A role for the fornix in temporal sequence memory.

Converging evidence from studies of human and nonhuman animals suggests that the hippocampus contributes to sequence learning by using temporal context to bind sequentially occurring items. The fornix is a white matter pathway containing the major input and output pathways of the hippocampus, including projections from medial septum and to diencephalon, striatum, lateral septum and prefrontal cortex. If the fornix meaningfully contributes to hippocampal function, then individual differences in fornix microstructure might predict sequence memory. Here, we tested this prediction by performing tractography in 51 healthy adults who had undertaken a sequence memory task. Microstructure properties of the fornix were compared with those of tracts connecting medial temporal lobe regions but not predominantly the hippocampus: the Parahippocampal Cingulum bundle (PHC) (conveying retrosplenial projections to parahippocampal cortex) and the Inferior Longitudinal Fasciculus (ILF) (conveying occipital projections to perirhinal cortex). Using principal components analysis, we combined Free-Water Elimination Diffusion Tensor Imaging and Neurite Orientation Dispersion and Density Imaging measures obtained from multi-shell diffusion MRI into two informative indices: the first (PC1) capturing axonal packing/myelin and the second (PC2) capturing microstructural complexity. We found a significant correlation between fornix PC2 and implicit reaction-time indices of sequence memory, indicating that greater fornix microstructural complexity is associated with better sequence memory. No such relationship was found with measures from the PHC and ILF. This study highlights the importance of the fornix in aiding memory for objects within a temporal context, potentially reflecting a role in mediating inter-regional communication within an extended hippocampal system.

Transient Neural Activation of Abstract Relations on an Incidental Analogy Task.

Although a large proportion of the lexicon consists of abstract concepts, little is known about how they are represented by the brain. Here, we investigated how the mind represents relations shared between sets of mental representations that are superficially unrelated, such as car-engine and dog-tongue, but that nonetheless share a more general, abstract relation, such as whole-part. Participants saw a pair of words on each trial and were asked to indicate whether they could think of a relation between them. Importantly, they were not explicitly asked whether different word pairs shared the same relation, as in analogical reasoning tasks. We observed representational similarity for abstract relations in regions in the "conceptual hub" network, even when controlling for semantic relatedness between word pairs. By contrast, we did not observe representational similarity in regions previously implicated in explicit analogical reasoning. A given relation was sometimes repeated across sequential word pairs, allowing us to test for behavioral and neural priming of abstract relations. Indeed, we observed faster RTs and greater representational similarity for primed than unprimed trials, suggesting that mental representations of abstract relations are transiently activated on this incidental analogy task. Finally, we found a significant correlation between behavioral and neural priming across participants. To our knowledge, this is the first study to investigate relational priming using functional neuroimaging and to show that neural representations are strengthened by relational priming. This research shows how abstract concepts can be brought to mind momentarily, even when not required for task performance.

Task-specific Disruptions in Theta Oscillations during Working Memory for Temporal Order in People with Schizophrenia.

Prior studies demonstrated that neural oscillations are enhanced during working memory (WM) maintenance and that this activity can predict behavioral performance in healthy individuals. However, it is unclear whether the relationship holds for people with WM deficits. People with schizophrenia have marked WM deficits, and such deficits are most prominent when patients are required to process relationships between items, such as temporal order. Here, we used EEG to compare the relationship between oscillatory activity and WM performance in patients and controls. EEG was recorded as participants performed tasks requiring maintenance of complex objects ("Item") or the temporal order of objects ("Order"). In addition to testing for group differences, we examined individual differences in EEG power and WM performance across groups. Behavioral results demonstrated that patients showed impaired performance on both Item and Order trials. EEG analyses revealed that patients showed an overall reduction in alpha power, but the relationship between alpha activity and performance was preserved. In contrast, patients showed a reduction in theta power specific to Order trials, and theta power could predict performance on Order trials in controls, but not in patients. These findings demonstrate that WM impairments in patients may reflect two different processes: a general deficit in alpha oscillations and a specific deficit in theta oscillations when temporal order information must be maintained. At a broader level, the results highlight the value of characterizing brain-behavior relationships, by demonstrating that the relationship between neural oscillations and WM performance can be fundamentally disrupted in those with WM deficits.

Neural repetition suppression effects in the human hippocampus.

