Working memory, long-term memory, and medial temporal lobe function

Early studies of memory-impaired patients with medial temporal lobe (MTL) damage led to the view that the hippocampus and related MTL structures are involved in the formation of long-term memory and that immediate memory and working memory are independent of these structures. This traditional idea has recently been revisited. Impaired performance in patients with MTL lesions on tasks with short retention intervals, or no retention interval, and neuroimaging findings with similar tasks have been interpreted to mean that the MTL is sometimes needed for working memory and possibly even for visual perception itself. We present a reappraisal of this interpretation. Our main conclusion is that, if the material to be learned exceeds working memory capacity, if the material is difficult to rehearse, or if attention is diverted, performance depends on long-term memory even when the retention interval is brief. This fundamental notion is better captured by the terms subspan memory and supraspan memory than by the terms short-term memory and long-term memory. We propose methods for determining when performance on short-delay tasks must depend on long-term (supraspan) memory and suggest that MTL lesions impair performance only when immediate memory and working memory are insufficient to support performance. In neuroimaging studies, MTL activity during encoding is influenced by the memory load and correlates positively with long-term retention of the material that was presented. The most parsimonious and consistent interpretation of all the data is that subspan memoranda are supported by immediate memory and working memory and are independent of the MTL.     

Percepts to recollections: insights from single neuron recordings in the human brain

Transformation of experience into memories that can guide future behavior is a common ability across species. However, only humans can declare their perceptions and memories of experienced events (episodes). The medial temporal lobe (MTL) is central to episodic memory, yet the neuronal code underlying the translation from sensory information to memory remains unclear. Recordings from neurons within the brain in patients who have electrodes implanted for clinical reasons provide an opportunity to bridge physiology with cognitive theories. Recent evidence illustrates several striking response properties of MTL neurons. Responses are selective yet invariant, associated with conscious perception, can be internally generated and modulated, and spontaneously retrieved. Representation of information by these neurons is highly explicit, suggesting abstraction of information for future conscious recall.     

The perceptual-mnemonic/feature conjunction model of perirhinal cortex function.

The perirhinal cortex was once thought to be "silent cortex", virtually ignored by researchers interested in the neurobiology of learning and memory. Following studies of brain damage associated with cases of amnesia, perirhinal cortex is now widely regarded as part of a "medial temporal lobe (MTL) memory system". This system is thought to be more or less functionally homogeneous, having a special role in declarative memory, and making little or no contribution to other functions such as perception. In the present article, we summarize an alternative view. First, we propose that components of the putative MTL system such as the hippocampus and perirhinal cortex have distinct and dissociable functions. Second, we provide evidence that the perirhinal cortex has a role in visual discrimination. In addition, we propose a specific role for perirhinal cortex in visual discrimination: the contribution of complex conjunctive representations to the solution of visual discrimination problems with a high degree of "feature ambiguity". These proposals constitute a new view of perirhinal cortex function, one that does not assume strict modularity of function in the occipito-temporal visual stream, but replaces this idea with the notion of a hierarchical representational continuum.     

The medial temporal lobe and visual working memory: Comparisons across tasks, delays, and visual similarity

Whether the hippocampus and medial temporal lobe (MTL) play any important role in visual working memory is a relatively new and controversial research question. The primary goal of this study was to assess working memory for faces over very short delays in patients with MTL damage. Patients and matched controls were required to remember one face that was parametrically morphed to be more or less similar to a probe face, over either a 1- or an 8-sec delay. Memory was assessed using both forced choice and old-new recognition tasks. The results show that MTL damage impairs both speed and accuracy of visual working memory across tasks. We speculate that the hippocampus is generally necessary for memory encoding.     

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 perceptual-mnemonic/feature conjunction model of perirhinal cortex function

The perirhinal cortex was once thought to be “silent cortex”, virtually ignored by researchers interested in the neurobiology of learning and memory. Following studies of brain damage associated with cases of amnesia, perirhinal cortex is now widely regarded as part of a “medial temporal lobe (MTL) memory system”. This system is thought to be more or less functionally homogeneous, having a special role in declarative memory, and making little or no contribution to other functions such as perception. In the present article, we summarize an alternative view. First, we propose that components of the putative MTL system such as the hippocampus and perirhinal cortex have distinct and dissociable functions. Second, we provide evidence that the perirhinal cortex has a role in visual discrimination. In addition, we propose a specific role for perirhinal cortex in visual discrimination: the contribution of complex conjunctive representations to the solution of visual discrimination problems with a high degree of “feature ambiguity”. These proposals constitute a new view of perirhinal cortex function, one that does not assume strict modularity of function in the occipito-temporal visual stream, but replaces this idea with the notion of a hierarchical representational continuum.     

