Event-induced theta responses as a window on the dynamics of memory

An important, but often ignored distinction in the analysis of EEG signals is that between evoked activity and induced activity. Whereas evoked activity reflects the summation of transient post-synaptic potentials triggered by an event, induced activity, which is mainly oscillatory in nature, is thought to reflect changes in parameters controlling dynamic interactions within and between brain structures. We hypothesize that induced activity may yield information about the dynamics of cell assembly formation, activation and subsequent uncoupling, which may play a prominent role in different types of memory operations. We then describe a number of analysis tools that can be used to study the reactivity of induced rhythmic activity, both in terms of amplitude changes and of phase variability.

We briefly discuss how alpha, gamma and theta rhythms are thought to be generated, paying special attention to the hypothesis that the theta rhythm reflects dynamic interactions between the hippocampal system and the neocortex. This hypothesis would imply that studying the reactivity of scalp-recorded theta may provide a window on the contribution of the hippocampus to memory functions.

We review studies investigating the reactivity of scalp-recorded theta in paradigms engaging episodic memory, spatial memory and working memory. In addition, we review studies that relate theta reactivity to processes at the interface of memory and language. Despite many unknowns, the experimental evidence largely supports the hypothesis that theta activity plays a functional role in cell assembly formation, a process which may constitute the neural basis of memory formation and retrieval. The available data provide only highly indirect support for the hypothesis that scalp-recorded theta yields information about hippocampal functioning. It is concluded that studying induced rhythmic activity holds promise as an additional important way to study brain function.     

Context-dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval

According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled.     

Differential functional connectivity of prefrontal and medial temporal cortices during episodic memory retrieval

Some theories of brain function emphasize the interactions between brain areas as the major determinant of cognitive and behavioral operations. We explored such interactions in a PET study of episodic memory retrieval having three retrieval conditions, with differing levels of retrieval success. Functional connectivity of voxels located within Brodmann areas 10 and 45/47 in the right prefrontal cortex (RPFC) and the left hippocampus (LGH) with the rest of the brain was estimated using partial least squares. Area 10 and LGH showed an opposite pattern of functional connectivity, with a large expanse of bilateral limbic cortices that was equivalent in all tasks. However, during high retrieval, area 45/47 was included in this pattern. The results suggest that activity in portions of the RPFC reflects either memory retrieval mode or retrieval success, depending on other brain regions to which it is functionally linked. Hum. Brain Mapping 5:323–327, 1997. © 1997 Wiley-Liss, Inc.     

Medial prefrontal cortex cells show dynamic modulation with the hippocampal theta rhythm dependent on behavior

Both the hippocampus and the medial prefrontal cortex are essential for successful performance in learning- and memory-related tasks. Within the hippocampus the theta rhythm plays an integral role in the timing of action potentials of hippocampal neurons responding to elements of any given task. Medial prefrontal cortex (mPFC) neurons display firing rate changes to specific facets of behavioral tasks (Jung et al., 1998. Cereb Cortex 8:437--450). We recorded units in the mPFC and field potentials in the hippocampus to determine whether behaviorally correlated mPFC cells fired with phase relationships to the hippocampal theta rhythm. In two different behavioral tasks (running a linear track and foraging in two distinct environments) we found mPFC cells that alternated between theta entrained firing and nonphasic firing depending on the ongoing behavior, while other cells were modulated during all conditions in both tasks. The majority of the mPFC cells with a significant correlation of firing rate changes with behavior were entrained to hippocampal theta. Cells that fired to specific events during only one direction of running were predisposed to theta modulation only in that direction. mPFC neurons have the capability to respond to behaviorally relevant elements by dynamically alternating between hippocampal theta entrained and nonphasic firing.     

Functional connectivity of hippocampal and prefrontal networks during episodic and spatial memory based on real‐world environments

Several recent studies have compared episodic and spatial memory in neuroimaging paradigms in order to understand better the contribution of the hippocampus to each of these tasks. In the present study, we build on previous findings showing common neural activation in default network areas during episodic and spatial memory tasks based on familiar, real‐world environments (Hirshhorn et al. (2012) Neuropsychologia 50:3094–3106). Following previous demonstrations of the presence of functionally connected sub‐networks within the default network, we performed seed‐based functional connectivity analyses to determine how, depending on the task, the hippocampus and prefrontal cortex differentially couple with one another and with distinct whole‐brain networks. We found evidence for a medial prefrontal‐parietal network and a medial temporal lobe network, which were functionally connected to the prefrontal and hippocampal seeds, respectively, regardless of the nature of the memory task. However, these two networks were functionally connected with one another during the episodic memory task, but not during spatial memory tasks. Replicating previous reports of fractionation of the default network into stable sub‐networks, this study also shows how these sub‐networks may flexibly couple and uncouple with one another based on task demands. These findings support the hypothesis that episodic memory and spatial memory share a common medial temporal lobe‐based neural substrate, with episodic memory recruiting additional prefrontal sub‐networks. © 2014 Wiley Periodicals, Inc.     

