Learning related interactions among neuronal systems involved in memory processes

Functional neuroimaging techniques using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have provided new insights in our understanding of brain function from the molecular to the systems level. While subtraction strategy based data analyses have revealed the involvement of distributed brain regions in memory processes, covariance analysis based data analysis strategies allow functional interactions between brain regions of a neuronal network to be assessed. The focus of this chapter is to (1) establish the functional topography of episodic and working memory processes in young and old normal volunteers, (2) to assess functional interactions between modules of networks of brain regions by means of covariance based analyses and systems level modelling and (3) to relate neuroimaging data to the underpinning neural networks. Male normal young and old volunteers without neurological or psychiatric illness participated in neuroimaging studies (PET, fMRI) on working and episodic memory. Distributed brain areas are involved in memory processes (episodic and working memory) in young volunteers and show much of an overlap with respect to the network components. Systems level modelling analyses support the hypothesis of bihemispheric, asymmetric networks subserving memory processes and revealed both similarities in general and differences in the interactions between brain regions during episodic encoding and retrieval as well as working memory. Changes in memory function with ageing are evident from studies in old volunteers activating more brain regions compared to young volunteers and revealing more and stronger influences of prefrontal regions. We finally discuss the way in which the systems level models based on PET and fMRI results have implications for the understanding of the underlying neural network functioning of the brain.     

The neural basis of episodic memory: evidence from functional neuroimaging

We review some of our recent research using functional neuroimaging to investigate neural activity supporting the encoding and retrieval of episodic memories, that is, memories for unique events. Findings from studies of encoding indicate that, at the cortical level, the regions responsible for the effective encoding of a stimulus event as an episodic memory include some of the regions that are also engaged to process the event 'online'. Thus, it appears that there is no single cortical site or circuit responsible for episodic encoding. The results of retrieval studies indicate that successful recollection of episodic information is associated with activation of lateral parietal cortex, along with more variable patterns of activity in dorsolateral and anterior prefrontal cortex. Whereas parietal regions may play a part in the representation of retrieved information, prefrontal areas appear to support processes that act on the products of retrieval to align behaviour with the demands of the retrieval task.     

Correlation between Inter-Blink Interval and Episodic Encoding during Movie Watching

Human eye blinking is cognitively suppressed to minimize loss of visual information for important real-world events. Despite the relationship between eye blinking and cognitive state, the effect of eye blinks on cognition in real-world environments has received limited research attention. In this study, we focused on the temporal pattern of inter-eye blink interval (IEBI) during movie watching and investigated its relationship with episodic memory. As a control condition, 24 healthy subjects watched a nature documentary that lacked a specific story line while electroencephalography was performed. Immediately after viewing the movie, the subjects were asked to report its most memorable scene. Four weeks later, subjects were asked to score 32 randomly selected scenes from the movie, based on how much they were able to remember and describe. The results showed that the average IEBI was significantly longer during the movie than in the control condition. In addition, the significant increase in IEBI when watching a movie coincided with the most memorable scenes of the movie. The results suggested that the interesting episodic narrative of the movie attracted the subjects’ visual attention relative to the documentary clip that did not have a story line. In the episodic memory test executed four weeks later, memory performance was significantly positively correlated with IEBI (p<0.001). In summary, IEBI may be a reliable bio-marker of the degree of concentration on naturalistic content that requires visual attention, such as a movie.     

Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events

Emotional events are remembered better than neutral events possibly because the amygdala enhances the function of medial temporal lobe (MTL) memory system (modulation hypothesis). Although this hypothesis has been supported by much animal research, evidence from humans has been scarce and indirect. We investigated this issue using event-related fMRI during encoding of emotional and neutral pictures. Memory performance after scanning showed a retention advantage for emotional pictures. Successful encoding activity in the amygdala and MTL memory structures was greater and more strongly correlated for emotional than for neutral pictures. Moreover, a double dissociation was found along the longitudinal axis of the MTL memory system: activity in anterior regions predicted memory for emotional items, whereas activity in posterior regions predicted memory for neutral items. These results provide direct evidence for the modulation hypothesis in humans and reveal a functional specialization within the MTL regarding the effects of emotion on memory formation.     

