Hippocampal theta activity during encoding promotes subsequent associative memory in humans.

Hippocampal theta oscillations have been implicated in associative memory in humans. However, findings from electrophysiological studies using scalp electroencephalography or magnetoencephalography, and those using intracranial electroencephalography are mixed. Here we asked 10 pre-surgical epilepsy patients undergoing intracranial electroencephalography recording, along with 21 participants undergoing magnetoencephalography recordings, to perform an associative memory task, and examined whether hippocampal theta activity during encoding was predictive of subsequent associative memory performance. Across the intracranial electroencephalography and magnetoencephalography studies, we observed that theta power in the hippocampus increased during encoding, and that this increase differed as a function of subsequent memory, with greater theta activity for pairs that were successfully retrieved in their entirety compared with those that were not remembered. This helps to clarify the role of theta oscillations in associative memory formation in humans, and further, demonstrates that findings in epilepsy patients undergoing intracranial electroencephalography recordings can be extended to healthy participants undergoing magnetoencephalography recordings.

Theta power and theta-gamma coupling support long-term spatial memory retrieval.

Hippocampal theta oscillations have been implicated in spatial memory function in both rodents and humans. What is less clear is how hippocampal theta interacts with higher frequency oscillations to support long-term memory. Here we asked 10 presurgical epilepsy patients undergoing intracranial EEG recording to perform a long-term spatial memory task in desktop virtual reality and found that increased theta power in two discrete bands ("low" 2-5 Hz and "high" 6-11 Hz) during cued retrieval was associated with improved task performance. Similarly, increased coupling between "low" theta phase and gamma amplitude during the same period was associated with improved task performance. Finally, low and high gamma amplitude appeared to peak at different phases of the theta cycle; providing a novel connection between human hippocampal function and rodent data. These results help to elucidate the role of theta oscillations and theta-gamma phase-amplitude coupling in human long-term memory.

Linked networks for learning and expressing location-specific threat.

Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were "picked." Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or "bee sting"); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC-hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula-hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula-dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders.

Behavioral evidence for pattern separation in human episodic memory.

An essential feature of episodic memory is the ability to recall the multiple elements relating to one event from the multitude of elements relating to other, potentially similar events. Hippocampal pattern separation is thought to play a fundamental role in this process, by orthogonalizing the representations of overlapping events during encoding, to reduce interference between them during the process of pattern completion by which one or other is recalled. We introduce a new paradigm to test the hypothesis that similar memories, but not unrelated memories, are actively separated at encoding. Participants memorized events which were either unique or shared a common element with another event (paired "overlapping" events). We used a measure of dependency, originally devised to measure pattern completion, to quantify how much the probability of successfully retrieving associations from one event depends on successful retrieval of associations from the same event, an unrelated event or the overlapping event. In two experiments, we saw that within event retrievals were highly dependent, indicating pattern completion; retrievals from unrelated events were independent; and retrievals from overlapping events were antidependent (i.e., less than independent), indicating pattern separation. This suggests that representations of similar (overlapping) memories are actively separated, resulting in lowered dependency of retrieval performance between them, as would be predicted by the pattern separation account.

Holistic Recollection via Pattern Completion Involves Hippocampal Subfield CA3.

Episodic memories typically comprise multiple elements. A defining characteristic of episodic retrieval is holistic recollection, i.e., comprehensive recall of the elements a memorized event encompasses. A recent study implicated activity in the human hippocampus with holistic recollection of multi-element events based on cues (Horner et al., 2015). Here, we obtained ultra-high resolution functional neuroimaging data at 7 tesla in 30 younger adults (12 female) using the same paradigm. In accordance with anatomically inspired computational models and animal research, we found that metabolic activity in hippocampal subfield CA3 (but less pronounced in dentate gyrus) correlated with this form of mnemonic pattern completion across participants. Our study provides the first evidence in humans for a strong involvement of hippocampal subfield CA3 in holistic recollection via pattern completion.SIGNIFICANCE STATEMENT Memories of daily events usually involve multiple elements, although a single element can be sufficient to prompt recollection of the whole event. Such holistic recollection is thought to require reactivation of brain activity representing the full event from one event element ("pattern completion"). Computational and animal models suggest that mnemonic pattern completion is accomplished in a specific subregion of the hippocampus called CA3, but empirical evidence in humans was lacking. Here, we leverage the ultra-high resolution of 7 tesla neuroimaging to provide first evidence for a strong involvement of the human CA3 in holistic recollection of multi-element events via pattern completion.