Neurons in the temporal lobe cortex exhibit reduced responses when a stimulus or a stimulus feature is repeated. This phenomenon, termed "repetition suppression", is the basis for many functional imaging studies that have used Blood Oxygenation Level Dependent (BOLD) activity differences between novel and repeated items as an index of neural selectivity in hippocampal subfields. However, it is not clear how hippocampal neural activity changes across repeated exposure to a stimulus. Here, we used direct intracranial electroencephalography (iEEG) recordings of hippocampal activity to examine whether neural activity in the human hippocampus is modulated across successive repetitions of an item. Time-frequency analyses revealed that high-frequency activity, which is thought to include gamma oscillations and possible correlates of multi-unit activity, declined monotonically across successive presentations of an item. In contrast, low-frequency oscillations in the alpha and beta bands monotonically increased across successive presentations of an object. These results provide support for the assumption that, at least under some circumstances, repetition suppression (as measured by declines in high-frequency activity) can be observed in the hippocampus, and these effects are accompanied by increases in low-frequency oscillations as well.

Distinct Patterns of Temporal and Directional Connectivity among Intrinsic Networks in the Human Brain.

To determine the spatiotemporal relationships among intrinsic networks of the human brain, we recruited seven neurosurgical patients (four males and three females) who were implanted with intracranial depth electrodes. We first identified canonical resting-state networks at the individual subject level using an iterative matching procedure on each subject's resting-state fMRI data. We then introduced single electrical pulses to fMRI pre-identified nodes of the default network (DN), frontoparietal network (FPN), and salience network (SN) while recording evoked responses in other recording sites within the same networks. We found bidirectional signal flow across the three networks, albeit with distinct patterns of evoked responses within different time windows. We used a data-driven clustering approach to show that stimulation of the FPN and SN evoked a rapid (<70 ms) response that was predominantly higher within the SN sites, whereas stimulation of the DN led to sustained responses in later time windows (85-200 ms). Stimulations in the medial temporal lobe components of the DN evoked relatively late effects (>130 ms) in other nodes of the DN, as well as FPN and SN. Our results provide temporal information about the patterns of signal flow between intrinsic networks that provide insights into the spatiotemporal dynamics that are likely to constrain the architecture of the brain networks supporting human cognition and behavior.SIGNIFICANCE STATEMENT Despite great progress in the functional neuroimaging of the human brain, we still do not know the precise set of rules that define the patterns of temporal organization between large-scale networks of the brain. In this study, we stimulated and then recorded electrical evoked potentials within and between three large-scale networks of the brain, the default network (DN), frontoparietal network (FPN), and salience network (SN), in seven subjects undergoing invasive neurosurgery. Using a data-driven clustering approach, we observed distinct temporal and directional patterns between the three networks, with FPN and SN activity predominant in early windows and DN stimulation affecting the network in later windows. These results provide important temporal information about the interactions between brain networks supporting human cognition and behavior.

Theta Phase Synchronization between the Human Hippocampus and Prefrontal Cortex Increases during Encoding of Unexpected Information: A Case Study.

Events that violate predictions are thought to not only modulate activity within the hippocampus and PFC but also enhance communication between the two regions. Scalp and intracranial EEG studies have shown that oscillations in the theta frequency band are enhanced during processing of contextually unexpected information. Some theories suggest that the hippocampus and PFC interact during processing of unexpected events, and it is possible that theta oscillations may mediate these interactions. Here, we had the rare opportunity to conduct simultaneous electrophysiological recordings from the human hippocampus and PFC from two patients undergoing presurgical evaluation for pharmacoresistant epilepsy. Recordings were conducted during a task that involved encoding of contextually expected and unexpected visual stimuli. Across both patients, hippocampal-prefrontal theta phase synchronization was significantly higher during encoding of contextually unexpected study items, relative to contextually expected study items. Furthermore, the hippocampal-prefrontal theta phase synchronization was larger for contextually unexpected items that were later remembered compared with later forgotten items. Moreover, we did not find increased theta synchronization between the PFC and rhinal cortex, suggesting that the observed effects were specific to prefrontal-hippocampal interactions. Our findings are consistent with the idea that theta oscillations orchestrate communication between the hippocampus and PFC in support of enhanced encoding of contextually deviant information.

Theta oscillations promote temporal sequence learning.

Many theoretical models suggest that neural oscillations play a role in learning or retrieval of temporal sequences, but the extent to which oscillations support sequence representation remains unclear. To address this question, we used scalp electroencephalography (EEG) to examine oscillatory activity over learning of different object sequences. Participants made semantic decisions on each object as they were presented in a continuous stream. For three "Consistent" sequences, the order of the objects was always fixed. Activity during Consistent sequences was compared to "Random" sequences that consisted of the same objects presented in a different order on each repetition. Over the course of learning, participants made faster semantic decisions to objects in Consistent, as compared to objects in Random sequences. Thus, participants were able to use sequence knowledge to predict upcoming items in Consistent sequences. EEG analyses revealed decreased oscillatory power in the theta (4-7 Hz) band at frontal sites following decisions about objects in Consistent sequences, as compared with objects in Random sequences. The theta power difference between Consistent and Random only emerged in the second half of the task, as participants were more effectively able to predict items in Consistent sequences. Moreover, we found increases in parieto-occipital alpha (10-13 Hz) and beta (14-28 Hz) power during the pre-response period for objects in Consistent sequences, relative to objects in Random sequences. Linear mixed effects modeling revealed that single trial theta oscillations were related to reaction time for future objects in a sequence, whereas beta and alpha oscillations were only predictive of reaction time on the current trial. These results indicate that theta and alpha/beta activity preferentially relate to future and current events, respectively. More generally our findings highlight the importance of band-specific neural oscillations in the learning of temporal order information.

