Two kinds of memory signals in neurons of the human hippocampus.

Prior studies of the neural representation of episodic memory in the human hippocampus have identified generic memory signals representing the categorical status of test items (novel vs. repeated), whereas other studies have identified item specific memory signals representing individual test items. Here, we report that both kinds of memory signals can be detected in hippocampal neurons in the same experiment. We recorded single-unit activity from four brain regions (hippocampus, amygdala, anterior cingulate, and prefrontal cortex) of epilepsy patients as they completed a continuous recognition task. The generic signal was found in all four brain regions, whereas the item-specific memory signal was detected only in the hippocampus and reflected sparse coding. That is, for the item-specific signal, each hippocampal neuron responded strongly to a small fraction of repeated words, and each repeated word elicited strong responding in a small fraction of neurons. The neural code was sparse, pattern-separated, and limited to the hippocampus, consistent with longstanding computational models. We suggest that the item-specific episodic memory signal in the hippocampus is fundamental, whereas the more widespread generic memory signal is derivative and is likely used by different areas of the brain to perform memory-related functions that do not require item-specific information.

One-trial perceptual learning in the absence of conscious remembering and independent of the medial temporal lobe.

A degraded, black-and-white image of an object, which appears meaningless on first presentation, is easily identified after a single exposure to the original, intact image. This striking example of perceptual learning reflects a rapid (one-trial) change in performance, but the kind of learning that is involved is not known. We asked whether this learning depends on conscious (hippocampus-dependent) memory for the images that have been presented or on an unconscious (hippocampus-independent) change in the perception of images, independently of the ability to remember them. We tested five memory-impaired patients with hippocampal lesions or larger medial temporal lobe (MTL) lesions. In comparison to volunteers, the patients were fully intact at perceptual learning, and their improvement persisted without decrement from 1 d to more than 5 mo. Yet, the patients were impaired at remembering the test format and, even after 1 d, were impaired at remembering the images themselves. To compare perceptual learning and remembering directly, at 7 d after seeing degraded images and their solutions, patients and volunteers took either a naming test or a recognition memory test with these images. The patients improved as much as the volunteers at identifying the degraded images but were severely impaired at remembering them. Notably, the patient with the most severe memory impairment and the largest MTL lesions performed worse than the other patients on the memory tests but was the best at perceptual learning. The findings show that one-trial, long-lasting perceptual learning relies on hippocampus-independent (nondeclarative) memory, independent of any requirement to consciously remember.

Neuropsychological and neuropathological observations of a long-studied case of memory impairment.

We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and circumscribed impairment in the formation of long-term, declarative memory (anterograde amnesia), together with temporally graded retrograde amnesia covering ∼5 y prior to the cardiac arrest. More remote memory for both facts and autobiographical events was intact. His neuropathology was extensive and involved the medial temporal lobe, the diencephalon, cerebral cortex, basal ganglia, and cerebellum. In the hippocampal formation, there was substantial cell loss in the CA1 and CA3 fields, the hilus of the dentate gyrus (with sparing of granule cells), and the entorhinal cortex. There was also cell loss in the CA2 field, but some remnants remained. The amygdala demonstrated substantial neuronal loss, particularly in its deep nuclei. In the thalamus, there was damage and atrophy of the anterior nuclear complex, the mediodorsal nucleus, and the pulvinar. There was also loss of cells in the medial and lateral mammillary nuclei in the hypothalamus. We suggest that the neuropathology resulted from two separate factors: the initial cardiac arrest (and respiratory distress) and the recurrent seizures that followed, which led to additional damage characteristic of temporal lobe epilepsy.

Spiking activity in the human hippocampus prior to encoding predicts subsequent memory.

Encoding activity in the medial temporal lobe, presumably evoked by the presentation of stimuli (postonset activity), is known to predict subsequent memory. However, several independent lines of research suggest that preonset activity also affects subsequent memory. We investigated the role of preonset and postonset single-unit and multiunit activity recorded from epilepsy patients as they completed a continuous recognition task. In this task, words were presented in a continuous series and eventually began to repeat. For each word, the patient's task was to decide whether it was novel or repeated. We found that preonset spiking activity in the hippocampus (when the word was novel) predicted subsequent memory (when the word was later repeated). Postonset activity during encoding also predicted subsequent memory, but was simply a continuation of preonset activity. The predictive effect of preonset spiking activity was much stronger in the hippocampus than in three other brain regions (amygdala, anterior cingulate, and prefrontal cortex). In addition, preonset and postonset activity around the encoding of novel words did not predict memory performance for novel words (i.e., correctly classifying the word as novel), and preonset and postonset activity around the time of retrieval did not predict memory performance for repeated words (i.e., correctly classifying the word as repeated). Thus, the only predictive effect was between preonset activity (along with its postonset continuation) at the time of encoding and subsequent memory. Taken together, these findings indicate that preonset hippocampal activity does not reflect general arousal/attention but instead reflects what we term "attention to encoding."