Spatial and episodic memory tasks promote temporal lobe interictal spikes.

Reflex epilepsies have been demonstrated to exploit specific networks that subserve normal physiological function. It is unclear whether more common forms of epilepsy share this particular feature. By measuring interictal spikes in patients with a range of epilepsies, we show that 2 tasks known to specifically engage the hippocampus and temporal neocortex promoted increased interictal spiking within these regions, whereas a nonhippocampal dependent task did not. This indicates that interictal spike frequency may reflect the processing demands being placed on specific functional-anatomical networks in epilepsy. ANN NEUROL 2019;86:304-309.

Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers: An FMRI study.

Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5-5/week) completed a decision-making task. First, participants stated how much they were willing-to-pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision-making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and "value signals" where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness-to-pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision-related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain.

Human hippocampal theta power indicates movement onset and distance travelled.

Theta frequency oscillations in the 6- to 10-Hz range dominate the rodent hippocampal local field potential during translational movement, suggesting that theta encodes self-motion. Increases in theta power have also been identified in the human hippocampus during both real and virtual movement but appear as transient bursts in distinct high- and low-frequency bands, and it is not yet clear how these bursts relate to the sustained oscillation observed in rodents. Here, we examine depth electrode recordings from the temporal lobe of 13 presurgical epilepsy patients performing a self-paced spatial memory task in a virtual environment. In contrast to previous studies, we focus on movement-onset periods that incorporate both initial acceleration and an immediately preceding stationary interval associated with prominent theta oscillations in the rodent hippocampal formation. We demonstrate that movement-onset periods are associated with a significant increase in both low (2-5 Hz)- and high (6-9 Hz)-frequency theta power in the human hippocampus. Similar increases in low- and high-frequency theta power are seen across lateral temporal lobe recording sites and persist throughout the remainder of movement in both regions. In addition, we show that movement-related theta power is greater both before and during longer paths, directly implicating human hippocampal theta in the encoding of translational movement. These findings strengthen the connection between studies of theta-band activity in rodents and humans and offer additional insight into the neural mechanisms of spatial navigation.

Acute stress - but not aversive scene content - impairs spatial configuration learning.

Contextual learning pervades our perception and cognition and plays a critical role in adjusting to aversive and stressful events. Our ability to memorise spatial context has been studied extensively with the contextual cueing paradigm, in which participants search for targets among simple distractor cues and show search advantages for distractor configurations that repeat across trials. Mixed evidence suggests that confrontation with adversity can enhance as well as impair the contextual cueing effect. We aimed to investigate this relationship more systematically by devising a contextual cueing task that tests spatial configuration learning within complex visual scenes that were emotionally neutral or negative (Study 1) and was preceded by the Maastricht Acute Stress Test (MAST) or a no-stress control condition (Study 2). We demonstrate a robust contextual cueing effect that was comparable across negative and neutral scenes (Study 1). In Study 2, acute stress disrupted spatial configuration learning irrespective of scene valence and endogenous cortisol reactivity to stress. Together with the emerging evidence in the literature, our findings suggest that spatial configuration learning may be subject to complex regulation as a function of spatial or temporal proximity to a stressor, with potential implications for the development of stress-related psychopathology.