Neonatal brain injury and neuroanatomy of memory processing following very preterm birth in adulthood: an fMRI study

Altered functional neuroanatomy of high-order cognitive processing has been described in very preterm individuals (born before 33 weeks of gestation; VPT) compared to controls in childhood and adolescence. However, VPT birth may be accompanied by different types of adverse neonatal events and associated brain injury, the severity of which may have differential effects on brain development and subsequent neurodevelopmental outcome. We conducted a functional magnetic resonance imaging (fMRI) study to investigate how differing degrees of neonatal brain injury, detected by neonatal ultrasounds, affect the functional neuroanatomy of memory processing in VPT young adults. We used a verbal paired associates learning task, consisting of four encoding, four cued-recall and four baseline condition blocks. To further investigate whether differences in neural activation between the groups were modulated by structural brain changes, structural MRI data were also collected. We studied 12 VPT young adults with a history of periventricular haemorrhage with associated ventricular dilatation, 17 VPT individuals with a history of uncomplicated periventricular haemorrhage, 12 individuals with normal ultrasonographic findings, and 17 controls. Results of a linear trend analysis demonstrated that during completion of the paired associates learning task right frontal and right parietal brain activation decreased as the severity of neonatal brain injury increased. There were no statistically significant between-group differences in on-line task performance and participants' intelligence quotient (IQ) at assessment. This pattern of differential activation across the groups was observed particularly in the right middle frontal gyrus during encoding and in the right posterior cingulate gyrus during recall. Structural MRI data analysis revealed that grey matter volume in the right superior temporal gyrus, right cerebellum, left middle temporal gyrus, right globus pallidus and right medial frontal gyrus decreased with increasing severity of neonatal brain injury. However, the significant between-group functional neuroanatomical differences were not directly attributable to the detected structural regional differences.     

Theories of episodic memory

Theories of episodic memory need to specify the encoding (representing), storage, and retrieval processes that underlie this form of memory and indicate the brain regions that mediate these processes and how they do so. Representation and re-representation (retrieval) of the spatiotemporally linked series of scenes, which constitute an episode, are probably mediated primarily by those parts of the posterior neocortex that process perceptual and semantic information. However, some role of the frontal neocortex and medial temporal lobes in representing aspects of context and high-level visual object information at encoding and retrieval cannot currently be excluded. Nevertheless, it is widely believed that the frontal neocortex is mainly involved in coordinating episodic encoding and retrieval and that the medial temporal lobes store aspects of episodic information. Establishing where storage is located is very difficult and disagreement remains about the role of the posterior neocortex in episodic memory storage. One view is that this region stores all aspects of episodic memory ab initio for as long as memory lasts. This is compatible with evidence that the amygdala, basal forebrain, and midbrain modulate neocortical storage. Another view is that the posterior neocortex only gradually develops the ability to store some aspects of episodic information as a function of rehearsal over time and that this information is initially stored by the medial temporal lobes. A third view is that the posterior neocortex never stores these aspects of episodic information because the medial temporal lobes store them for as long as memory lasts in an increasingly redundant fashion. The last two views both postulate that the medial temporal lobes initially store contextual markers that serve to cohere featural information stored in the neocortex. Lesion and functional neuroimaging evidence still does not clearly distinguish between these views. Whether the feeling that an episodic memory is familiar depends on retrieving an association between a retrieved episode and this feeling, or by an attribution triggered by a priming process, is unclear. Evidence about whether the hippocampus and medial temporal lobe cortices play different roles in episodic memory is conflicting. Identifying similarities and differences between episodic memory and both semantic memory and priming will require careful componential analysis of episodic memory.     

