FMRI activity in the medial temporal lobe during recognition memory as a function of study-test interval

The human entorhinal-hippocampal circuitry is characterized by an information-specific functional organization where two routes, that are preferentially connected to the parahippocampal cortex or the perirhinal and retrosplenial cortices, divide the entorhinal cortex as well as hippocampal subiculum and CA1 subregions.

The goal of the present study was to determine whether alumina gel injections into temporal lobe structures cause complex partial seizures (CPS) and pathological changes observed in human temporal lobe epilepsy. Rhesus monkeys with alumina gel injections in the amygdala, perirhinal and entorhinal cortices, or Ammon's horn and dentate gyrus all initially displayed focal pathological electroencephalographic (EEG) slowing limited to the site of injection. After clinical seizures developed, they also displayed widespread pathological EEG slowing over both hemispheres, interictal and ictal epileptiform EEG abnormalities limited to the mesial-inferior temporal lobe on the side of injection, and different degrees of spread to other ipsilateral and contralateral structures. Noninjected control and nonepileptic monkeys with injections into the middle and inferior temporal gyri displayed no hippocampal neuronal loss or mossy fiber sprouting. When alumina gel was injected into the amygdala, CPS began within 3-6 weeks and degeneration of neurons and gliosis occurred in the perirhinal cortex or the hippocampus, with consequent sprouting of mossy fibers in the dentate gyrus. Dispersion of the granule cell layer was also observed. Other monkeys with alumina gel in the perirhinal and entorhinal cortices developed CPS within 2-3 weeks after the injections and displayed mossy fiber sprouting only after 4 weeks after the injections. Alumina gel in Ammon's horn and the dentate gyrus also induced CPS, but mossy fiber sprouting was limited to sites immediately adjacent to the injection, probably because none survived more than 4 weeks after the injections. This nonhuman primate model of CPS displayed similar anatomical, behavioral, and EEG features as observed in human temporal lobe epilepsy and provides opportunities to analyze the chronological sequence of epileptogenesis and to test potential therapies.

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.

Although the majority of research on human memory has concentrated on a person's ability to recall or recognize items as having been presented in a particular situation, the effects of memory are also revealed in a person's performance of a perceptual task. Prior experience with material can make that material more easily identified or comprehended in perceptually difficult situations. Unlike with standard retention tests, effects of prior experience on a perceptual task do not logically require that a person be aware that he or she is remembering. Indeed, amnesic patients purportedly show effects of practice in their subsequent performance of a perceptual or motor task even though they profess that they do not remember having engaged in that prior experience. The experiments that are reported were designed to explore the relationship between the more aware autobiographical form of memory that is measured by a recognition memory test and the less aware form of memory that is expressed in perceptual learning. Comparisons of effects on perceptual learning and recognition memory reveal two classes of variables. Variables such as the level of processing of words during study influenced recognition memory, although they had no effect on subsequent perceptual recognition. A study presentation of a word had as large an effect on its later perceptual recognition when recognition memory performance was very poor as it did when recognition memory performance was near perfect. In contrast, variables such as the number and the spacing of repetitions produced parallel effects on perceptual recognition and recognition memory. Following Mandler and others, it is suggested that there are two bases for recognition memory. If an item is readily perceived so that it seems to "jump out" from the page, a person is likely to judge that he or she has previously seen the item in the experimental situation. Variables that influence ease of perceptual recognition, then, can also have an effect on recognition memory, so parallel effects are found. The second basis for recognition memory involves elaboration of a word's study context and depends on such factors as level of processing during study--factors that are not important for perceptual recognition of isolated words. Comparisons of perceptual recognition and recognition memory are shown to be useful for determining how a variable has its effect. Effects of study on perceptual recognition appear to be totally due to memory for physical or graphemic information. Results reported are also relevant to theories of perceptual learning. A single presentation of an item is shown to have large and long-lasting effects on its later perceptual recognition. At least partially, effects of study on perceptual recognition depend on the same variables as do effects on more standard memory tests.

