Distinct roles for medial temporal lobe structures in memory for objects and their locations

The ability to learn and retain novel information depends on a system of structures in the medial temporal lobe (MTL) including the hippocampus and the surrounding entorhinal, perirhinal, and parahippocampal cortices. Damage to these structures produces profound memory deficits; however, the unique contribution to memory of each of these structures remains unclear. Here we have used functional magnetic resonance imaging (fMRI) to determine whether the perirhinal and parahippocampal cortices show differential memory-related activity. Based on the distinct patterns of cortical input to these two areas, we reasoned that these structures might show differential activity for spatial and object recognition memory. In each of 11 subjects, we found that the perirhinal cortex was active during both spatial and object memory encoding, while the anterior parahippocampal cortex was active only during spatial encoding. These data support the idea that MTL structures make distinct contributions to recognition memory performance.     

The consolidation of object and context recognition memory involve different regions of the temporal lobe

These experiments investigated the involvement of several temporal lobe regions in consolidation of recognition memory. Anisomycin, a protein synthesis inhibitor, was infused into the hippocampus, perirhinal cortex, insular cortex, or basolateral amygdala of rats immediately after the sample phase of object or object-in-context recognition memory training. Anisomycin infused into perirhinal or insular cortices blocked long-term (24 h), but not short-term (90 min) object recognition memory. Infusions into the hippocampus or amygdala did not impair object recognition memory. Anisomycin infused into the hippocampus blocked long-term, but not short-term object-in-context recognition memory, whereas infusions administered into the perirhinal cortex, insular cortex, or amygdala did not affect object-in-context recognition memory. These results clearly indicate that distinct regions of the temporal lobe are differentially involved in long-term object and object-in-context recognition memory. Whereas perirhinal and insular cortices are required for consolidation of familiar objects, the hippocampus is necessary for consolidation of contextual information of recognition memory. Altogether, these results suggest that temporal lobe structures are differentially involved in recognition memory consolidation.     

Neural correlates of successful and unsuccessful verbal memory encoding

Recent neuroimaging studies suggest that episodic memory encoding involves a network of neocortical structures which may act interdependently with medial temporal lobe (mTL) structures to promote the formation of durable memories, and that activation in certain structures is modulated according to task performance. Functional magnetic resonance imaging (fMRI) was used to determine the neural structures recruited during a verbal episodic encoding task and to examine the relationship between activation during encoding and subsequent recognition memory performance across subjects. Our results show performance-correlated activation during encoding both in neocortical and medial temporal structures. Neocortical activations associated with later successful and unsuccessful recognition memory were found to differ not only in magnitude, but also in hemispheric laterality. These performance-related hemispheric effects, which have not been previously reported, may correspond to between-subject differences in encoding strategy.     

The role of medial temporal lobe in item recognition and source recollection of emotional stimuli

Recent neuroimaging results suggest that distinct regions within the medial temporal lobe (MTL) may differentially support the episodic encoding of item and relational information for nonemotional stimuli (for a review, see Davachi, 2006). The present study was designed to assess whether these findings generalize to emotional stimuli. Behaviorally, we found that emotion reduced item recognition accuracy but did not reliably affect relational memory. fMRI analyses revealed that neutral and emotional words elicited distinct activation patterns within MTL regions predictive of subsequent memory. Consistent with previous findings for neutral words, hippocampal activation predicted later relational memory, whereas activation in the perirhinal cortex predicted successful item recognition. However, for emotional words, activation in the amygdala, hippocampus, and posterior parahippocampal cortex predicted item recognition only. These data suggest that MTL regions differentially support encoding of neutral and emotional stimuli.     