Differential consolidation and pattern reverberations within episodic cell assemblies in the mouse hippocampus

One hallmark feature of consolidation of episodic memory is that only a fraction of original information, which is usually in a more abstract form, is selected for long-term memory storage. How does the brain perform these differential memory consolidations? To investigate the neural network mechanism that governs this selective consolidation process, we use a set of distinct fearful events to study if and how hippocampal CA1 cells engage in selective memory encoding and consolidation. We show that these distinct episodes activate a unique assembly of CA1 episodic cells, or neural cliques, whose response-selectivity ranges from general-to-specific features. A series of parametric analyses further reveal that post-learning CA1 episodic pattern replays or reverberations are mostly mediated by cells exhibiting event intensity-invariant responses, not by the intensity-sensitive cells. More importantly, reactivation cross-correlations displayed by intensity-invariant cells encoding general episodic features during immediate post-learning period tend to be stronger than those displayed by invariant cells encoding specific features. These differential reactivations within the CA1 episodic cell populations can thus provide the hippocampus with a selection mechanism to consolidate preferentially more generalized knowledge for long-term memory storage.     

Priming picture naming with a semantic task: an fMRI investigation

Prior semantic processing can enhance subsequent picture naming performance, yet the neurocognitive mechanisms underlying this effect and its longevity are unknown. This functional magnetic resonance imaging study examined whether different neurological mechanisms underlie short-term (within minutes) and long-term (within days) facilitation effects from a semantic task in healthy older adults. Both short- and long-term facilitated items were named significantly faster than unfacilitated items, with short-term items significantly faster than long-term items. Region of interest results identified decreased activity for long-term facilitated items compared to unfacilitated and short-term facilitated items in the mid-portion of the middle temporal gyrus, indicating lexical-semantic priming. Additionally, in the whole brain results, increased activity for short-term facilitated items was identified in regions previously linked to episodic memory and object recognition, including the right lingual gyrus (extending to the precuneus region) and the left inferior occipital gyrus (extending to the left fusiform region). These findings suggest that distinct neurocognitive mechanisms underlie short- and long-term facilitation of picture naming by a semantic task, with long-term effects driven by lexical-semantic priming and short-term effects by episodic memory and visual object recognition mechanisms.     

Hippocampal involvement in human topographical memory: evidence from functional imaging.

Functional brain imaging in humans is beginning to reveal a network of brain regions that subserve topographical learning: the medial parietal lobe, the posterior cingulate gyrus, occipitotemporal areas, the parahippocampal gyrus and the right hippocampus. These findings illuminate the patient lesion literature where all of these brain regions have been implicated at one time or another in cases of topographical disorientation. Once topographical information is acquired, the neuroanatomy that supports its use from either episodic or semantic memory is similar to that activated during encoding. The specific contributions of extrahippocampal regions within the topographical memory system are being revealed, such as the role of the right parahippocampal gyrus in object-in-place encoding. The right hippocampus is clearly involved in processing spatial layouts over long as well as short time-courses, and participates in both the encoding and the retrieval of topographical memory. The ventromedial orbitofrontal cortex is recruited when information in the topographical memory system is not sufficient to produce direct navigation to a goal place.     

Mesmerizing memories: brain substrates of episodic memory suppression in posthypnotic amnesia

Two groups of participants, one susceptible to posthypnotic amnesia (PHA) and the other not, viewed a movie. A week later, they underwent hypnosis in the fMRI scanner and received a suggestion to forget the movie details after hypnosis until receiving a reversal cue. The participants were tested twice for memory for the movie and for the context in which it was shown, under the posthypnotic suggestion and after its reversal, while their brain was scanned. The PHA group showed reduced memory for movie but not for context while under suggestion. Activity in occipital, temporal, and prefrontal areas differed among the groups, and, in the PHA group, between suggestion and reversal conditions. We propose that whereas some of these regions subserve retrieval of long-term episodic memory, others are involved in inhibiting retrieval, possibly already in a preretrieval monitoring stage. Similar mechanisms may also underlie other forms of functional amnesia.     

