Reactivation of medial temporal lobe and occipital lobe during the retrieval of color information: A positron emission tomography study

It is widely accepted that memory traces of an event include various types of information about the content of the event and about the circumstances in which the individual experienced it. However, how these various types of information are stored and later retrieved is poorly understood. One hypothesis postulates that the retrieval of specific event information reactivates regions that were active during the encoding of this information, with the aid of binding functions of the medial temporal lobe (MTL) structures. We used positron emission tomography to identify the brain regions related to the encoding and retrieval of color information. Specifically, we assessed whether overlapping activity was found in both the MTL structures and color-related cortical regions during the encoding and retrieval of color information attached with meaningless shapes. During the study, subjects were asked to encode colored (red or green) and achromatic random shapes. At subsequent testing, subjects were presented with only achromatic shapes, which had been presented with or without colors during encoding, and were engaged in retrieval tasks of shapes and colors. Overlapping activity was found in the MTL and occipital lobe (the lingual and inferior occipital gyri) in the right hemisphere during the encoding and retrieval of meaningless shapes with color information compared with those without color information. Although there are some limitations to be considered, the present findings seem to support the view that the retrieval of specific event information is associated with reactivation of both the MTL structures and the regions involved during encoding of the information.     

Dynamic neural networks supporting memory retrieval

How do separate neural networks interact to support complex cognitive processes such as remembrance of the personal past? Autobiographical memory (AM) retrieval recruits a consistent pattern of activation that potentially comprises multiple neural networks. However, it is unclear how such large-scale neural networks interact and are modulated by properties of the memory retrieval process. In the present functional MRI (fMRI) study, we combined independent component analysis (ICA) and dynamic causal modeling (DCM) to understand the neural networks supporting AM retrieval. ICA revealed four task-related components consistent with the previous literature: 1) medial prefrontal cortex (PFC) network, associated with self-referential processes, 2) medial temporal lobe (MTL) network, associated with memory, 3) frontoparietal network, associated with strategic search, and 4) cingulooperculum network, associated with goal maintenance. DCM analysis revealed that the medial PFC network drove activation within the system, consistent with the importance of this network to AM retrieval. Additionally, memory accessibility and recollection uniquely altered connectivity between these neural networks. Recollection modulated the influence of the medial PFC on the MTL network during elaboration, suggesting that greater connectivity among subsystems of the default network supports greater re-experience. In contrast, memory accessibility modulated the influence of frontoparietal and MTL networks on the medial PFC network, suggesting that ease of retrieval involves greater fluency among the multiple networks contributing to AM. These results show the integration between neural networks supporting AM retrieval and the modulation of network connectivity by behavior.     

Material-specific lateralization of memory encoding in the medial temporal lobe: blocked versus event-related design

Lesion-deficit studies have provided evidence for a functional dissociation between the left medial temporal lobe (MTL) mediating verbal memory encoding and right MTL mediating non-verbal memory encoding. While a small number of functional MRI studies have demonstrated similar findings, none has looked specifically for material-specific lateralization using subsequent memory effects. In addition, in many fMRI studies, encoding activity has been located in posterior MTL structures, at odds with lesion-deficit and positron emission tomography (PET) evidence. In this study, we used an event-related fMRI memory encoding paradigm to demonstrate a material-specific lateralization of encoding in the medial temporal lobes of ten healthy control subjects. Activation was left-lateralized for word encoding, bilateral for picture encoding, and right-lateralized for face encoding. Secondly, we demonstrated the locations of activations revealed using an event-related analysis to be more anterior than those revealed using a blocked analysis of the same data. This suggests that anterior MTL structures underlie memory encoding as judged by subsequent memory effects, and that more posterior activity detected in other fMRI studies is related to deficiencies of blocked designs in the analysis of memory encoding.     

Dissociating intentional learning from relative novelty responses in the medial temporal lobe

The establishment of a role for medial temporal lobe (MTL) structures in episodic memory has led to an investigative focus on the specific contributions and interactions between constituent MTL regions, including the hippocampus and surrounding medial temporal cortices. By dissociating an intentional stimulus-category learning condition from a passive viewing condition, we demonstrate, using fMRI, that novelty- and familiarity-driven responses in human anterior and posterior hippocampus, respectively, only occur during intentional learning. With increasing familiarity of stimulus-category associations, there is a shift in neuronal responses from anterior to posterior hippocampal regions. This anterior/posterior response gradient may reflect a weighting of functional hippocampal architecture related to encoding of novel and retrieval of familiar information. By contrast, perirhinal cortex is engaged by novel stimuli irrespective of task, highlighting this region as a component of a generic familiarity discrimination system. By introducing distinct stimulus types, we further demonstrate that these MTL responses are independent of stimulus complexity. Different patterns of activity for intentional learning vs. passive viewing indicate that intentional encoding/retrieval of stimulus-category associations and automatic novelty/familiarity assessment of stimuli are processed in anatomically dissociable neuronal ensembles within the MTL memory system.     