Hippocampal‐prefrontal theta phase synchrony in planning of multi‐step actions based on memory retrieval

Planning of multi‐step actions based on the retrieval of acquired information is essential for efficient foraging. The hippocampus (HPC) and prefrontal cortex (PFC) may play critical roles in this process. However, in rodents, many studies investigating such roles utilized T‐maze tasks that only require one‐step actions (i.e., selection of one of two alternatives), in which memory retrieval and selection of an action based on the retrieval cannot be clearly differentiated. In monkeys, PFC has been suggested to be involved in planning of multi‐step actions; however, the synchrony between HPC and PFC has not been evaluated. To address the combined role of the regions in planning of multi‐step actions, we introduced a task in rats that required three successive nose‐poke responses to three sequentially illuminated nose‐poke holes. During the task, local field potentials (LFP) and spikes from hippocampal CA1 and medial PFC (mPFC) were simultaneously recorded. The position of the first hole indicated whether the following two holes would be presented in a predictable sequence or not. During the first nose‐poke period, phase synchrony of LFPs in the theta range (4–10 Hz) between the regions was not different between predictable and unpredictable trials. However, only in trials of predictable sequences, the magnitude of theta phase synchrony during the first nose‐poke period was negatively correlated with latency of the two‐step ahead nose‐poke response. Our findings point to the HPC‐mPFC theta phase synchrony as a key mechanism underlying planning of multi‐step actions based on memory retrieval rather than the retrieval itself.     

Medial septal modulation of hippocampal theta cell discharges

The effect of small electrolytic lesions in various areas of the septum on the behavioral correlates and firing repertoires of hippocampal theta cells, was investigated in the freely moving rabbit. Lesions localized to the medial septum were found to abolish both slow wave theta and the rhythmic firing of CA1 and dentate layer theta cells, in both the type 1 theta (movement) and type 2 theta (sensory processing) behavior conditions. Small lesions of the diagonal band, lateral septum and fimbria/fornix regions only affected rhythmicity to the extent that they also involved the medial septal region. The same medial septal lesions that abolished rhythmicity were also shown to reduce the mean discharge rate of theta cells occurring during the type 1 movement condition by approximately 50%, while the discharge rate occurring during the type 2 sensory processing condition did not change significantly. Behavioral changes were also only observed for lesions involving the medial septum. The importance of afferent input from the medial septum in the generation of hippocampal theta cell rhythmicity was discussed.     

Increase in hippocampal theta oscillations during spatial decision making

The processing of spatial and mnemonic information is believed to depend on hippocampal theta oscillations (5–12 Hz). However, in rats both the power and the frequency of the theta rhythm are modulated by locomotor activity, which is a major confounding factor when estimating its cognitive correlates. Previous studies have suggested that hippocampal theta oscillations support decision‐making processes. In this study, we investigated to what extent spatial decision making modulates hippocampal theta oscillations when controlling for variations in locomotion speed. We recorded local field potentials from the CA1 region of rats while animals had to choose one arm to enter for reward (goal) in a four‐arm radial maze. We observed prominent theta oscillations during the decision‐making period of the task, which occurred in the center of the maze before animals deliberately ran through an arm toward goal location. In speed‐controlled analyses, theta power and frequency were higher during the decision period when compared to either an intertrial delay period (also at the maze center), or to the period of running toward goal location. In addition, theta activity was higher during decision periods preceding correct choices than during decision periods preceding incorrect choices. Altogether, our data support a cognitive function for the hippocampal theta rhythm in spatial decision making. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Hippocampal–prefrontal interactions during spatial decision-making