Memory for events and their spatial context: models and experiments

The computational role of the hippocampus in memory has been characterized as: (i) an index to disparate neocortical storage sites; (ii) a time-limited store supporting neocortical long-term memory; and (iii) a content-addressable associative memory. These ideas are reviewed and related to several general aspects of episodic memory, including the differences between episodic, recognition and semantic memory, and whether hippocampal lesions differentially affect recent or remote memories. Some outstanding questions remain, such as: what characterizes episodic retrieval as opposed to other forms of read-out from memory; what triggers the storage of an event memory; and what are the neural mechanisms involved? To address these questions a neural-level model of the medial temporal and parietal roles in retrieval of the spatial context of an event is presented. This model combines the idea that retrieval of the rich context of real-life events is a central characteristic of episodic memory, and the idea that medial temporal allocentric representations are used in long-term storage while parietal egocentric representations are used to imagine, manipulate and re-experience the products of retrieval. The model is consistent with the known neural representation of spatial information in the brain, and provides an explanation for the involvement of Papez''s circuit in both the representation of heading direction and in the recollection of episodic information. Two experiments relating to the model are briefly described. A functional neuroimaging study of memory for the spatial context of life-like events in virtual reality provides support for the model''s functional localization. A neuropsychological experiment suggests that the hippocampus does store an allocentric representation of spatial locations.     

Effects of the BDNF Val66Met Polymorphism and Met Allele Load on Declarative Memory Related Neural Networks

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.     

Episodic Future Thinking in Semantic Dementia: A Cognitive and fMRI Study

Semantic dementia (SD) is characterized by gradual loss of semantic memory. While episodic autobiographical memory seems relatively preserved, behavioral studies suggest that episodic future thinking is impaired. We used fMRI to measure brain activity in four SD patients (JPL, EP, LL, EG) while they envisioned future events and remembered personal past events. Twelve healthy elders served as controls. Episodic quality, emotion, mental imagery and level of consciousness (via remember/know judgements) were checked at debriefing. We analyzed the future compared to the past for each patient. All patients presented lateral temporal atrophy, but varied in terms of frontal and anterior hippocampal atrophy. Patient JPL presented atrophy in bilateral superior medial frontal gyri and left anterior hippocampus and was unable to engage in episodic future thinking, despite hyperactivations in frontal and occipital regions. Patient EP presented no atrophy in the anterior hippocampus, but atrophy in bilateral superior medial frontal gyrus and had difficulties to engage in episodic future thinking. Patient LL presented atrophy in left anterior hippocampus, but hyperactivated its right counterpart for future compared to past thinking, permitting her to project efficiently in the future in an episodic way. Patient EG presented no atrophy in the superior medial frontal gyri or anterior hippocampi and was able to engage in episodic future thinking. Altogether, patients'' future projections differed depending on the severity and localization of their atrophy. The functional integrity of bilateral superior medial frontal gyri and anterior hippocampus appear crucial for episodic future thinking: atrophy of both structures strongly impairs future projection, while integrity of these structures or hyperactivation of residual tissue normalizes episodic future projection.     

Episodic Memory in Detoxified Alcoholics: Contribution of Grey Matter Microstructure Alteration

Even though uncomplicated alcoholics may likely have episodic memory deficits, discrepancies exist regarding to the integrity of brain regions that underlie this function in healthy subjects. Possible relationships between episodic memory and 1) brain microstructure assessed by magnetic resonance diffusion tensor imaging (DTI), 2) brain volumes assessed by voxel-based morphometry (VBM) were investigated in uncomplicated, detoxified alcoholics.Diffusion and morphometric analyses were performed in 24 alcohol dependent men without neurological or somatic complications and in 24 healthy men. The mean apparent coefficient of diffusion (ADC) and grey matter volumes were measured in the whole brain. Episodic memory performance was assessed using a French version of the Free and Cued Selective Reminding Test (FCSRT). Correlation analyses between verbal episodic memory, brain microstructure, and brain volumes were carried out using SPM2 software.In those with alcohol dependence, higher ADC was detected mainly in frontal, temporal and parahippocampal regions, and in the cerebellum. In alcoholics, regions with higher ADC typically also had lower grey matter volume. Low verbal episodic memory performance in alcoholism was associated with higher mean ADC in parahippocampal areas, in frontal cortex and in the left temporal cortex; no correlation was found between regional volumes and episodic memory scores. Regression analyses for the control group were not significant.These findings support the hypothesis that regional microstructural but no macrostructural alteration of the brain might be responsible, at least in part, for episodic memory deficits in alcohol dependence.     