Content-specific source encoding in the human medial temporal lobe

Although the medial temporal lobe (MTL) is known to be essential for episodic encoding, the contributions of individual MTL subregions remain unclear. Data from recognition memory studies have provided evidence that the hippocampus supports relational encoding important for later episodic recollection, whereas the perirhinal cortex has been linked with encoding that supports later item familiarity. However, extant data also strongly implicate the perirhinal cortex in object processing and encoding, suggesting that perirhinal processes may contribute to later episodic recollection of object source details. To investigate this possibility, encoding activation in MTL subregions was analyzed on the basis of subsequent memory outcome while participants processed novel scenes paired with 1 of 6 repeating objects. Specifically, encoding activation correlating with later successful scene recognition memory was evaluated against that of source recollection for the object paired with the scene during encoding. In contrast to studies reporting a link between perirhinal cortex and item familiarity, it was found that encoding activation in the right perirhinal cortex correlates with successful recollection of the paired object. Furthermore, other MTL subregions also exhibited content-specific source encoding patterns of activation, suggesting that MTL subsequent memory effects are sensitive to stimulus category.     

Perirhinal cortex lesions produce retrograde amnesia for spatial information in rats: consolidation or retrieval?

Several lines of evidence in humans and experimental animals suggest that the hippocampus is critical for the formation and retrieval of spatial memory. However, although the hippocampus is reciprocally connected to adjacent cortices within the medial temporal lobe and they, in turn, are connected to the neocortex, little is known regarding the function of these cortices in memory. Here, using a reference spatial memory task in the radial maze, we show that neurotoxic perirhinal cortex lesions produce a profound retrograde amnesia when learning-surgery intervals of 1 or 50 d are used (Experiment 1). With the aim of dissociating between consolidation and retrieval processes, we injected lidocaine either daily after training (Experiment 2) or before a retention test once the learning had been completed (Experiment 3). Results show that reversible perirhinal inactivation impairs retrieval but not consolidation. However, the same procedure followed in Experiment 2 disrupted consolidation when the lidocaine was injected into the dorsal hippocampus. The results of Experiment 4 rule out the possibility that the deficit in retrieval is due to a state-dependent effect. These findings demonstrate the differential contribution of various regions of the medial temporal lobe to memory, suggesting that the perirhinal cortex plays a key role in the retrieval of spatial information for a long period of time.     

The role of the human medial temporal lobe in object recognition and object discrimination.

This paper reviews evidence from neuropsychological patient studies relevant to two questions concerning the functions of the medial temporal lobe in humans. The first is whether the hippocampus and the adjacent perirhinal cortex make different contributions to memory. Data are discussed from two patients with adult-onset bilateral hippocampal damage who show a sparing of item recognition relative to recall and certain types of associative recognition. It is argued that these data are consistent with Aggleton and Brown's (1999) proposal that familiarity-based recognition memory is not dependent on the hippocampus but is mediated by the perirhinal cortex and dorso-medial thalamic nucleus. The second question is whether the recognition memory deficit observed in medial temporal lobe amnesia can be explained by a deficit in perceptual processing and representation of objects rather than a deficit in memory per se. The finding that amnesics were impaired at recognizing, after short delays, patterns that they could successfully discriminate suggests that their memory impairment did not result from an object-processing deficit. The possibility remains, however, that the human perirhinal cortex plays a role in object processing, as well as in recognition memory, and data are presented that support this possibility.     

Dissociable contributions within the medial temporal lobe to encoding of object-location associations

The crucial role of the medial temporal lobe (MTL) in episodic memory is well established. Although there is little doubt that its anatomical subregions-the hippocampus, peri-, entorhinal and parahippocampal cortex (PHC)-contribute differentially to mnemonic processes, their specific functions in episodic memory are under debate. Data from animal, human lesion, and neuroimaging studies suggest somewhat contradictory perspectives on this functional specialization: a general participation in declarative memory, an exclusive involvement in associative mnemonic processes, and a specific contribution to spatial memory are reported for the hippocampus, adjacent cortices, and the PHC. A functional lateralization in humans dependent on the verbalizability of the material is also discussed herein. To further elucidate the differential contributions of the various MTL subregions to encoding, we employed an object-location association memory paradigm. The memory for each of the studied associations was tested twice: by the object, and by the location serving as retrieval cue. The memory accuracy in response to both cue types was also assessed parametrically. Brain activity during encoding which leads to different degrees of subsequent memory accuracy under the two retrieval conditions was compared. We found the bilateral posterior PHC to participate in encoding of both the object associated with a location and the location associated with an object. In contrast, activity in an area in the left anterior PHC and the right anterior MTL was only correlated with the memory for the location associated with an object.     