The hippocampus has been linked to memory encoding and spatial navigation, while the prefrontal cortex is associated with cognitive functions such as decision-making. These regions are hypothesized to communicate in tasks that demand both spatial navigation and decision-making processes. However, the electrophysiological signatures underlying this communication remain to be better elucidated. To investigate the dynamics of the hippocampal–prefrontal interactions, we have analyzed their local field potentials and spiking activity recorded from rats performing a spatial alternation task on a figure eight-shaped maze. We found that the phase coherence of theta peaked around the choice point area of the maze. Moreover, Granger causality revealed a hippocampus → prefrontal cortex directionality of information flow at theta frequency, peaking at starting areas of the maze, and on the reverse direction at delta frequency, peaking near the turn onset. Additionally, the patterns of phase-amplitude cross-frequency coupling within and between the regions also showed spatial selectivity, and hippocampal theta and prefrontal delta modulated not only gamma amplitude but also inter-regional gamma synchrony. Finally, we found that the theta rhythm dynamically modulated neurons in both regions, with the highest modulation at the choice area; interestingly, prefrontal cortex neurons were more strongly modulated by the hippocampal theta rhythm than by their local field rhythm. In all, our results reveal maximum electrophysiological interactions between the hippocampus and the prefrontal cortex near the decision-making period of the spatial alternation task, corroborating the hypothesis that a dynamic interplay between these regions takes place during spatial decisions.     

Left temporal alpha band activity increases during working memory retention of pitches

The functional role and regional specificity of ～10 Hz alpha band activity remains of debate. Alpha band activity is strongly modulated in visual working memory tasks and it has been proposed to subserve resource allocation by disengaging task‐irrelevant regions. It remains unknown if alpha band activity plays a similar role during auditory working memory processing. In this study we applied whole‐head magnetoencephalography to investigate brain activity in a delayed‐match‐to‐sample task including pure tones, non‐harmonic complex tones and harmonic tones. The paradigm included a control condition in which no active auditory maintenance was required. We observed a bilateral increase in 5–12 Hz power during the perception of harmonic and non‐harmonic complex tones compared with the control tone. During the maintenance period a left‐lateralized increase in 5–12 Hz was found for all stimuli compared with the control condition. Using a beam‐forming approach we identified the sources in left temporal regions. Given that functional magnetic resonance imaging, positron emission tomography and lesion studies have identified right hemisphere regions to be engaged in memory of pitch, we propose that the 5–12 Hz activity serves to functionally disengage left temporal regions. Our findings support the notion that alpha activity is a general mechanism for disengaging task‐irrelevant regions.     

Medial prefrontal cortex and nucleus accumbens core are involved in retrieval of the methamphetamine-associated memory

Immunohistochemical Fos staining has proven to be a method to identify the neurons that are activated by stimulation. Although methamphetamine (MA)-conditioned place preference (CPP) memory was long-lasting, how this memory was established and retrieved remained unknown. We used the vehicle- and MA-conditioned environment (including cues and context) to reactivate the MA-CPP memory in mice. In the limbic system, Fos-positive neurons were examined following retrieval of the MA-CPP memory. We demonstrated that the current conditioning procedure produced reliable MA-CPP performance. Moreover, enhanced Fos expressions were found in the medial prefrontal cortex and the core of the nucleus accumbens after reactivation of the MA-CPP memory. Furthermore, familiarity with the environmental cues/context was found to significantly enhance Fos expressions in dorsal striatum and dentate gyrus. Nucleus accumbens shell, basolateral or lateral amygdala, in this regard, did not seem to be involved in retrieval of the MA-CPP memory. These results, taken together, suggest that the medial prefrontal cortex and the core of the nucleus accumbens are anatomical substrates responsible for reactivation of the MA-CPP memory.     

Ventrolateral prefrontal cortex and self-initiated semantic elaboration during memory retrieval

Left ventrolateral prefrontal cortex (LVPFC) is often implicated in neuroimaging studies of context memory retrieval. This activation has been argued to reflect proactive semantic processing that facilitates recollection of past events, or instead to reflect a reactive response to experienced episodic interference. We investigated these characterizations in an fMRI study that manipulated the relative distinctiveness of encoding across subsequent targets and lures by varying encoding task manipulations. Critically, during later testing, retrieval queries and prior target processing where held constant across the distinctive and non-distinctive testing conditions, and therefore any differences in cortical activity would be linked to subject-initiated retrieval strategies. We found that LVPFC activity was specific to context retrieval under distinctive conditions even though this condition demonstrated the least interference. The results suggest that this region is critical for self-initiated semantic elaboration during retrieval, and this conclusion was bolstered by finding that LVPFC activity predicted individual differences in context memory discrimination. In line with Tulving's Encoding Specificity Principle, we suggest that subjects actively construct semantic retrieval cues, reflected in increased VLPFC activation, in an attempt to isolate the distinctive semantic features of hypothetical experiences when possible. If successful, this improves the match between retrieval cue and engram and facilitates performance.     