Allocentric spatial memory performance predicts intrusive memory severity in posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is characterized by distressing trauma-related memories. According to the dual representation theory, intrusive memories arise from strengthened egocentric encoding and a poor contextual encoding, with spatial context requiring allocentric processing. Contextualization of mental imagery is proposed to be formed hierarchically through the ventral visual stream (VVS) to the hippocampal formation. Here, we tested this notion by investigating whether neuronal aberrations in structures of the VVS or in the hippocampus, as well as allocentric memory performance are associated with intrusive memory severity. METHODS: The sample comprised 33 women with PTSD due to childhood trauma. Allocentric memory performance was measured with the virtual Town Square Task and T1-weighted images acquired on a 3T Siemens Scanner. Intrusive memories were evoked by presenting an audio script describing parts of their trauma (script-driven imagery). RESULTS: Using hierarchical linear regression analysis, we found a significant association between lower intrusive memory severity and higher allocentric spatial memory, controlling for age, working memory, and general visuospatial ability. No significant association was found between cortical thickness of VVS structures, hippocampal volume and intrusive memory severity. Post hoc exploratory analyses revealed a negative correlation between years since index trauma and left hippocampal volume. LIMITATIONS: Our results are based on correlational analyses, causality cannot be inferred. CONCLUSION: This study supports the dual representation theory, which emphasizes the role of allocentric spatial memory for the contextualization of mental imagery in PTSD. Clinical implications are discussed.

Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion.

Background: Despite the current shift towards permissive cannabis policies, few studies have investigated the pleasurable effects users seek. Here, we investigate the effects of cannabis on listening to music, a rewarding activity that frequently occurs in the context of recreational cannabis use. We additionally tested how these effects are influenced by cannabidiol, which may offset cannabis-related harms. Methods: Across 3 sessions, 16 cannabis users inhaled cannabis with cannabidiol, cannabis without cannabidiol, and placebo. We compared their response to music relative to control excerpts of scrambled sound during functional Magnetic Resonance Imaging within regions identified in a meta-analysis of music-evoked reward and emotion. All results were False Discovery Rate corrected (P<.05). Results: Compared with placebo, cannabis without cannabidiol dampened response to music in bilateral auditory cortex (right: P=.005, left: P=.008), right hippocampus/parahippocampal gyrus (P=.025), right amygdala (P=.025), and right ventral striatum (P=.033). Across all sessions, the effects of music in this ventral striatal region correlated with pleasure ratings (P=.002) and increased functional connectivity with auditory cortex (right: P< .001, left: P< .001), supporting its involvement in music reward. Functional connectivity between right ventral striatum and auditory cortex was increased by cannabidiol (right: P=.003, left: P=.030), and cannabis with cannabidiol did not differ from placebo on any functional Magnetic Resonance Imaging measures. Both types of cannabis increased ratings of wanting to listen to music (P<.002) and enhanced sound perception (P<.001). Conclusions: Cannabis dampens the effects of music in brain regions sensitive to reward and emotion. These effects were offset by a key cannabis constituent, cannabidol.

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.

Medial Prefrontal Cortex: Adding Value to Imagined Scenarios.

The medial prefrontal cortex (mPFC) is consistently implicated in the network supporting autobiographical memory. Whereas more posterior regions in this network have been related to specific processes, such as the generation of visuospatial imagery or the association of items and contexts, the functional contribution of the mPFC remains unclear. However, the involvement of mPFC in estimation of value during decision-making suggests that it might play a similar role in memory. We investigated whether mPFC activity reflects the subjective value of elements in imagined scenarios. Participants in an MRI scanner imagined scenarios comprising a spatial context, a physiological state of need (e.g., thirst), and two items that could be congruent (e.g., drink) or incongruent (e.g., food) with the state of need. Memory for the scenarios was tested outside the scanner. Our manipulation of subjective value by imagined need was verified by increased subjective ratings of value for congruent items and improved subsequent memory for them. Consistent with our hypothesis, fMRI signal in mPFC reflected the modulation of an item's subjective value by the imagined physiological state, suggesting the mPFC selectively tracked subjective value within our imagination paradigm. Further analyses showed uncorrected effects in non-mPFC regions, including increased activity in the insula when imagining states of need, the caudate nucleus when imagining congruent items, and the anterior hippocampus/amygdala when imagining subsequently remembered items. We therefore provide evidence that the mPFC plays a role in constructing the subjective value of the components of imagined scenarios and thus potentially in reconstructing the value of components of autobiographical recollection.