Encoding the future: Successful processing of intentions engages predictive brain networks

Evidence from cognitive, patient and neuroimaging research indicates that “remembering to remember” intentions, i.e., prospective memory (PM) retrieval, requires both general memory systems involving the medial temporal lobes and an executive system involving rostral PFC (BA 10). However, it is not known how prospective memories are initially formed. Using fMRI, we investigated whether brain activity during encoding of future intentions and present actions differentially predicted later memory for those same intentions (PM) and actions (retrospective memory). We identified two significant patterns of neural activity: a network linked to overall memory and another linked specifically to PM. While overall memory success was predicted by temporal lobe activations that included the hippocampus, PM success was also uniquely predicted by activations in additional regions, including left rostrolateral PFC and the right parahippocampal gyrus. This finding extends the role of these structures to the formation of individual intentions. It also provides the first evidence that PM encoding, like PM retrieval, is supported by both a common episodic memory network and an executive network specifically recruited by future-oriented processing.     

Regional activation of the human medial temporal lobe during intentional encoding of objects and positions

The medial temporal lobe (MTL) consists of several regions thought to be involved in learning and memory. However, the degree of functional specialization among these regions remains unclear. Previous studies have demonstrated effects of both content and processing stage, but findings have been inconsistent. In particular, studies have suggested that the perirhinal cortex is more involved in object processing than spatial processing, while other regions such as the parahippocampal cortex have been implicated in spatial processing. In this study, functional magnetic resonance imaging (fMRI) optimized for the MTL region was used to probe MTL activation during intentional encoding of object identities or positions. A region of interest analysis showed that object encoding evoked stronger activation than position encoding in bilateral perirhinal cortex, temporopolar cortex, parahippocampal cortex, hippocampus and amygdala. Results also indicate an unexpected significant correlation in activation level between anterior and posterior portions in both the left parahippocampal cortex and left hippocampus. Exploratory analysis did not show any regional content effects during preparation and rehearsal stages. These results provide additional evidence for functional specialization within the MTL, but were less clear regarding the specific nature of content specificity in these regions.     

Encoding activity in anterior medial temporal lobe supports subsequent associative recognition

The ability to bind information together, such as linking a name with a face or a car with a parking space, is a vital process in human episodic memory. To identify the neural bases for this binding process, we measured brain activity during a verbal associative encoding task using event-related functional MRI (fMRI), followed by an associative recognition test for the studied word pairs. Analysis of the encoding data sorted by the associative recognition accuracy allowed us to isolate regions involved in successfully creating associations. We found that encoding activity in bilateral anterior medial temporal lobe (MTL) regions was greater for successfully bound pairs, that is, those later recognized as intact, than for all other pairs. These findings provide evidence that the anterior medial temporal lobes support the successful binding of information in memory.     

Instruction-specific brain activations during episodic encoding. a generalized level of processing effect

In a within-subject design we investigated the levels-of-processing (LOP) effect using visual material in a behavioral and a corresponding PET study. In the behavioral study we characterize a generalized LOP effect, using pleasantness and graphical quality judgments in the encoding situation, with two types of visual material, figurative and nonfigurative line drawings. In the PET study we investigate the related pattern of brain activations along these two dimensions. The behavioral results indicate that instruction and material contribute independently to the level of recognition performance. Therefore the LOP effect appears to stem both from the relative relevance of the stimuli (encoding opportunity) and an altered processing of stimuli brought about by the explicit instruction (encoding mode). In the PET study, encoding of visual material under the pleasantness (deep) instruction yielded left lateralized frontoparietal and anterior temporal activations while surface-based perceptually oriented processing (shallow instruction) yielded right lateralized frontoparietal, posterior temporal, and occipitotemporal activations. The result that deep encoding was related to the left prefrontal cortex while shallow encoding was related to the right prefrontal cortex, holding the material constant, is not consistent with the HERA model. In addition, we suggest that the anterior medial superior frontal region is related to aspects of self-referential semantic processing and that the inferior parts of the anterior cingulate as well as the medial orbitofrontal cortex is related to affective processing, in this case pleasantness evaluation of the stimuli regardless of explicit semantic content. Finally, the left medial temporal lobe appears more actively engaged by elaborate meaning-based processing and the complex response pattern observed in different subregions of the MTL lends support to the suggestion that this region is functionally segregated.     