Differential activation of ventrolateral prefrontal cortex during working memory retrieval

Brain imaging studies have suggested a predominant involvement of prefrontal areas during retrieval of information from working memory (WM). This study used event-related functional magnetic resonance imaging to assess the gradual recruitment of brain areas during verbal WM-retrieval with a parametrically varied modified version of the Sternberg Item Recognition Paradigm. In particular, we were interested in activation differences during retrieval of negative and positive probes. Fifteen subjects performed a WM-task which required the retrieval of a probe letter from a set of a maximum of three letters. The analysis of the retrieval period regardless of probe type revealed bilateral VLPFC activation during retrieval from a single remembered item. These initially activated regions showed a gradual activation increase of left VLPFC (BA 47) and anterior PFC (BA 10) as well as and bilateral DLPFC (BA 9) with increasing retrieval demand, i.e. during retrieval of two and three previously remembered letters. The comparison of negative and positive probes (non-targets versus targets) revealed greater activity in VLPFC (BA 47) in response to negative than to positive probes. These findings demonstrate that ventral areas of prefrontal cortex seem to be differentially engaged during the discrimination of a non-target from a previously manipulated set.     

Medial temporal lobe activation during encoding and retrieval of novel face-name pairs

The human medial temporal lobe (MTL) is known to be involved in declarative memory, yet the exact contributions of the various MTL structures are not well understood. In particular, the data as to whether the hippocampal region is preferentially involved in the encoding and/or retrieval of associative memory have not allowed for a consensus concerning its specific role. To investigate the role of the hippocampal region and the nearby MTL cortical areas in encoding and retrieval of associative versus non-associative memories, we used functional magnetic resonance imaging (fMRI) to measure brain activity during learning and later recognition testing of novel face-name pairs. We show that there is greater activity for successful encoding of associative information than for non-associative information in the right hippocampal region, as well as in the left amygdala and right parahippocampal cortex. Activity for retrieval of associative information was greater than for non-associative information in the right hippocampal region also, as well as in the left perirhinal cortex, right entorhinal cortex, and right parahippocampal cortex. The implications of these data for a clear functional distinction between the hippocampal region and the MTL cortical structures are discussed.     

The role of replay and theta sequences in mediating hippocampal‐prefrontal interactions for memory and cognition

Sequential activity is seen in the hippocampus during multiple network patterns, prominently as replay activity during both awake and sleep sharp‐wave ripples (SWRs), and as theta sequences during active exploration. Although various mnemonic and cognitive functions have been ascribed to these hippocampal sequences, evidence for these proposed functions remains primarily phenomenological. Here, we briefly review current knowledge about replay events and theta sequences in spatial memory tasks. We reason that in order to gain a mechanistic and causal understanding of how these patterns influence memory and cognitive processing, it is important to consider how these sequences influence activity in other regions, and in particular, the prefrontal cortex, which is crucial for memory‐guided behavior. For spatial memory tasks, we posit that hippocampal‐prefrontal interactions mediated by replay and theta sequences play complementary and overlapping roles at different stages in learning, supporting memory encoding and retrieval, deliberative decision making, planning, and guiding future actions. This framework offers testable predictions for future physiology and closed‐loop feedback inactivation experiments for specifically targeting hippocampal sequences as well as coordinated prefrontal activity in different network states, with the potential to reveal their causal roles in memory‐guided behavior.     

Interplay of the long axis of the hippocampus and ventromedial prefrontal cortex in schema‐related memory retrieval

When new information is relevant to prior knowledge or schema, it can be learned and remembered better. Rodent studies have suggested that the hippocampus and ventromedial prefrontal cortex (vmPFC) are important for processing schema‐related information. However, there are inconsistent findings from human studies on the involvement of the hippocampus and its interaction with the vmPFC in schema‐related memory retrieval. To address these issues, we used a human analog of the rodent spatial schema task to compare brain activity during immediate retrieval of paired associations (PAs) in schema‐consistent and schema‐inconsistent conditions. The results showed that the anterior hippocampus was more involved in retrieving PAs in the schema‐consistent condition than in the schema‐inconsistent condition. Connectivity analyses showed that the anterior hippocampus had stronger coupling with the vmPFC when the participants retrieved newly learned PAs successfully in the schema‐consistent (vs. schema‐inconsistent) condition, whereas the coupling of the posterior hippocampus with the vmPFC showed the opposite. Taken together, the results shed light on how the long axis of the hippocampus and vmPFC interact to serve memory retrieval via different networks that differ by schema condition.     