Preserved capacity for learning statistical regularities and directing selective attention after hippocampal lesions.

Prior knowledge about the probabilistic structure of visual environments is necessary to resolve ambiguous information about objects in the world. Expectations based on stimulus regularities exert a powerful influence on human perception and decision making by improving the efficiency of information processing. Another type of prior knowledge, termed top-down attention, can also improve perceptual performance by facilitating the selective processing of relevant over irrelevant information. While much is known about attention, the mechanisms that support expectations about statistical regularities are not well-understood. The hippocampus has been implicated as a key structure involved in or perhaps necessary for the learning of statistical regularities, consistent with its role in various kinds of learning and memory. Here, we tested this hypothesis using a motion discrimination task in which we manipulated the most likely direction of motion, the degree of attention afforded to the relevant stimulus, and the amount of available sensory evidence. We tested memory-impaired patients with bilateral damage to the hippocampus and compared their performance with controls. Despite a modest slowing in response initiation across all task conditions, patients performed similar to controls. Like controls, patients exhibited a tendency to respond faster and more accurately when the motion direction was more probable, the stimulus was better attended, and more sensory evidence was available. Together, these findings demonstrate a robust, hippocampus-independent capacity for learning statistical regularities in the sensory environment in order to improve information processing.

The nature of recollection across months and years and after medial temporal lobe damage.

We studied the narrative recollections of memory-impaired patients with medial temporal lobe (MTL) damage who took a 25-min guided walk during which 11 planned events occurred. The recollections of the patients, recorded directly after the walk, were compared with the recollections of controls tested directly after the walk (C1), after one month (C2), or after 2.6 years (C3). With respect to memory for the walk, the narrative recollections of the patients were impoverished compared with C1 but resembled the recollections of volunteers tested after long delays (C2 and C3). In addition, how language was used by the patients in their recollections resembled how language was used by groups C2 and C3 (higher-frequency words, less concrete words, fewer nouns, more adverbs, more pronouns, and more indefinite articles). These findings appear to reflect how individuals, either memory-impaired patients or controls, typically speak about the past when memory is weak and lacks detail and need not have special implications about language use and MTL function beyond the domain of memory. A notable exception to the similarity between patient narratives and the narratives of C2 and C3 was that the control groups reported the events of the walk in correct chronological order, whereas the order in which patients reported events bore no relationship to the order in which events occurred. We suggest that the MTL is especially important for accessing global information about events and the relationships among their elements.

Awareness of what is learned as a characteristic of hippocampus-dependent memory.

We explored the relationship between memory performance and conscious knowledge (or awareness) of what has been learned in memory-impaired patients with hippocampal lesions or larger medial temporal lesions. Participants viewed familiar scenes or familiar scenes where a change had been introduced. Patients identified many fewer of the changes than controls. Across all of the scenes, controls preferentially directed their gaze toward the regions that had been changed whenever they had what we term robust knowledge about the change: They could identify that a change occurred, report what had changed, and indicate where the change occurred. Preferential looking did not occur when they were unaware of the change or had only partial knowledge about it. The patients, overall, did not direct their gaze toward the regions that had been changed, but on the few occasions when they had robust knowledge about the change they (like controls) did exhibit this effect. Patients did not exhibit this effect when they were unaware of the change or had partial knowledge. The findings support the idea that awareness of what has been learned is a key feature of hippocampus-dependent memory.

Eye movements support the link between conscious memory and medial temporal lobe function.

When individuals select the recently studied (and familiar) item in a multiple-choice memory test, they direct a greater proportion of viewing time toward the to-be-selected item when their choice is correct than when their choice is incorrect. Thus, for both correct and incorrect choices, individuals indicate that the chosen item is old, but viewing time nevertheless distinguishes between old and new items. What kind of memory supports this preferential viewing effect? We recorded eye movements while participants made three-alternative, forced-choice recognition memory judgments for scenes. In experiment 1 (n = 30), the magnitude of the preferential viewing effect was strongly correlated with measures of conscious, declarative memory: recognition accuracy as well as the difference in confidence ratings and in response times for correct and incorrect choices. In four analyses that minimized the contribution of declarative memory in order to detect a possible contribution from other processes, the preferential viewing effect was absent. In experiment 2, five memory-impaired patients with medial temporal lobe lesions exhibited a diminished preferential viewing effect. These patients also exhibited poor recognition accuracy and reduced differences in confidence ratings and response times for correct and incorrect choices. We propose that the preferential viewing effect is a phenomenon of conscious, declarative memory and is dependent on the medial temporal lobe. The findings support the link between medial temporal lobe function and declarative memory. When the effects of experience depend on the medial temporal lobe, the effects reflect conscious memory.

Coding of episodic memory in the human hippocampus.