A theory of hippocampal memory based on theta phase precession

 The neural dynamics of the hippocampal network for memory encoding of novel temporal sequences is proposed based on the theta rhythm modulated firing of place cells called theta phase precession. It is hypothesized that theta phase precession is generated at the entorhinal cortex by phase locking between local field theta oscillation and neural oscillators and that the hippocampal closed network with feedforward and backward projections employ theta phase precession to create selectivity in the associative connections needed for temporal sequence storage. Our analyses and computer experiments reveal that the phase precession generated by phase locking instantaneously endows stable phase relations among neural activities in the successively changing neural population. It is concluded that theta phase precession provides biologically plausible dynamics for the memory encoding of novel temporal sequences as episodic events. Received: 18 December 2002 / Accepted: 18 March 2003 / Published online: 20 May 2003 Correspondence to: Y. Yamaguchi (e-mail: yokoy@brain.riken.go.jp, Fax: +81-48-4676938) Acknowledgements. The author would like to express acknowledgement to Drs. McNaughton and Skaggs for their discussion and comment and to Dr. Amari for his continuous encouragement. Further thanks are given to Mr. Haga and Dr. Wu for their discussion and cooperation.     

Age-Related Changes in the Functional Network Underlying Specific and General Autobiographical Memory Retrieval: A Pivotal Role for the Anterior Cingulate Cortex

Age-related changes in autobiographical memory (AM) recall are characterized by a decline in episodic details, while semantic aspects are spared. This deleterious effect is supposed to be mediated by an inefficient recruitment of executive processes during AM retrieval. To date, contrasting evidence has been reported on the neural underpinning of this decline, and none of the previous studies has directly compared the episodic and semantic aspects of AM in elderly. We asked 20 young and 17 older participants to recall specific and general autobiographical events (i.e., episodic and semantic AM) elicited by personalized cues while recording their brain activity by means of fMRI. At the behavioral level, we confirmed that the richness of episodic AM retrieval is specifically impoverished in aging and that this decline is related to the reduction of executive functions. At the neural level, in both age groups, we showed the recruitment of a large network during episodic AM retrieval encompassing prefrontal, cortical midline and posterior regions, and medial temporal structures, including the hippocampus. This network was very similar, but less extended, during semantic AM retrieval. Nevertheless, a greater activity was evidenced in the dorsal anterior cingulate cortex (dACC) during episodic, compared to semantic AM retrieval in young participants, and a reversed pattern in the elderly. Moreover, activity in dACC during episodic AM retrieval was correlated with inhibition and richness of memories in both groups. Our findings shed light on the direct link between episodic AM retrieval, executive control, and their decline in aging, proposing a possible neuronal signature. They also suggest that increased activity in dACC during semantic AM retrieval in the elderly could be seen as a compensatory mechanism underpinning successful AM performance observed in aging. These results are discussed in the framework of recently proposed models of neural reorganization in aging.     

A unified view of theta-phase coding in the entorhinal-hippocampal system

The discovery of theta-rhythm-dependent firing of rodent hippocampal neurons highlighted the functional significance of temporal encoding in hippocampal memory. However, earlier theoretical studies on this topic seem divergent and experimental implications are invariably complicated. To obtain a unified understanding of neural dynamics in the hippocampal memory, we here review recent developments in computational models and experimental discoveries on the 'theta-phase precession' of hippocampal place cells and entorhinal grid cells. We identify a theoretical hypothesis that is well supported by experimental facts; this model reveals a significant contribution of theta-phase coding to the on-line real-time operation of episodic events, through highly parallel representation of spatiotemporal information.     