The CAN‐In network: A biologically inspired model for self‐sustained theta oscillations and memory maintenance in the hippocampus

During working memory tasks, the hippocampus exhibits synchronous theta‐band activity, which is thought to be correlated with the short‐term memory maintenance of salient stimuli. Recent studies indicate that the hippocampus contains the necessary circuitry allowing it to generate and sustain theta oscillations without the need of extrinsic drive. However, the cellular and network mechanisms supporting synchronous rhythmic activity are far from being fully understood. Based on electrophysiological recordings from hippocampal pyramidal CA1 cells, we present a possible mechanism for the maintenance of such rhythmic theta‐band activity in the isolated hippocampus. Our model network, based on the Hodgkin‐Huxley formalism, comprising pyramidal neurons equipped with calcium‐activated nonspecific cationic (CAN) ion channels, is able to generate and sustain synchronized theta oscillations (4–12 Hz), following a transient stimulation. The synchronous network activity is maintained by an intrinsic CAN current (I_CAN), in the absence of constant external input. When connecting the pyramidal‐CAN network to fast‐spiking inhibitory interneurons, the dynamics of the model reveal that feedback inhibition improves the robustness of fast theta oscillations, by tightening the synchronization of the pyramidal CAN neurons. The frequency and power of the theta oscillations are both modulated by the intensity of the I_CAN, which allows for a wide range of oscillation rates within the theta band. This biologically plausible mechanism for the maintenance of synchronous theta oscillations in the hippocampus aims at extending the traditional models of septum‐driven hippocampal rhythmic activity. © 2017 Wiley Periodicals, Inc.     

Oscillatory activity in parietal and dorsolateral prefrontal cortex during retention in visual short‐term memory: Additive effects of spatial attention and memory load

We used whole‐head magnetoencephalography to study the representation of objects in visual short‐term memory (VSTM) in the human brain. Subjects remembered the location and color of either two or four colored disks that were encoded from the left or right visual field (equal number of distractors in the other visual hemifield). The data were analyzed using time‐frequency methods, which enabled us to discover a strong oscillatory activity in the 8–15 Hz band during the retention interval. The study of the alpha power variation revealed two types of responses, in different brain regions. The first was a decrease in alpha power in parietal cortex, contralateral to the stimuli, with no load effect. The second was an increase of alpha power in parietal and lateral prefrontal cortex, as memory load increased, but without interaction with the hemifield of the encoded stimuli. The absence of interaction between side of encoded stimuli and memory load suggests that these effects reflect distinct underlying mechanisms. A novel method to localize the neural generators of load‐related oscillatory activity was devised, using cortically‐constrained distributed source‐localization methods. Some activations were found in the inferior intraparietal sulcus (IPS) and intraoccipital sulcus (IOS). Importantly, strong oscillatory activity was also found in dorsolateral prefrontal cortex (DLPFC). Alpha oscillatory activity in DLPFC was synchronized with the activity in parietal regions, suggesting that VSTM functions in the human brain may be implemented via a network that includes bilateral DLPFC and bilateral IOS/IPS as key nodes. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Recollective qualities modulate hippocampal activation during autobiographical memory retrieval

Recent neuroimaging studies report preferential hippocampal engagement during autobiographical memory (AM) retrieval. Although the basis of this preferential activation remains unclear, it may be related to the temporal specificity, recency, or recollective qualities of AMs, such as detail, emotionality, and personal significance. Typically, however, these variables are confounded, and thus we sought to investigate the contributions of each to hippocampal activation during AM retrieval. We conducted an event-related functional magnetic resonance imaging (fMRI) study in which participants retrieved temporally specific AMs and general, repeated AMs, and rated each for level of detail, emotion, or personal significance. These ratings, as well as the recency of AMs, were used in parametric modulation analyses to identify brain regions that correlated positively with ratings, independent of recency, and vice versa. Retrieval of AMs activated a number of regions, including the hippocampus. No differences in hippocampal activation were evident between specific and general AM retrieval, suggesting that temporal specificity, on its own, is not a key modulator of hippocampal activation. Activation of the left hippocampus during specific AM retrieval did vary with the level of detail, personal significance, and at a subthreshold level, emotionality, when the effect of recency was covaried out. Further, during general AM retrieval, all three recollective qualities modulated activity in the right hippocampus. Although the recency of specific AMs modulated hippocampal activation bilaterally, this effect dissipated in the left hippocampus when detail or emotionality was included as a covariate, and was no longer present in either hippocampus when personal significance was taken into account. Our results suggest that recollective qualities are important predictors of hippocampal engagement during AM retrieval independent of factors such as recency. These findings are consistent with theories of hippocampal function that emphasize its role in the recollection of multifaceted autobiographical experiences.