19]. Moreover, the number of ripples after learning predicts subsequent memory performance in rodents [20-22] and humans [23], whereas electrical stimulation of the hippocampus after learning interferes with memory consolidation [24-26]. A recent study in macaques showed diffuse fMRI neocortical activation and subcortical deactivation specifically after ripples [27]. Yet it is unclear whether ripples and other hippocampal neural events influence endogenous fluctuations in specific RSNs-like the DMN-unitarily. Here, we examine fMRI datasets from anesthetized monkeys with simultaneous hippocampal electrophysiology recordings, where we observe a dramatic increase in the DMN fMRI signal following ripples, but not following other hippocampal electrophysiological events. Crucially, we find increases in ongoing DMN activity after ripples, but not in other RSNs. Our results relate endogenous DMN fluctuations to hippocampal ripples, thereby linking network-level resting fMRI fluctuations with behaviorally relevant circuit-level neural dynamics.

Human hippocampal processing of environmental novelty during spatial navigation.

The detection and processing of novel information encountered as we explore our environment is crucial for learning and adaptive behavior. The human hippocampus has been strongly implicated in laboratory tests of novelty detection and episodic memory, but has been less well studied during more ethological tasks such as spatial navigation, typically used in animals. We examined fMRI BOLD activity as a function of environmental and object novelty as humans performed an object-location virtual navigation task. We found greater BOLD response to novel relative to familiar environments in the hippocampus and adjacent parahippocampal gyrus. Object novelty was associated with increased activity in the posterior parahippocampal/fusiform gyrus and anterior hippocampus extending into the amygdala and superior temporal sulcus. Importantly, whilst mid-posterior hippocampus was more sensitive to environmental novelty than object novelty, the anterior hippocampus responded similarly to both forms of novelty. Amygdala activity showed an increase for novel objects that decreased linearly over the learning phase. By investigating how participants learn and use different forms of information during spatial navigation, we found that medial temporal lobe (MTL) activity reflects both the novelty of the environment and of the objects located within it. This novelty processing is likely supported by distinct, but partially overlapping, sets of regions within the MTL.

Medial prefrontal theta phase coupling during spatial memory retrieval.

Memory retrieval is believed to involve a disparate network of areas, including medial prefrontal and medial temporal cortices, but the mechanisms underlying their coordination remain elusive. One suggestion is that oscillatory coherence mediates inter-regional communication, implicating theta phase and theta-gamma phase-amplitude coupling in mnemonic function across species. To examine this hypothesis, we used non-invasive whole-head magnetoencephalography (MEG) as participants retrieved the location of objects encountered within a virtual environment. We demonstrate that, when participants are cued with the image of an object whose location they must subsequently navigate to, there is a significant increase in 4-8 Hz theta power in medial prefrontal cortex (mPFC), and the phase of this oscillation is coupled both with ongoing theta phase in the medial temporal lobe (MTL) and perceptually induced 65-85 Hz gamma amplitude in medial parietal cortex. These results suggest that theta phase coupling between mPFC and MTL and theta-gamma phase-amplitude coupling between mPFC and neocortical regions may play a role in human spatial memory retrieval.

Movement-related theta rhythm in humans: coordinating self-directed hippocampal learning.

The hippocampus is crucial for episodic or declarative memory and the theta rhythm has been implicated in mnemonic processing, but the functional contribution of theta to memory remains the subject of intense speculation. Recent evidence suggests that the hippocampus might function as a network hub for volitional learning. In contrast to human experiments, electrophysiological recordings in the hippocampus of behaving rodents are dominated by theta oscillations reflecting volitional movement, which has been linked to spatial exploration and encoding. This literature makes the surprising cross-species prediction that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. We examined the links between theta, spatial exploration, and memory encoding by designing an interactive human spatial navigation paradigm combined with multimodal neuroimaging. We used both non-invasive whole-head Magnetoencephalography (MEG) to look at theta oscillations and Functional Magnetic Resonance Imaging (fMRI) to look at brain regions associated with volitional movement and learning. We found that theta power increases during the self-initiation of virtual movement, additionally correlating with subsequent memory performance and environmental familiarity. Performance-related hippocampal theta increases were observed during a static pre-navigation retrieval phase, where planning for subsequent navigation occurred. Furthermore, periods of the task showing movement-related theta increases showed decreased fMRI activity in the parahippocampus and increased activity in the hippocampus and other brain regions that strikingly overlap with the previously observed volitional learning network (the reverse pattern was seen for stationary periods). These fMRI changes also correlated with participant's performance. Our findings suggest that the human hippocampal theta rhythm supports memory by coordinating exploratory movements in the service of self-directed learning. These findings directly extend the role of the hippocampus in spatial exploration in rodents to human memory and self-directed learning.