A central debate in the systems neuroscience of memory concerns whether different medial temporal lobe (MTL) structures support different processes in recognition memory. Using two recognition memory paradigms, we tested a rare patient (MH) with a perirhinal lesion that appeared to spare the hippocampus. Consistent with a similar previous case, MH showed impaired familiarity and preserved recollection. When compared with patients with hippocampal lesions appearing to spare perirhinal cortex, MH showed greater impairment on familiarity and less on recollection. Nevertheless, the hippocampal patients also showed impaired familiarity compared with healthy controls. However, when replacing this traditional categorization of patients with analyses relating memory performance to continuous measures of damage across patients, hippocampal volume uniquely predicted recollection, whereas parahippocampal, rather than perirhinal, volume uniquely predicted familiarity. We consider whether the familiarity impairment in MH and our patients with hippocampal lesions arises from “subthreshold” damage to parahippocampal cortex (PHC). Our data provide the most compelling neuropsychological support yet for dual-process models of recognition memory, whereby recollection and familiarity depend on different MTL structures, and may support a role for PHC in familiarity. Our study highlights the value of supplementing single-case studies with examinations of continuous brain–behavior relationships across larger patient groups.

The essential role of the medial temporal lobe (MTL) in long-term memory for individual events is well established, yet important questions remain regarding the mnemonic functions of the component structures that constitute the region. Within the hippocampus, recent functional neuroimaging findings suggest that formation of new memories depends on the dentate gyrus and the CA(3) field, whereas the contribution of the subiculum may be limited to retrieval. During encoding, it has been further hypothesized that structures within MTL cortex contribute to encoding in a content-sensitive manner, whereas hippocampal structures may contribute to encoding in a more domain-general manner. In the current experiment, high-resolution fMRI techniques were utilized to assess novelty and subsequent memory effects in MTL subregions for two classes of stimuli--faces and scenes. During scanning, participants performed an incidental encoding (target detection) task with novel and repeated faces and scenes. Subsequent recognition memory was indexed for the novel stimuli encountered during scanning. Analyses revealed voxels sensitive to both novel faces and novel scenes in all MTL regions. However, similar percentages of voxels were sensitive to novel faces and scenes in perirhinal cortex, entorhinal cortex, and a combined region comprising the dentate gyrus, CA(2), and CA(3), whereas parahippocampal cortex, CA(1), and subiculum demonstrated greater sensitivity to novel scene stimuli. Paralleling these findings, subsequent memory effects in perirhinal cortex were observed for both faces and scenes, with the magnitude of encoding activation being related to later memory strength, as indexed by a graded response tracking recognition confidence, whereas subsequent memory effects were scene-selective in parahippocampal cortex. Within the hippocampus, encoding activation in the subiculum correlated with subsequent memory for both stimulus classes, with the magnitude of encoding activation varying in a graded manner with later memory strength. Collectively, these findings suggest a gradient of content sensitivity from posterior (parahippocampal) to anterior (perirhinal) MTL cortex, with MTL cortical regions differentially contributing to successful encoding based on event content. In contrast to recent suggestions, the present data further indicate that the subiculum may contribute to successful encoding irrespective of event content.

P3-081 Development of automated identification of cortical regions on MRI scans in AD patients

Functional connectivity based parcellation of the human medial temporal lobe

How landmark suitability shapes recognition memory signals for objects in the medial temporal lobes

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

Monkeys Recall and Reproduce Simple Shapes from Memory

Recent models of episodic memory propose a division of labor among medial temporal lobe cortices comprising the parahippocampal gyrus. Specifically, perirhinal and lateral entorhinal cortices are thought to comprise an object/item information pathway, whereas parahippocampal and medial entorhinal cortices are thought to comprise a spatial/contextual information pathway. Although several studies in human subjects have demonstrated a perirhinal/parahippocampal division, such a division among subregions of the human entorhinal cortex has been elusive. Other recent work has implicated pattern separation computations in the dentate gyrus and CA3 subregions of the hippocampus as a mechanism supporting the resolution of mnemonic interference. However, the nature of contributions of medial temporal lobe cortices to downstream hippocampal computations is largely unknown. We used high-resolution fMRI during a task selectively taxing mnemonic discrimination of object identity or spatial location, designed to differentially engage the two information pathways in the medial temporal lobes. Consistent with animal models, we demonstrate novel evidence for a domain-selective dissociation between lateral and medial entorhinal cortex in humans, and between perirhinal and parahippocampal cortex as a function of information content. Conversely, hippocampal dentate gyrus/CA3 demonstrated signals consistent with resolution of mnemonic interference across domains. These results provide insight into the information processing capacities and hierarchical interference resolution throughout the human medial temporal lobe.