Cortical and subcortical contributions to sequence retrieval: Schematic coding of temporal context in the neocortical recollection network.

Episodic memory entails the ability to remember what happened when. Although the available evidence indicates that the hippocampus plays a role in structuring serial order information during retrieval of event sequences, information processed in the hippocampus must be conveyed to other cortical and subcortical areas in order to guide behavior. However, the extent to which other brain regions contribute to the temporal organization of episodic memory remains unclear. Here, we examined multivoxel activity pattern changes during retrieval of learned and random object sequences, focusing on a neocortical "core recollection network" that includes the medial prefrontal cortex, retrosplenial cortex, and angular gyrus, as well as on striatal areas including the caudate nucleus and putamen that have been implicated in processing of sequence information. The results demonstrate that regions of the core recollection network carry information about temporal positions within object sequences, irrespective of object information. This schematic coding of temporal information is in contrast to the putamen, which carried information specific to objects in learned sequences, and the caudate, which carried information about objects, irrespective of sequence context. Our results suggest a role for the cortical recollection network in the representation of temporal structure of events during episodic retrieval, and highlight the possible mechanisms by which the striatal areas may contribute to this process. More broadly, the results indicate that temporal sequence retrieval is a useful paradigm for dissecting the contributions of specific brain regions to episodic memory.

Frontal midline theta oscillations during working memory maintenance and episodic encoding and retrieval.

Neural oscillations in the theta band (4-8 Hz) are prominent in the human electroencephalogram (EEG), and many recent electrophysiological studies in animals and humans have implicated scalp-recorded frontal midline theta (FMT) in working memory and episodic memory encoding and retrieval processes. However, the functional significance of theta oscillations in human memory processes remains largely unknown. Here, we review studies in human and animals examining how scalp-recorded FMT relates to memory behaviors and also their possible neural generators. We also discuss models of the functional relevance of theta oscillations to memory processes and suggest promising directions for future research.

Neural oscillations associated with item and temporal order maintenance in working memory.

The ability to retain information in working memory (WM) requires not only the active maintenance of information about specific items, but also the temporal order in which the items appeared. Although many studies have investigated the neural mechanisms of item maintenance, little is known about the neural mechanisms of temporal order maintenance in WM. Here, we used electroencephalography (EEG) to compare neural oscillations during WM tasks that required maintenance of item or temporal order information. Behavioral results revealed that accuracy and reaction times were comparable between the two conditions, suggesting that task difficulty was matched between the item and temporal order WM tasks. EEG analyses indicated that theta (5-7 Hz) oscillations over prefrontal sites were increased during temporal order maintenance, whereas alpha oscillations (9-12 Hz) over posterior parietal and lateral occipital sites were increased during item maintenance. The frontal theta enhancement was primarily evident in high performers on the order WM task, whereas the posterior alpha enhancement was primarily evident in high performers on the item WM task. These results support the idea that frontal theta and posterior alpha oscillations are differentially related to maintenance of item and temporal order information.

Disrupted Modulation of Alpha and Low Beta Oscillations Mediates Temporal Sequence Memory Deficits in People With Schizophrenia.

BACKGROUND: People with schizophrenia (SZ) exhibit impaired episodic memory when relating objects to each other in time and space. Empirical studies and computational models suggest that low-frequency neural oscillations may be a mechanism by which the brain keeps track of temporal relationships during encoding and retrieval, with modulation of oscillatory power as sequences are learned. It is unclear whether sequence memory deficits in SZ are associated with altered neural oscillations. METHODS: Using electroencephalography, this study examined neural oscillations in 51 healthy control subjects and 37 people with SZ during a temporal sequence learning task. Multiple 5-object picture sequences were presented across 4 study-test blocks in either fixed or random order. Participants answered semantic questions for each object (e.g., living/nonliving), and sequence memory was operationalized as faster responses for fixed versus random sequences. Differences in oscillatory power between fixed versus random sequences provided a neural index of temporal sequence memory. RESULTS: Although both groups showed reaction time differences in late blocks (blocks 3 and 4), this evidence of sequence memory was reduced in people with SZ relative to healthy control subjects. Decreases in globally distributed prestimulus alpha (8-12 Hz) and beta 1 (13-20 Hz) power for fixed versus random sequences in late blocks were also attenuated in people with SZ relative to healthy control subjects. Moreover, changes in oscillatory power predicted individual reaction time differences and fully mediated the relationship between group and sequence memory. CONCLUSIONS: Disrupted modulation of alpha and beta 1 electroencephalography oscillations is a candidate mechanism of temporal sequence memory deficits in people with SZ.