Interindividual differences of medial temporal lobe activation during encoding in an elderly population studied by fMRI

Functional MRI (fMRI) is used to study medial temporal lobe (MTL) activation during encoding of new information into memory. In most studies, fMRI data of different subjects are averaged in standard coordinate space. However, interindividual differences in activation can be extensive, reflecting functional heterogeneity. Further, anatomical differences in brain structure cause additional variance and loss of registration accuracy. Such differences in structural and functional MTL characteristics may interfere with the efficiency of averaging data across subjects, and may become more significant with aging and dementia. The current study concerns the analysis of individual differences in MTL activation associated with episodic encoding.Twenty-nine healthy elderly men between 60 and 70 years old performed a simple face encoding task during fMRI scanning. Individual data were analyzed in native space, and compared to the group average in standard space (Talairach and Tournoux).MTL volumes between subjects varied between 6.34 and 11.27 cm(3), and had considerable variation when mapped to standard space. Eighteen of the 29 subjects showed MTL activity and activation patterns varied both in location and size (ranging from 0.11 to 1.78 cm(3)), with the strongest activation in the left posterior part of the MTL. In standard space, no region was significantly activated on a group level at a comparable alpha level. We conclude that while the majority of elderly subjects show MTL activation during episodic encoding of faces, there is considerable structural and functional variability between subjects. Group analysis in standard space may not be appropriate for studies of a complex structure such as the MTL, particularly not in aging and dementia.     

The effect of encoding strategies on medial temporal lobe activations during the recognition of words: an event-related fMRI study

It is known that manipulation of the encoding strategy affects behavioral and activation data during later retrieval. In the present fMRI study, we examined brain activity during the recognition of words encoded using three different strategies formed by the combination of two factors of relational and self-performed processes. The first encoding strategy involved subjects learning words using both relational and self-performed processes (R+S+). In the second, subjects learned words using only a relational process (R+S-). In the third, subjects learned words without using either process (R-S-). During fMRI after encoding, subjects were randomly presented with words encoded previously and with new words (New) and were required to judge whether or not the word presented had been previously encoded. The fMRI experiment was performed with the event-related design. Compared to New, activation of the left medial temporal lobe (MTL) occurred during the recognition of words encoded using R+S+ and R+S-, whereas right MTL activations only occurred with the R+S+ strategy. ROI analysis for the bilateral hippocampus and parahippocampal gyrus showed a linear increase in left MTL activity (hippocampus and parahippocampal gyrus) during the recognition of words encoded with the R-S-, R+S-, to R+S+, whereas right MTL activity (parahippocampal gyrus) was only increased with the R+S+ strategy. The findings suggest that the left and right MTL structures may contribute differentially to the processes involved in the recognition of stimuli and that these differential activities may depend on the encoding strategies formed by the two factors of relational and self-performed processes.     

Medial temporal lobe amnesia: a case study for nursing.

Maintaining and enhancing cognitive function is a crucial but challenging intervention for patients with memory problems. Research on the medial temporal lobe (MTL) memory system has yielded much information that can guide nurses in planning, evaluating, and performing effective interventions. A patient, Mrs. N, with a diagnosis of anaplastic astrocytoma of the left medial temporal lobe provides an example. Information from research guides assessment of Mrs. N and affords development of specific patient-centered interventions to maintain function, cope, and compensate. Data have been gathered from the patient, relatives, and caregivers to compare with and augment existing research, because few nursing case studies of amnesia involving patients with left medial temporal lobe tumors are available for analysis.     

Retrieval of relational information: a role for the left inferior prefrontal cortex

Neuroimaging studies have implicated different areas of prefrontal cortex and medial temporal lobe structures (MTL) in episodic retrieval tasks. However, the role of specific regions in particular aspects of episodic memory is still unclear. In this experiment we studied changes in regional cerebral blood flow (rCBF) associated with relational and nonrelational retrieval of studied pairs of words. For relational retrieval, a list of either studied or rearranged pairs was presented and subjects (n = 8) were asked to indicate whether pairs had appeared on the study list. Under the nonrelational retrieval condition they indicated whether one or both words of the pair had appeared on the study list. As compared to the baseline condition (looking at a cross-mark), increased rCBF was observed in the left inferior prefrontal cortex (LIPFC) for both studied pairs and rearranged pairs under the relational retrieval condition. Under the nonrelational condition, an increase was observed in right inferior frontal gyrus. The MTL showed a trend for increased rCBF in the rearranged-pair condition. This increase was probably associated with the encoding that accompanies retrieval of novel stimuli. Results suggest that the lateralized activation of prefrontal cortex observed in episodic memory tasks may be related to the degree of relational processing involved. The LIPFC appears to be associated with relational retrieval and the right prefrontal cortex with nonrelational retrieval.     