The role of the human medial temporal lobe in object recognition and object discrimination

This paper reviews evidence from neuropsychological patient studies relevant to two questions concerning the functions of the medial temporal lobe in humans. The first is whether the hippocampus and the adjacent perirhinal cortex make different contributions to memory. Data are discussed from two patients with adult-onset bilateral hippocampal damage who show a sparing of item recognition relative to recall and certain types of associative recognition. It is argued that these data are consistent with Aggleton and Brown's (1999) proposal that familiarity-based recognition memory is not dependent on the hippocampus but is mediated by the perirhinal cortex and dorso-medial thalamic nucleus. The second question is whether the recognition memory deficit observed in medial temporal lobe amnesia can be explained by a deficit in perceptual processing and representation of objects rather than a deficit in memory per se. The finding that amnesics were impaired at recognizing, after short delays, patterns that they could successfully discriminate suggests that their memory impairment did not result from an object-processing deficit. The possibility remains, however, that the human perirhinal cortex plays a role in object processing, as well as in recognition memory, and data are presented that support this possibility.     

A neural circuit analysis of visual recognition memory: role of perirhinal, medial, and lateral entorhinal cortex

Using a continuous recognition memory procedure for visual object information, we sequentially presented rats with eight novel objects and four repeated objects (chosen from the 8). These were selected from 120 different three-dimensional objects of varying sizes, shapes, textures, and degree of brightness. Repeated objects had lags ranging from 0 to 4 (from 0 to 4 different objects between the first and repeated presentation). An object was presented on one side of a long table divided in half by an opaque Plexiglas guillotine door, and the latency between opening the door and the rat moving the object was measured. The first presentation of an object resulted in reinforcement, but repeated presentations did not result in a reinforcement. After completion of acquisition training (significantly longer latencies for repeated presentation compared with the first presentation of an object), rats received lesions of the perirhinal, medial, or lateral entorhinal cortex or served as sham operated controls. On the basis of postsurgery testing and additional tests, the results indicated that rats with perirhinal cortex lesions had a sustained impairment in performing the task. There were no sustained deficits with medial or lateral entorhinal cortex lesions. The data suggest that recognition memory for visual object information is mediated primarily by the perirhinal cortex but not by the medial or lateral entorhinal cortex.     

Muscarinic receptors activity in the perirhinal cortex and hippocampus has differential involvement in the formation of recognition memory

In this work we probed the effects of post-trial infusions of the muscarinic receptor antagonist scopolamine on object recognition memory formation. Scopolamine was infused bilaterally immediately after the sample phase in the perirhinal cortex or dorsal hippocampus and animals were tested for short-term (90 min) or long-term (24 h) memory. Results showed that scopolamine impaired short-term memory when injected in either the perirhinal cortex or hippocampus. Nevertheless, scopolamine disrupted long-term memory when administrated in the perirhinal cortex but not when applied in the hippocampus. Long-term memory was unaffected when scopolamine was infused 160 min after the sample phase or 90 min before test phase. Our data indicate that short-term recognition memory requires muscarinic receptors signaling in both the perirhinal cortex and hippocampus, whereas long-term recognition memory depends on muscarinic receptors in the perirhinal cortex but not hippocampus. These results support a differential involvement of muscarinic activity in these two medial temporal lobe structures in the formation of recognition memory.     

Imaging recollection and familiarity in the medial temporal lobe: a three-component model

The medial temporal lobe (MTL) plays a crucial role in supporting memory for events, but the functional organization of regions in the MTL remains controversial, especially regarding the extent to which different subregions support recognition based on familiarity or recollection. Here we review results from functional neuroimaging studies showing that, whereas activity in the hippocampus and posterior parahippocampal gyrus is disproportionately associated with recollection, activity in the anterior parahippocampal gyrus is disproportionately associated with familiarity. The results are consistent with the idea that the parahippocampal cortex (located in the posterior parahippocampal gyrus) supports recollection by encoding and retrieving contextual information, whereas the hippocampus supports recollection by associating item and context information. By contrast, perirhinal cortex (located in the anterior parahippocampal gyrus) supports familiarity by encoding and retrieving specific item information. We discuss the implications of a 'binding of item and context' (BIC) model for studies of recognition memory. This model argues that there is no simple mapping between MTL regions and recollection and familiarity, but rather that the involvement of MTL regions in these processes depends on the specific demands of the task and the type of information involved. We highlight several predictions for future imaging studies that follow from the BIC model.     