Neural correlates underlying true and false associative memories

Despite the fact that associative memory studies produce a large number of false memories, neuroimaging analyses utilizing this paradigm typically focus only on neural activity mediating successful retrieval. The current study sought to expand on this prior research by examining the neural basis of both true and false associative memories. Though associative false memories are substantially different than those found in semantic or perceptual false memory paradigms, results suggest that associative false memories are mediated by similar neural mechanisms. Specifically, we found increased frontal activity that likely represents enhanced monitoring and evaluation compared to that needed for true memories and correct rejections. Results also indicated that true, and not false associative memories, are mediated by neural activity in the MTL, specifically the hippocampus. Finally, while activity in early visual cortex distinguished true from false memories, a lack of neural differences between hits and correct rejections failed to support previous findings suggesting that activity in early visual cortex represents sensory reactivation of encoding-related processing.     

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.     

Can neuroimaging really tell us what the human brain is doing? The relevance of indirect measures of population activity

Neuroimaging studies using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) give an indication towards the localization of mental representations and processes in the human brain. It is not clear to what extent such global measures of neuronal activity, pooling across large populations of neurons, can reveal how certain computations are implemented by the neurons in such population ('computational neuroimaging'). Population activity is related tightly to single-cell activity when all neurons in the population have similar response properties. We describe some evidence from single-cell recordings in monkeys that indicates that neurons with similar response properties are not scattered randomly throughout the visual cortex. Notwithstanding this clustering, populations of nearby neurons are still rather heterogeneous, requiring some prudence in deriving single-cell response properties from population activity. The following review of recent neuroimaging studies of the visual system describes to what degree inferences about computations and representations can be drawn from these studies.     

Imaging the medial temporal lobe: exploring new dimensions

Cognitive scientists have used developments in functional imaging to explore the role of the medial temporal lobe (MTL) in memory formation. Lesion studies have suggested that separate MTL subregions make distinct contributions to memory. Functional imaging of these distinct contributions, however, remains a challenge, because the proximity of the MTL substructures tests the spatial resolution limits of current techniques. Recent findings using electrophysiological measures of neural activity highlight the importance of using information from other imaging modalities. Integrating the different modalities of neuroimaging with lesion studies, and, further, combining modalities within experiments, will provide new insights into the function of MTL subregions.     

Theta synchronizes the activity of medial prefrontal neurons during learning

Memory consolidation is thought to involve the gradual transfer of transient hippocampal-dependent traces to distributed neocortical sites via the rhinal cortices. Recently, medial prefrontal (mPFC) neurons were shown to facilitate this process when their activity becomes synchronized. However, the mechanisms underlying this enhanced synchrony remain unclear. Because the hippocampus projects to the mPFC, we tested whether theta oscillations contribute to synchronize mPFC neurons during learning. Thus, we obtained field (LFP) and unit recordings from multiple mPFC sites during the acquisition of a trace-conditioning task, where a visual conditioned stimulus (CS) predicted reward delivery. In quiet waking, the activity of mPFC neurons was modulated by theta oscillations. During conditioning, CS presentation caused an increase in mPFC theta power that augmented as the CS gained predictive value for reward delivery. This increased theta power coincided with a transient theta phase locking at distributed mPFC sites, an effect that was also manifest in the timing of mPFC unit activity. Overall, these results show that theta oscillations contribute to synchronize neuronal activity at distributed mPFC sites, suggesting that the hippocampus, by generating a stronger theta source during learning, can synchronize mPFC activity, in turn facilitating rhinal transfer of its activity to the neocortex.     