Ecphory of autobiographical memories: an fMRI study of recent and remote memory retrieval

Ecphory occurs when one recollects a past event cued by a trigger, such as a picture, odor, or name. It is a central component of autobiographical memory, which allows us to "travel mentally back in time" and re-experience specific events from our personal past. Using fMRI and focusing on the role of medial temporal lobe (MTL) structures, we investigated the brain bases of autobiographical memory and whether they change with the age of memories. Importantly, we used an ecphory task in which the remote character of the memories was ensured. The results showed that a large bilateral network supports autobiographical memory: temporal lobe, temporo-parieto-occipital junction, dorsal prefrontal cortex, medial frontal cortex, retrosplenial cortex and surrounding areas, and MTL structures. This network, including MTL structures, changed little with the age of the memories.     

Dissecting out conscious and unconscious memory (sub)processes within the human medial temporal lobe

The human medial temporal lobe (MTL) system mediates memories that can be consciously recollected. However, the specific natures of the individual contributions of its various subregions to conscious memory processes remain equivocal. Here we show a functional dissociation between the hippocampus proper and the parahippocampal region in conscious and unconscious memory as revealed by invasive recordings of limbic event-related brain potentials recorded during explicit and implicit word recognition: Only hippocampal and not parahippocampal neural activity exhibits a sensitivity to the implicit versus explicit nature of the recognition memory task. Moreover, only within the hippocampus proper do the neural responses to repeated words differ not only from those to new words but also from each other as a function of recognition success. By contrast parahippocampal (rhinal) responses are sensitive to repetition independent of conscious recognition. These findings thus demonstrate that it is the hippocampus proper among the MTL structures that is specifically engaged during conscious memory processes.     

The role of precuneus and left inferior frontal cortex during source memory episodic retrieval

The posterior medial parietal cortex and left prefrontal cortex (PFC) have both been implicated in the recollection of past episodes. In a previous study, we found the posterior precuneus and left lateral inferior frontal cortex to be activated during episodic source memory retrieval. This study further examines the role of posterior precuneal and left prefrontal activation during episodic source memory retrieval using a similar source memory paradigm but with longer latency between encoding and retrieval. Our results suggest that both the precuneus and the left inferior PFC are important for regeneration of rich episodic contextual associations and that the precuneus activates in tandem with the left inferior PFC during correct source retrieval. Further, results suggest that the left ventro-lateral frontal region/frontal operculum is involved in searching for task-relevant information (BA 47) and subsequent monitoring or scrutiny (BA 44/45) while regions in the dorsal inferior frontal cortex are important for information selection (BA 45/46).     

Stimulus pacing affects the activation of the medial temporal lobe during a semantic classification task: an fMRI study

Our purpose was to explore the influence of stimulus pacing in blocked functional MRI studies on the activation pattern elicited by a semantic retrieval task. Twenty-two participants performed both a fixed-paced and a self-paced functional MR imaging experiment in which a semantic categorization (animal/object) task was contrasted with a perceptual (small/capital letter string) categorization task. Group and single-subject ROI analyses were computed. In both the fixed-paced and self-paced experiments, semantic categorization contrasted with perceptual categorization elicited a cerebral network generally accepted to be involved in semantic processing comprising left inferior prefrontal, left lateral temporal, paracingular and right cerebellar areas. Our main finding was that the self-paced stimulus modality additionally yielded significant activation in the medial temporal lobe (MTL) structures including the hippocampus and the parahippocampal gyrus. More elaborative single-subject ROI analyses revealed MTL activation in 86% of the subjects for the self-paced design, but only in 21% of subjects for the fixed-paced design. The discussion focuses on possible explanations for this finding. We conclude that a self-paced as opposed to a fixed-paced semantic retrieval paradigm is able to detect significant MTL activation in groups as well as in single-subjects. This offers opportunities for the application of such a design in clinical practice.     