Extinction learning is slower, weaker and less context specific after alcohol.

Alcohol is frequently involved in psychological trauma and often used by individuals to reduce fear and anxiety. We examined the effects of alcohol on fear acquisition and extinction within a virtual environment. Healthy volunteers were administered alcohol (0.4g/kg) or placebo and underwent acquisition and extinction from different viewpoints of a virtual courtyard, in which the conditioned stimulus, paired with a mild electric shock, was centrally located. Participants returned the following day to test fear recall from both viewpoints of the courtyard. Skin conductance responses were recorded as an index of conditioned fear. Successful fear acquisition under alcohol contrasted with impaired extinction learning evidenced by persistent conditioned responses (Experiment 1). Participants' impairments in extinction under alcohol correlated with impairments in remembering object-locations in the courtyard seen from one viewpoint when tested from the other viewpoint. Alcohol-induced extinction impairments were overcome by increasing the number of extinction trials (Experiment 2). However, a test of fear recall the next day showed persistent fear in the alcohol group across both viewpoints. Thus, alcohol impaired extinction rather than acquisition of fear, suggesting that extinction is more dependent than acquisition on alcohol-sensitive representations of spatial context. Overall, extinction learning under alcohol was slower, weaker and less context-specific, resulting in persistent fear at test that generalized to the extinction viewpoint. The selective effect on extinction suggests an effect of alcohol on prefrontal involvement, while the reduced context-specificity implicates the hippocampus. These findings have important implications for the use of alcohol by individuals with clinical anxiety disorders.

Negative affect impairs associative memory but not item memory.

The formation of associations between items and their context has been proposed to rely on mechanisms distinct from those supporting memory for a single item. Although emotional experiences can profoundly affect memory, our understanding of how it interacts with different aspects of memory remains unclear. We performed three experiments to examine the effects of emotion on memory for items and their associations. By presenting neutral and negative items with background contexts, Experiment 1 demonstrated that item memory was facilitated by emotional affect, whereas memory for an associated context was reduced. In Experiment 2, arousal was manipulated independently of the memoranda, by a threat of shock, whereby encoding trials occurred under conditions of threat or safety. Memory for context was equally impaired by the presence of negative affect, whether induced by threat of shock or a negative item, relative to retrieval of the context of a neutral item in safety. In Experiment 3, participants were presented with neutral and negative items as paired associates, including all combinations of neutral and negative items. The results showed both above effects: compared to a neutral item, memory for the associate of a negative item (a second item here, context in Experiments 1 and 2) is impaired, whereas retrieval of the item itself is enhanced. Our findings suggest that negative affect impairs associative memory while recognition of a negative item is enhanced. They support dual-processing models in which negative affect or stress impairs hippocampal-dependent associative memory while the storage of negative sensory/perceptual representations is spared or even strengthened.

Hot metacognition: poorer metacognitive efficiency following acute but not traumatic stress.

Aberrations to metacognition-the ability to reflect on and evaluate self-performance-are a feature of poor mental health. Theoretical models of post-traumatic stress disorder propose that following severe stress or trauma, maladaptive metacognitive evaluations and appraisals of the event drive the development of symptoms. Empirical research is required in order to reveal whether disruptions to metacognition cause or contribute to symptom development in line with theoretical accounts, or are simply a consequence of ongoing psychopathology. In two experiments, using hierarchical Bayesian modelling of metacognition measured in a memory recognition task, we assessed whether distortions to metacognition occur at a state-level after an acute stress induction, and/or at a trait-level in a sample of individuals experiencing intrusive memories following traumatic stress. Results from experiment 1, an in-person laboratory-based experiment, demonstrated that heightened psychological responses to the stress induction were associated with poorer metacognitive efficiency, despite there being no overall change in metacognitive efficiency from pre- to post-stress (N = 27). Conversely, in experiment 2, an online experiment using the same metamemory task, we did not find evidence of metacognitive alterations in a transdiagnostic sample of patients with intrusive memory symptomatology following traumatic stress (N = 36, compared to 44 matched controls). Our results indicate a relationship between state-level psychological responses to stress and metacognitive alterations. The lack of evidence for pre- to post-stress differences in metamemory illustrates the importance for future studies to reveal the direction of this relationship, and consequently the duration of stress-associated metacognitive impairments and their impact on mental health.