A Computational Predictor of Human Episodic Memory Based on a Theta Phase Precession Network

In the rodent hippocampus, a phase precession phenomena of place cell firing with the local field potential (LFP) theta is called “theta phase precession” and is considered to contribute to memory formation with spike time dependent plasticity (STDP). On the other hand, in the primate hippocampus, the existence of theta phase precession is unclear. Our computational studies have demonstrated that theta phase precession dynamics could contribute to primate–hippocampal dependent memory formation, such as object–place association memory. In this paper, we evaluate human theta phase precession by using a theory–experiment combined analysis. Human memory recall of object–place associations was analyzed by an individual hippocampal network simulated by theta phase precession dynamics of human eye movement and EEG data during memory encoding. It was found that the computational recall of the resultant network is significantly correlated with human memory recall performance, while other computational predictors without theta phase precession are not significantly correlated with subsequent memory recall. Moreover the correlation is larger than the correlation between human recall and traditional experimental predictors. These results indicate that theta phase precession dynamics are necessary for the better prediction of human recall performance with eye movement and EEG data. In this analysis, theta phase precession dynamics appear useful for the extraction of memory-dependent components from the spatio–temporal pattern of eye movement and EEG data as an associative network. Theta phase precession may be a common neural dynamic between rodents and humans for the formation of environmental memories.     

The hippocampus is coupled with the default network during memory retrieval but not during memory encoding

The brain's default mode network (DMN) is activated during internally-oriented tasks and shows strong coherence in spontaneous rest activity. Despite a surge of recent interest, the functional role of the DMN remains poorly understood. Interestingly, the DMN activates during retrieval of past events but deactivates during encoding of novel events into memory. One hypothesis is that these opposing effects reflect a difference between attentional orienting towards internal events, such as retrieved memories, vs. external events, such as to-be-encoded stimuli. Another hypothesis is that hippocampal regions are coupled with the DMN during retrieval but decoupled from the DMN during encoding. The present fMRI study investigated these two hypotheses by combining a resting-state coherence analysis with a task that measured the encoding and retrieval of both internally-generated and externally-presented events. Results revealed that the main DMN regions were activated during retrieval but deactivated during encoding. Counter to the internal orienting hypothesis, this pattern was not modulated by whether memory events were internal or external. Consistent with the hippocampal coupling hypothesis, the hippocampus behaved like other DMN regions during retrieval but not during encoding. Taken together, our findings clarify the relationship between the DMN and the neural correlates of memory retrieval and encoding.     

Neural dynamics of the cognitive map in the hippocampus

The rodent hippocampus has been thought to represent the spatial environment as a cognitive map. In the classical theory, the cognitive map has been explained as a consequence of the fact that different spatial regions are assigned to different cell populations in the framework of rate coding. Recently, the relation between place cell firing and local field oscillation theta in terms of theta phase precession was experimentally discovered and suggested as a temporal coding mechanism leading to memory formation of behavioral sequences accompanied with asymmetric Hebbian plasticity. The cognitive map theory is apparently outside of the sequence memory view. Therefore, theoretical analysis is necessary to consider the biological neural dynamics for the sequence encoding of the memory of behavioral sequences, providing the cognitive map formation. In this article, we summarize the theoretical neural dynamics of the real-time sequence encoding by theta phase precession, called theta phase coding, and review a series of theoretical models with the theta phase coding that we previously reported. With respect to memory encoding functions, instantaneous memory formation of one-time experience was first demonstrated, and then the ability of integration of memories of behavioral sequences into a network of the cognitive map was shown. In terms of memory retrieval functions, theta phase coding enables the hippocampus to represent the spatial location in the current behavioral context even with ambiguous sensory input when multiple sequences were coded. Finally, for utilization, retrieved temporal sequences in the hippocampus can be available for action selection, through the process of reverting theta rhythm-dependent activities to information in the behavioral time scale. This theoretical approach allows us to investigate how the behavioral sequences are encoded, updated, retrieved and used in the hippocampus, as the real-time interaction with the external environment. It may indeed be the bridge to the episodic memory function in human hippocampus.