Episodic encoding and recognition of pictures and words: role of the human medial temporal lobes

In the present PET study, we examined brain activity related to processing of pictures and printed words in episodic memory. Our goal was to determine how the perceptual format of objects (verbal versus pictorial) is reflected in the neural organization of episodic memory for common objects. We investigated this issue in relation to encoding and recognition with a particular focus on medial temporal-lobe (MTL) structures. At encoding, participants saw pictures of objects or their written names and were asked to make semantic judgments. At recognition, participants made yes-no recognition judgments in four different conditions. In two conditions, target items were pictures of objects; these objects had originally been encoded either in picture or in word format. In two other conditions, target items were words; they also denoted objects originally encoded either as pictures or as words. Our data show that right MTL structures are differentially involved in picture processing during encoding and recognition. A posterior MTL region showed higher activation in response to the presentation of pictures than of words across all conditions. During encoding, this region may be involved in setting up a representation of the perceptual information that comprises the picture. At recognition, it may play a role in guiding retrieval processes based on the perceptual input, i.e. the retrieval cue. Another more anterior right MTL region was found to be differentially involved in recognition of objects that had been encoded as pictures, irrespective of whether the retrieval cue provided was pictorial or verbal in nature; this region may be involved in accessing stored pictorial representations. Our results suggest that left MTL structures contribute to picture processing only during encoding. Some regions in the left MTL showed an involvement in semantic encoding that was picture specific; others showed a task-specific involvement across pictures and words. Together, our results provide evidence that the involvement of some but not all MTL regions in episodic encoding and recognition is format specific.     

Selective adaptation of monocular and binocular neurons in human vision

Psychophysical techniques were used to examine how subpopulations of visual neurons varying in their ocular dominance interacted in determining performance on a visual task. Using an asymmetric alternating adaptation of the left and right eyes, we manipulated the sensitivity of monocularly driven neurons while keeping the sensitivity of binocularly driven neurons constant. Relative threshold elevations were measured in the left eye, right eye, and both eyes of five observers following different ratios of alternating adaptation. It was found that whereas monocularly measured aftereffects varied monotonically as a function of the adaptation duration of the measured eye, the magnitude of the binocularly measured aftereffect remained constant regardless of how the adaptation was divided between the two eyes. This suggests that neurons differing in their ocular dominance pool their activity in determining sensitivity to a test target.     

Disproportionate deficit in associative recognition relative to item recognition in global amnesia

In two experiments, we tested the hypothesis that medial temporal lobe (MTL) amnesic patients and, likewise, diencephalic (DNC) amnesic patients evidence a disproportionate deficit in memory for associations in comparison with memory for single items. In Experiment 1, we equated item recognition in amnesic and control participants and found that, under these conditions, associative recognition remained impaired both for MTL patients and for DNC patients. To rule out an alternative interpretation of the results of Experiment 1, in Experiment 2 we compared the performance of amnesic and control participants on a one-item recognition task and a two-item recognition task that required no memory for the association between members of word pairs. In the MTL group, when single-item recognition was equated to that of the controls, two-item nonassociative pair memory was equivalent as well. In the DNC group, nonassociative pair memory was impaired, but this impairment did not fully account for the impairment in associative memory. These findings indicate that memory for novel associations between items is disproportionately impaired in comparison with memory for single items in amnesia.     

Overcoming interference: an fMRI investigation of pattern separation in the medial temporal lobe

The medial temporal lobe (MTL) supports the formation and retrieval of long-term declarative memories, or memories for facts and everyday events. One challenge posed for this type of memory stems from the highly overlapping nature of common episodes. Within cognitive psychology, it is widely accepted that interference between information learned at different times is a major limitation on memory. In spite of several decades of intense research in the fields of interference theory and the neurobiological underpinnings of declarative memory, there is little direct evidence bearing on how the MTL resolves this interference to form accurate memories of everyday facts and events. Computational models of MTL function have proposed a mechanism in which the MTL, specifically the hippocampus, performs pattern separation, whereby overlapping representations are made less similar. However, there is little evidence bearing on how this process is carried out in the intact human MTL. Using high-resolution fMRI, we conducted a set of experiments that taxed behavioral pattern separation by using highly similar, interfering stimuli in a modified continuous recognition task. Regions within the parahippocampal gyrus demonstrated activity consistent with a "recall to reject" strategy. In contrast and critical to performing the task, activity within the hippocampus distinguished between correctly identified true stimulus repetitions, correctly rejected presentations of similar lure stimuli, and false alarms to similar lures. These data support the computational models' assertion that the hippocampus plays a key role in pattern separation.     