Fear-relevant outcomes modulate the neural correlates of probabilistic classification learning

Although much work has implicated the contributions of frontostriatal and medial temporal lobe (MTL) systems during probabilistic classification learning, the impact of emotion on these learning circuits is unknown. We used a modified version of the weather prediction task in which two participant groups were scanned with identical neutral cue cards probabilistically linked to either emotional (snake/spider) or neutral (mushroom/flower) outcomes. Owing to the differences in visual information shown as outcomes, analyses were restricted to the cue phase of the trials. Learning rates did not differ between the two groups, although the Emotional group was more likely to use complex strategies and to respond more slowly during initial learning. The Emotional group had reduced frontostriatal and MTL activation relative to the Neutral group, especially for participants who scored higher on snake/spider phobia questionnaires. Accurate performance was more tied to medial prefrontal activity in the Emotional group early in training, and to MTL activity in the Neutral group later in training. Trial-by-trial fluctuations in functional connectivity between the caudate and MTL were also reduced in the Emotional group compared to the Neutral group. Across groups, reaction time indexed a switch in learning systems, with faster trials mediated by the caudate and slower trials mediated by the MTL and frontal lobe. The extent to which the caudate was activated early in training predicted later performance improvements. These results reveal insights into how emotional outcomes modulate procedural learning systems, and the dynamics of MTL-striatal engagement across training trials.     

Cerebral blood flow and BOLD responses to a memory encoding task: a comparison between healthy young and elderly adults

Functional magnetic resonance imaging (fMRI) studies of the medial temporal lobe have primarily made use of the blood oxygenation level dependent (BOLD) response to neural activity. The interpretation of the BOLD signal as a measure of medial temporal lobe function can be complicated, however, by changes in the cerebrovascular system that can occur with both normal aging and age-related diseases, such as Alzheimer's disease. Quantitative measures of the functional cerebral blood flow (CBF) response offer a useful complement to BOLD measures and have been shown to aid in the interpretation of fMRI studies. Despite these potential advantages, the application of ASL to fMRI studies of cognitive tasks and at-risk populations has been limited. In this study, we demonstrate the application of ASL fMRI to obtain measures of the CBF and BOLD responses to the encoding of natural scenes in healthy young (mean 25 years) and elderly (mean 74 years) adults. The percent CBF increase in the medial temporal lobe was significantly higher in the older adults, whereas the CBF levels during baseline and task conditions and during a separate resting-state scan were significantly lower in the older group. The older adults also showed slightly higher values for the BOLD response amplitude and the absolute change in CBF, but the age group differences were not significant. The percent CBF and BOLD responses are consistent with an age-related increase in the cerebral metabolic rate of oxygen metabolism (CMRO(2)) response to memory encoding.     

Parahippocampal Activation during Successful Recognition of Words: A Self-Paced Event-Related fMRI Study

In this study, we investigated retrieval from verbal episodic memory using a self-paced event-related fMRI paradigm, similar to the designs typically used in behavioral studies of memory function. We tested the hypothesis that the medial temporal lobe (MTL) is involved in the actual recovery of verbal information (retrieval success) rather than in the attempt to retrieve information (retrieval attempt). To this end, we used a verbal recognition task, distinguishing correctly recognized words, correctly rejected words, and a low-level baseline condition. Directly contrasting correct recognition with correct rejection of words, we found activation in the left fusiform/parahippocampal gyrus, indicating that this region has a distinct role in the successful retrieval of verbal information. Furthermore, our results were in agreement with those of previous imaging studies that compared a fixed-paced verbal recognition task to a baseline condition, showing activation in bilateral inferior frontal cortex, left dorsolateral prefrontal cortex, left anterior insular cortex, and anterior cingulate. This demonstrates the applicability of a self-paced event-related design within imaging studies of memory function.     

Activation of human hippocampal formation reflects success in both encoding and cued recall of paired associates

Contemporary theories of hippocampal function suggest that both encoding and retrieval of episodic memories may be accomplished by neural circuitry embedded within the same anatomical structures, but neuroimaging support for this hypothesis has been ambiguous. Recent studies suggest that the best available indicators of hippocampal encoding and retrieval operations are selective activations due to novelty, encoding success, and recall success in a paired associate learning paradigm. In the current study, both encoding and cued recall of paired associate words were conducted during a single session of fMRI scanning. Bilateral activation in the medial temporal lobe was detected for encoding word pairs vs. a fixation baseline and for encoding novel word pairs vs. repeated word pairs. These activations were stronger in subjects who successfully memorized more word pairs. In cued recall, greater responses were seen in higher performing subjects. In lower performing subjects, responses were greater to cue words whose paired associate was correctly recalled than to cue words whose correct associate had been forgotten (or not encoded). The difference between correct and incorrect trials was more pronounced on repeated presentations of the same cue words, but not apparent on their first presentation alone. Overlap of encoding and retrieval effects was maximal in the middle of the longitudinal extent of the right hippocampus, with one additional locus of overlap outside the MTL, in left occipitotemporal cortex. The conjunction of these effects suggests that it is correct to view both encoding and recall of associative memories as functions of an integrated hippocampal system.