A mini-review of fMRI studies of human medial temporal lobe activity associated with recognition memory.

This review considers event-related functional magnetic resonance imaging (fMRI) studies of human recognition memory that have or have not reported activations within the medial temporal lobes (MTL). For comparisons both between items at study (encoding) and between items at test (recognition), MTL activations are characterized as left/right, anterior/posterior, and hippocampus/surrounding cortex, and as a function of the stimulus material and relevance of item/source information. Though no clear pattern emerges, there are trends suggesting differences between item and source information, and verbal and spatial information, and a role for encoding processes during recognition tests. Important future directions are considered.     

Spatial and temporal episodic memory retrieval recruit dissociable functional networks in the human brain

Imaging, electrophysiological studies, and lesion work have shown that the medial temporal lobe (MTL) is important for episodic memory; however, it is unclear whether different MTL regions support the spatial, temporal, and item elements of episodic memory. In this study we used fMRI to examine retrieval performance emphasizing different aspects of episodic memory in the context of a spatial navigation paradigm. Subjects played a taxi-driver game ("yellowcab"), in which they freely searched for passengers and delivered them to specific landmark stores. Subjects then underwent fMRI scanning as they retrieved landmarks, spatial, and temporal associations from their navigational experience in three separate runs. Consistent with previous findings on item memory, perirhinal cortex activated most strongly during landmark retrieval compared with spatial or temporal source information retrieval. Both hippocampus and parahippocampal cortex activated significantly during retrieval of landmarks, spatial associations, and temporal order. We found, however, a significant dissociation between hippocampal and parahippocampal cortex activations, with spatial retrieval leading to greater parahippocampal activation compared with hippocampus and temporal order retrieval leading to greater hippocampal activation compared with parahippocampal cortex. Our results, coupled with previous findings, demonstrate that the hippocampus and parahippocampal cortex are preferentially recruited during temporal order and spatial association retrieval--key components of episodic "source" memory.     

A mini-review of fMRI studies of human medial temporal lobe activity associated with recognition memory

This review considers event-related functional magnetic resonance imaging (fMRI) studies of human recognition memory that have or have not reported activations within the medial temporal lobes (MTL). For comparisons both between items at study (encoding) and between items at test (recognition), MTL activations are characterized as left/right, anterior/posterior, and hippocampus/surrounding cortex, and as a function of the stimulus material and relevance of item/source information. Though no clear pattern emerges, there are trends suggesting differences between item and source information, and verbal and spatial information, and a role for encoding processes during recognition tests. Important future directions are considered.     

Perirhinal cortical contributions to object perception

The traditional theory of the medial temporal lobe (MTL) memory system asserts that the primate MTL (hippocampus, perirhinal, entorhinal and parahippocampal cortices) is exclusively involved in consolidating declarative memories. However, several recent reports have directly challenged this dogma by arguing that MTL structures also contribute to perception. Controversy remains as many of the behavioural tasks used have confounded memory with perception. We review the evidence here and highlight new studies in humans and macaques that indicate a perceptual role for MTL in the absence of such confounds. We argue that the challenge to MTL memory system theory is substantiated and that the implications are considerable, namely that most psychologists and neuroscientists have held a fundamentally flawed view of how memory is implemented in the brain.     

Neural correlates of temporal-order judgments versus those of spatial-location: deactivation of hippocampus may facilitate spatial performance

The retrieval of temporal-order versus spatial-location information was investigated using fMRI. The primary finding in the hippocampus proper, seen in region of interest analyses, was an increase in BOLD signal intensity for temporal retrieval, and a decrease in signal intensity for spatial retrieval, relative to baseline. The negative BOLD signal change with spatial memory processing, while unexpected, is consistent with the recent fMRI literature indicating decreased BOLD can be associated with neuronal activation, and it is argued that the deactivation observed here may facilitate spatial performance. Spatial-location judgments also yielded a stronger (positive) response in the right midfrontal gyrus, while temporal-order judgments (autobiographic condition only) showed greater activity in the left superior temporal gyrus, suggesting greater working memory demands and greater semantization for each judgment type, respectively. Finally, all conditions activated the left midfrontal gyrus, although autobiographic memories showed additional activity in the medial frontal gyrus.     