Anxiety, a benefit and detriment to cognition: behavioral and magnetoencephalographic evidence from a mixed-saccade task.

Anxiety is typically considered an impediment to cognition. We propose anxiety-related impairments in cognitive-behavioral performance are the consequences of enhanced stimulus-driven attention. Accordingly, reflexive, habitual behaviors that rely on stimulus-driven mechanisms should be facilitated in an anxious state, while novel, flexible behaviors that compete with the former should be impaired. To test these predictions, healthy adults (N=17) performed a mixed-saccade task, which pits habitual actions (pro-saccades) against atypical ones (anti-saccades), under anxiety-inducing threat of shock and safe conditions. Whole-head magnetoencephalography (MEG) captured oscillatory responses in the preparatory interval preceding target onset and saccade execution. Results showed threat-induced anxiety differentially impacted response times based on the type of saccade initiated, slowing anti-saccades but facilitating erroneous pro-saccades on anti-saccade trials. MEG source analyses revealed that successful suppression of reflexive pro-saccades and correct initiation of anti-saccades during threat was marked by increased theta power in right ventrolateral prefrontal cortical and midbrain regions (superior colliculi) implicated in stimulus-driven attention. Theta activity may delay stimulus-driven processes to enable generation of an anti-saccade. Moreover, compared to safety, threat reduced beta desynchronization in inferior parietal cortices during anti-saccade preparation but increased it during pro-saccade preparation. Differential effects in inferior parietal cortices indicate a greater readiness to execute anti-saccades during safety and to execute pro-saccades during threat. These findings suggest that, in an anxiety state, reduced cognitive-behavioral flexibility may stem from enhanced stimulus-driven attention, which may serve the adaptive function of optimizing threat detection.

Parahippocampal cortex: translating vision into space.

Two recent imaging studies have shed new light on information representation in human parahippocampal cortex. Despite their different approaches, the two studies both support the view that this brain region represents space at an elementary level.

Anxiety overrides the blocking effects of high perceptual load on amygdala reactivity to threat-related distractors.

Amygdala reactivity to threat-related distractor stimuli can be abolished in perceptually demanding contexts. Premised on the biological imperative to respond swiftly to threat, we demonstrate, however, that when participants are threatened by shock, greater amygdala responses to fearful compared to neutral distractor faces is preserved under conditions of high attentional demand. Lateral prefrontal cortices also showed selective responding to fearful distractor faces under these conditions, suggesting that threat-related distractor stimuli engaged attentional control mechanisms. We conclude that anxiety elicited by looming threat promotes neurocognitive processes that broaden attention and enhance sensitivity to potential danger cues, even when perceptual systems are taxed.

Phasic and sustained fear in humans elicits distinct patterns of brain activity.

Aversive events are typically more debilitating when they occur unpredictably than predictably. Studies in humans and animals indicate that predictable and unpredictable aversive events can induce phasic and sustained fear, respectively. Research in rodents suggests that anatomically related but distinct neural circuits may mediate phasic and sustained fear. We explored this issue in humans by examining threat predictability in three virtual reality contexts, one in which electric shocks were predictably signaled by a cue, a second in which shocks occurred unpredictably but never paired with a cue, and a third in which no shocks were delivered. Evidence of threat-induced phasic and sustained fear was presented using fear ratings and skin conductance. Utilizing recent advances in functional magnetic resonance imaging (fMRI), we were able to conduct whole-brain fMRI at relatively high spatial resolution and still have enough sensitivity to detect transient and sustained signal changes in the basal forebrain. We found that both predictable and unpredictable threat evoked transient activity in the dorsal amygdala, but that only unpredictable threat produced sustained activity in a forebrain region corresponding to the bed nucleus of the stria terminalis complex. Consistent with animal models hypothesizing a role for the cortex in generating sustained fear, sustained signal increases to unpredictable threat were also found in anterior insula and a frontoparietal cortical network associated with hypervigilance. In addition, unpredictable threat led to transient activity in the ventral amygdala-hippocampal area and pregenual anterior cingulate cortex, as well as transient activation and subsequent deactivation of subgenual anterior cingulate cortex, limbic structures that have been implicated in the regulation of emotional behavior and stress responses. In line with basic findings in rodents, these results provide evidence that phasic and sustained fear in humans may manifest similar signs of distress, but appear to be associated with different patterns of neural activity in the human basal forebrain.