The relevance of the nature of learned associations for the differentiation of human memory systems

In a previous functional magnetic resonance imaging (fMRI) study we demonstrated an involvement of the medial temporal lobe (MTL) during an implicit learning task. We concluded that the MTL was engaged because of the complex contingencies that were implicitly learned. In addition, the basal ganglia demonstrated effects of a paralleled proceduralization of fixed stimulus-response associations. In the present study we directly tested the hypothesis that the MTL activation depends upon implementing the complex regularity in task material, whereas activation of basal ganglia does not. Therefore, we rearranged task material such that it did not contain any complex regularity. The statistical comparison of behavioral and fMRI data between the materials allowed for isolating effects that were directly related to the implicit learning process regarding the complex regularity. The results showed a reliable difference of fMRI signal limited to the MTL, indicating a specific functional role of the MTL in implicit learning of complex contingencies. Furthermore, no difference of BOLD (Blood-Oxygenation Level Dependent) signal in the basal ganglia and cerebellum were detected, supporting the assumption of a functional involvement of the structures in proceduralization of simple stimulus-response associations but not in implicitly learning complex relations. We therefore conclude that the nature of the learned associations is relevant for determining the neuronal focus of learning, rather than the accompanying awareness.     

The influence of stimulus properties on multisensory processing in the awake primate superior colliculus.

Multisensory integration is a process whereby information converges from different sensory modalities to produce a response that is different from that elicited by the individual modalities presented alone. A neural basis for multisensory integration has been identified within a variety of brain regions, but the most thoroughly examined model has been that of the superior colliculus (SC). Multisensory processing in the SC of anaesthetized animals has been shown to be dependent on the physical parameters of the individual stimuli presented (e.g., intensity, direction, velocity) as well as their spatial relationship. However, it is unknown whether these stimulus features are important, or evident, in the awake behaving animal. To address this question, we evaluated the influence of physical properties of sensory stimuli (visual intensity, direction, and velocity; auditory intensity and location) on sensory activity and multisensory integration of SC neurons in awake, behaving primates. Monkeys were trained to fixate a central visual fixation point while visual and/or auditory stimuli were presented in the periphery. Visual stimuli were always presented within the contralateral receptive field of the neuron whereas auditory stimuli were presented at either ipsi- or contralateral locations. Many of the SC neurons responsive to these sensory stimuli (n = 66/84; 76%) had stronger responses when the visual and auditory stimuli were combined at contralateral locations than when the auditory stimulus was located on the ipsilateral side. This trend was significant across the population of auditory-responsive neurons. In addition, some SC neurons (n = 31) were presented a battery of tests in which the quality of one stimulus of a pair was systematically manipulated. A small proportion of these neurons (n = 8/31; 26%) showed preferential responses to stimuli with specific physical properties, and these preferences were not significantly altered when multisensory stimulus combinations were presented. These data demonstrate that multisensory processing in the awake behaving primate is influenced by the spatial congruency of the stimuli as well as their individual physical properties.     

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.     

Contributions of the medial temporal lobe to declarative memory retrieval: manipulating the amount of contextual retrieval

We investigated how the hippocampus and its adjacent mediotemporal structures contribute to contextual and noncontextual declarative memory retrieval by manipulating the amount of contextual information across two levels of the same contextual dimension in a source memory task. A first analysis identified medial temporal lobe (MTL) substructures mediating either contextual or noncontextual retrieval. A linearly weighted analysis elucidated which MTL substructures show a gradually increasing neural activity, depending on the amount of contextual information retrieved. A hippocampal engagement was found during both levels of source memory but not during item memory retrieval. The anterior MTL including the perirhinal cortex was only engaged during item memory retrieval by an activity decrease. Only the posterior parahippocampal cortex showed an activation increasing with the amount of contextual information retrieved. If one assumes a roughly linear relationship between the blood-oxygenation level-dependent (BOLD) signal and the associated cognitive process, our results suggest that the posterior parahippocampal cortex is involved in contextual retrieval on the basis of memory strength while the hippocampus processes representations of item-context binding. The anterior MTL including perirhinal cortex seems to be particularly engaged in familiarity-based item recognition. If one assumes departure from linearity, however, our results can also be explained by one-dimensional modulation of memory strength.     

The contribution of the human medial temporal lobe to perception: Bridging the gap between animal and human studies

The medial temporal lobe (MTL) has been considered traditionally to subserve declarative memory processes only. Recent studies in nonhuman primates suggest, however, that the MTL may also be critical to higher order perceptual processes, with the hippocampus and perirhinal cortex being involved in scene and object perception, respectively. The current article reviews the human neuropsychological literature to determine whether there is any evidence to suggest that these same views may apply to the human MTL. Although the majority of existing studies report intact perception following MTL damage in human amnesics, there have been recent studies that suggest that when scene and object perception are assessed systematically, signifi-cant impairments in perception become apparent. These findings have important implications for current mnemonic theories of human MTL function and our understanding of human amnesia as a result of MTL lesions.