Dissociation between the effects of damage to perirhinal cortex and area TE

Perirhinal cortex and area TE are immediately adjacent to each other in the temporal lobe and reciprocally interconnected. These areas are thought to lie at the interface between visual perception and visual memory, but it has been unclear what their separate contributions might be. In three experiments, monkeys with bilateral lesions of the perirhinal cortex exhibited a different pattern of impairment than monkeys with bilateral lesions of area TE. In experiment 1, lesions of the perirhinal cortex produced a multimodal deficit in recognition memory (delayed nonmatching to sample), whereas lesions of area TE impaired performance only in the visual modality. In experiment 2, on a test of visual recognition memory (the visual paired comparison task) lesions of the perirhinal cortex impaired performance at long delays but spared performance at a very short delay. In contrast, lesions of area TE impaired performance even at the short delay. In experiment 3, lesions of the perirhinal cortex and lesions of area TE produced an opposite pattern of impairment on two visual discrimination tasks, simple object discrimination learning (impaired only by perirhinal lesions), and concurrent discrimination learning (impaired only by TE lesions). Taken together, the findings suggest that the perirhinal cortex, like other medial temporal lobe structures, is important for the formation of memory, whereas area TE is important for visual perceptual processing.     

Brain activity during the encoding, retention, and retrieval of stimulus representations

Studies of delayed nonmatching-to-sample (DNMS) performance following lesions of the monkey cortex have revealed a critical circuit of brain regions involved in forming memories and retaining and retrieving stimulus representations. Using event-related functional magnetic resonance imaging (fMRI), we measured brain activity in 10 healthy human participants during performance of a trial-unique visual DNMS task using novel barcode stimuli. The event-related design enabled the identification of activity during the different phases of the task (encoding, retention, and retrieval). Several brain regions identified by monkey studies as being important for successful DNMS performance showed selective activity during the different phases, including the mediodorsal thalamic nucleus (encoding), ventrolateral prefrontal cortex (retention), and perirhinal cortex (retrieval). Regions showing sustained activity within trials included the ventromedial and dorsal prefrontal cortices and occipital cortex. The present study shows the utility of investigating performance on tasks derived from animal models to assist in the identification of brain regions involved in human recognition memory.     

Learning related modulation of functional retrieval networks in man

The medial temporal lobe has been implicated in studies of episodic memory tasks involving spatio-temporal context and object-location conjunctions. We have previously demonstrated that an increased level of practice in a free-recall task parallels a decrease in the functional activity of several brain regions, including the medial temporal lobe, the prefrontal, the anterior cingulate, the anterior insular, and the posterior parietal cortices, that in concert demonstrate a move from elaborate controlled processing towards a higher degree of automaticity. Here we report data from two experiments that extend these initial observations. We used a similar experimental approach but probed for effects of retrieval paradigms and stimulus material. In the first experiment we investigated practice related changes during recognition of object-location conjunctions and in the second during free-recall of pseudo-words. Learning in a neural network is a dynamic consequence of information processing and network plasticity. The present and previous PET results indicate that practice can induce a learning related functional restructuring of information processing. Different adaptive processes likely subserve the functional re-organisation observed. These may in part be related to different demands for attentional and working memory processing. It appears that the role(s) of the prefrontal cortex and the medial temporal lobe in memory retrieval are complex, perhaps reflecting several different interacting processes or cognitive components. We suggest that an integrative interactive perspective on the role of the prefrontal and medial temporal lobe is necessary for an understanding of the processing significance of these regions in learning and memory. It appears necessary to develop elaborated and explicit computational models for prefrontal and medial temporal functions in order to derive detailed empirical predictions, and in combination with an efficient use and development of functional neuroimaging approaches, to further the understanding of the processing significance of these regions in memory.