Wake slow waves in focal human epilepsy impact network activity and cognition.

Slow waves of neuronal activity are a fundamental component of sleep that are proposed to have homeostatic and restorative functions. Despite this, their interaction with pathology is unclear and there is only indirect evidence of their presence during wakefulness. Using intracortical recordings from the temporal lobe of 25 patients with epilepsy, we demonstrate the existence of local wake slow waves (LoWS) with key features of sleep slow waves, including a down-state of neuronal firing. Consistent with a reduction in neuronal activity, LoWS were associated with slowed cognitive processing. However, we also found that LoWS showed signatures of a homeostatic relationship with interictal epileptiform discharges (IEDs): exhibiting progressive adaptation during the build-up of network excitability before an IED and reducing the impact of subsequent IEDs on network excitability. We therefore propose an epilepsy homeostasis hypothesis: that slow waves in epilepsy reduce aberrant activity at the price of transient cognitive impairment.

Selective 5HT3 antagonists and sensory processing: a systematic review.

Ondansetron is a selective serotonin (5HT3) receptor antagonist that is under evaluation as an adjunctive treatment for schizophrenia, and a novel treatment for hallucinations in Parkinson's disease. Ondansetron reverses sensory gating deficits and improves visuoperceptual processing in animal models of psychosis, but it is unclear to what extent preclinical findings have been replicated in humans. We systematically reviewed human studies that evaluated the effects of ondansetron and other 5HT3 receptor antagonists on sensory gating deficits or sensory processing. Of 11 eligible studies, eight included patients with schizophrenia who were chronically stable on antipsychotic medication; five measured sensory gating using the P50 suppression response to a repeated auditory stimulus; others included tests of visuoperceptual function. Three studies in healthy participants included tests of visuoperceptual and sensorimotor function. A consistent and robust finding (five studies) was that ondansetron and tropisetron (5HT3 antagonist and α7-nicotinic receptor partial agonist) improved sensory gating in patients with schizophrenia. Tropisetron also improved sustained visual attention in non-smoking patients. There was inconsistent evidence of the effects of 5HT3 antagonists on other measures of sensory processing, but interpretation was limited by the small number of studies, methodological heterogeneity and the potential confounding effects of concomitant medication in patients. Despite these limitations, we found strong evidence that selective 5HT3 antagonists (with or without direct α7-nicotinic partial agonist effects) improved sensory gating. Future studies should investigate how this relates to potential improvement in neurocognitive symptoms in antipsychotic naive patients with prodromal or milder symptoms, in order to understand the clinical implications.

Location-dependent threat and associated neural abnormalities in clinical anxiety.

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment.

Reduced Memory Coherence for Negative Events and Its Relationship to Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is characterized by disruptions in memory, including vivid sensory images of the trauma that are involuntarily reexperienced. However, the extent and nature of disruptions to deliberate memory for trauma remain controversial. A unitary account posits that all aspects of memory for a traumatic event are strengthened. In contrast, a dual-representation account proposes up-modulation of sensory and affective representations of the negative content and down-modulation of hippocampal representations of the context in which the event occurred. We take a neuroscientific approach and review the literature concerning the mechanisms required to produce coherent episodic memories and how they are affected in experiments involving negative content. We find, in healthy volunteers, that negative content can reduce associative binding and the coherence of episodic memories. Finally, we bring these findings together with the literature on PTSD to highlight how similar associative mechanisms are affected in patients, consistent with hippocampal impairment, supporting a dual-representation view of disrupted memory coherence.