The hippocampus: a special place for time.

Many findings have demonstrated that memories of past events are temporally organized. It is well known that the hippocampus is critical for such episodic memories, but, until recently, little was known about the temporal organization of mnemonic representations in the hippocampus. Recent developments in human and animal research have revealed important insights into the role of the hippocampus in learning and retrieving sequences of events. Here, we review these findings, including lesion and single-unit recording studies in rodents, functional magnetic resonance imaging studies in humans, and computational models that link findings from these studies to the anatomy of the hippocampal circuit. The findings converge toward the idea that the hippocampus is essential for learning sequences of events, allowing the brain to distinguish between memories for conceptually similar but temporally distinct episodes, and to associate representations of temporally contiguous, but otherwise unrelated experiences.

Hippocampal activity patterns carry information about objects in temporal context.

The hippocampus is critical for human episodic memory, but its role remains controversial. One fundamental question concerns whether the hippocampus represents specific objects or assigns context-dependent representations to objects. Here, we used multivoxel pattern similarity analysis of fMRI data during retrieval of learned object sequences to systematically investigate hippocampal coding of object and temporal context information. Hippocampal activity patterns carried information about the temporal positions of objects in learned sequences, but not about objects or temporal positions in random sequences. Hippocampal activity patterns differentiated between overlapping object sequences and between temporally adjacent objects that belonged to distinct sequence contexts. Parahippocampal and perirhinal cortex showed different pattern information profiles consistent with coding of temporal position and object information, respectively. These findings are consistent with models proposing that the hippocampus represents objects within specific temporal contexts, a capability that might explain its critical role in episodic memory.

Oscillatory activity during maintenance of spatial and temporal information in working memory.

Working memory (WM) processes help keep information in an active state so it can be used to guide future behavior. Although numerous studies have investigated brain activity associated with spatial WM in humans and monkeys, little research has focused on the neural mechanisms of WM for temporal order information, and how processing of temporal and spatial information might differ. Available evidence indicates that similar frontoparietal regions are recruited during temporal and spatial WM, although there are data suggesting that they are distinct processes. The mechanisms that allow for differential maintenance of these two types of information are unclear. One possibility is that neural oscillations may differentially contribute to temporal and spatial WM. In the present study, we used scalp electroencephalography (EEG) to compare patterns of oscillatory activity during maintenance of spatial and temporal information in WM. Time-frequency analysis of EEG data revealed enhanced left frontal theta (5-8 Hz), enhanced posterior alpha (9-12 Hz), and enhanced left posterior beta (14-28 Hz) power during the delay period of correct temporal order trials compared to correct spatial trials. In contrast, gamma (30-50 Hz) power at right lateral frontal sites was increased during the delay period of spatial WM trials, as compared to temporal WM trials. The present results are consistent with the idea that neural oscillatory patterns provide distinct mechanisms for the maintenance of temporal and spatial information in WM. Specifically, theta oscillations are most critical for the maintenance of temporal information in WM. Possible roles of higher frequency oscillations in temporal and spatial memory are also discussed.

An event-related potential investigation of the processing of Remember/Forget cues and item encoding in item-method directed forgetting.

This study examined the electrophysiological correlates of the processing of the Remember/Forget cues and the successful encoding of study items in item-method directed forgetting. Subjects engaged in an old/new recognition test and an item-method directed forgetting task. Event-related potentials (ERPs) time-locked to study items and Remember/Forget cues were compared according to the subsequent recognition performance. A reliable subsequent memory effect was elicited by the study items in the old/new recognition test. In contrast, the study items in the directed forgetting task did not yield reliable subsequent memory effects. Importantly, the Remember/Forget cues gave rise to ERPs that were predictive of the subsequent recognition performance to the study items preceding the cues. The subsequent memory effect elicited by the Remember cues was more sustained than that elicited by the Forget cues and showed distinct scalp distribution during the extended period. These results suggest that study items in the directed forgetting task are maintained in short-term memory with minimal further processing until the presentation of the Remember/Forget cues. In addition, the encoding mechanisms engaged by Remember cues and Forget cues are not entirely equivalent.