Many studies have focused on the function of hippocampal region CA1 as a critical site for associative memory, but much less is known about changes in the afferents to CA1. Here we report the activity of multiple single neurons from perirhinal and entorhinal cortex and from dentate gyrus during trace eyeblink conditioning as well as consolidated recall, and in pseudo-conditioned control rabbits. We also report an analysis of theta activity filtered from the local field potential (LFP). Our results show early associative changes in single-neuron firing rate as well as theta oscillations in lateral entorhinal cortex (EC) and dentate gyrus (DG), and increases in the number of responsive neurons in perirhinal cortex. In both EC and DG, a subset of neurons from conditioned animals exhibited an elevated baseline firing rate and large responses to the conditioned stimulus and trace period. A similar population of cells has been seen in DG and in medial, but not lateral, EC during spatial tasks, suggesting that lateral EC contains cells responsive to a temporal associative task. In contrast to recent studies in our laboratory that found significant CA1 contributions to long-term memory, the activity profiles of neurons within EC and DG were similar for conditioned and pseudoconditioned rabbits during post-consolidation sessions. Collectively these results demonstrate that individual subregions of medial temporal lobe differentially support new and remotely acquired memories. Neuron firing profiles were similar on training trials when conditioned responses were and were not exhibited, demonstrating that these temporal lobe regions represent the CS-US association and do not control the behavioral response. The analysis of theta activity revealed that theta power was modulated by the conditioning stimuli in both the conditioned and pseudoconditioned groups and that although both groups exhibited a resetting of phase to the corneal airpuff, only the conditioned group exhibited a resetting of phase to the whisker conditioned stimulus.

In the last few decades, there has been extensive research in the cognitive neurophysiology of learning and memory. Most relevant experimental studies were focused on the possible role of neuropeptides on memory performance and the neurobiological bases of their actions. In general, scientists believe that the answers to those questions relies in understanding how the information about new events is acquired and coded by neurons, how this information is modulated and if it is possible to revert age-related or diseases associated cognitive to failures. Memory is broadly divided into declarative and nondeclarative forms. The formation of declarative memory depends on a neural system anatomically connected in the medial temporal lobe that recruits hippocampus, dentate gyrus, the subicular complex, and the adjacent perirhinal, entorhinal, and parahippocampal cortices) (Squire & Zola-Morgan, 1991; Eichenbaum & Cohen, 2001). In both, animals and humans, declarative memory supports the capacity to recollect facts and events and can be contrasted with a collection of nondeclarative memory abilities: habits and skills, simple forms of conditioning, and other ways that the effects of experience can be expressed through performance rather than recollection (Squire, 1992; Schacter & Tulving, 1994). Numerous tests have been used for studying memory; they differ in several ways other than just the type of information that must be remembered. Other differences include the nature of the motivation or reward, the reinforcement contingencies, and the amount of training required. The behaviors that are measured to assess memory also vary considerably and include conditioned reflexes (e.g., Pavlovian fear conditioning), speed or accuracy of spatial navigation (which can involve either swimming -water mazeor running -radial maze-). The object recognition test (e.g., novel object recognition -NORor novel object preference -NOP), also known as the visual paired comparison task in studies with humans and monkeys, is a non-spatial and non-aversive procedure extensively applied to study neuronanatomical and molecular mechanism involves in recognition memory process, a form of declarative memory (Ennaceur & Delacour, 1988; Puma et al., 1999; Bizot et al., 2005). Recognition memory is a fundamental facet of our ability to remember. It requires a capacity for both identification and judgment of the prior occurrence of what has been identified (Mandler, 1980). This memory includes two components, a recollective (episodic) component that supports the ability to remember the episode in which an item was encountered, and a familiarity component that supports the ability to know that an item was presented (Mandler,

How the different elements of our experiences are encoded into episodic memories has remained one of the major questions in memory research. Although the pivotal role of the medial temporal lobe as a whole for memory formation is well established, much controversy surrounds the precise contributions of the subregions in the medial temporal lobe cortex (MTLC), most notably the perirhinal cortex (PrC) and the parahippocampal cortex (PhC). While one prominent view links PrC processes with familiarity-based memory and PhC with recollection, an alternative organizing principle is the representational domain critical for successful memory performance, e.g., object- vs. scene-related information. In this fMRI study, we directly compared successful source encoding during object- vs. scene-imagery, holding perceptual input constant across the two representational domains. While the hippocampus contributed to associative encoding of both object and scene information, our results revealed a clear double dissociation between PrC and PhC for object- vs. scene-related source encoding. In particular, PrC, but not PhC, encoding activation predicted later source memory for the object imagery task, whereas PhC, but not PrC, encoding activation predicted later source memory for the scene imagery task. Interestingly, the transitional zone between PrC and posterior PhC contributed to both object and scene source encoding, possibly reflecting a gradient in domain-preference along MTLC. In sum, these results strongly point to representational domain as a key factor determining the involvement of different MTLC subregions during successful episodic memory formation.