Neurocomputational models have long posited that episodic memories in the human hippocampus are represented by sparse, stimulus-specific neural codes. A concomitant proposal is that when sparse-distributed neural assemblies become active, they suppress the activity of competing neurons (neural sharpening). We investigated episodic memory coding in the hippocampus and amygdala by measuring single-neuron responses from 20 epilepsy patients (12 female) undergoing intracranial monitoring while they completed a continuous recognition memory task. In the left hippocampus, the distribution of single-neuron activity indicated that only a small fraction of neurons exhibited strong responding to a given repeated word and that each repeated word elicited strong responding in a different small fraction of neurons. This finding reflects sparse distributed coding. The remaining large fraction of neurons exhibited a concurrent reduction in firing rates relative to novel words. The observed pattern accords with longstanding predictions that have previously received scant support from single-cell recordings from human hippocampus.

Medial temporal lobe and topographical memory.

There has been interest in the idea that medial temporal lobe (MTL) structures might be especially important for spatial processing and spatial memory. We tested the proposal that the MTL has a specific role in topographical memory as assessed in tasks of scene memory where the viewpoint shifts from study to test. Building on materials used previously for such studies, we administered three different tasks in a total of nine conditions. Participants studied a scene depicting four hills of different shapes and sizes and made a choice among four test images. In the Rotation task, the correct choice depicted the study scene from a shifted perspective. MTL patients succeeded when the study and test images were presented together but failed the moment the study scene was removed (even at a 0-s delay). In the No-Rotation task, the correct choice was a duplicate of the study scene. Patients were impaired to the same extent in the No-Rotation and Rotation tasks after matching for difficulty. Thus, an inability to accommodate changes in viewpoint does not account for patient impairment. In the Nonspatial-Perceptual task, the correct choice depicted the same overall coloring as the study scene. Patients were intact at a 2-s delay but failed at longer, distraction-filled delays. The different results for the spatial and nonspatial tasks are discussed in terms of differences in demand on working memory. We suggest that the difficulty of the spatial tasks rests on the neocortex and on the limitations of working memory, not on the MTL.

Spared Perception of the Structure of Scenes after Hippocampal Damage.

To explore whether the hippocampus might be important for certain spatial operations in addition to its well-known role in memory, we administered two tasks in which participants judged whether objects embedded in scenes or whether scenes themselves could exist in 3-D space. Patients with damage limited to the hippocampus performed as well as controls in both tasks. A patient with large medial-temporal lobe lesions had a bias to judge objects in scenes and scenes themselves as possible, performing well with possible stimuli but poorly with impossible stimuli in both tasks. All patients were markedly impaired at remembering the tasks. The hippocampus appears not to be essential for judging the structural coherence of objects in scenes or the coherence of scenes. The findings conform to what is now a sizeable literature emphasizing the importance of the hippocampus for memory. We discuss our results in light of findings that other patients have sometimes been reported to be disadvantaged by spatial tasks like the ones studied here, despite less hippocampal damage and milder memory impairment.

The cognitive neuroscience of human memory since H.M.

Work with patient H.M., beginning in the 1950s, established key principles about the organization of memory that inspired decades of experimental work. Since H.M., the study of human memory and its disorders has continued to yield new insights and to improve understanding of the structure and organization of memory. Here we review this work with emphasis on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medial temporal lobe structures may contribute differently to memory functions.

Map reading, navigating from maps, and the medial temporal lobe.

We administered map-reading tasks in which participants navigated an array of marks on the floor by following paths on hand-held maps that made up to nine turns. The burden on memory was minimal because the map was always available. Nevertheless, because the map was held in a fixed position in relation to the body, spatial computations were continually needed to transform map coordinates into geographical coordinates as participants followed the maps. Patients with lesions limited to the hippocampus (n = 5) performed similar to controls at all path lengths (experiment 1). They were also intact at executing single moves to an adjacent location, even when trials began by facing in a direction that put the map coordinates and geographical coordinates into conflict (experiment 2). By contrast, one patient with large medial temporal lobe (MTL) lesions performed poorly overall in experiment 1 and poorly in experiment 2 when trials began by facing in the direction that placed the map coordinates and geographical coordinates in maximal conflict. Directly after testing, all patients were impaired at remembering factual details about the task. The findings suggest that the hippocampus is not needed to carry out the spatial computations needed for map reading and navigating from maps. The impairment in map reading associated with large MTL lesions may depend on damage in or near the parahippocampal cortex.

Autobiographical memory, future imagining, and the medial temporal lobe.

In two experiments, patients with damage to the medial temporal lobe (MTL) and healthy controls produced detailed autobiographical narratives as they remembered past events (recent and remote) and imagined future events (near and distant). All recent events occurred after the onset of memory impairment. The first experiment aimed to replicate the methods of Race et al. [Race E, Keane MM, Verfaellie M (2011) J Neurosci 31(28):10262-10269]. Transcripts from that study were kindly made available for independent analysis, which largely reproduced the findings from that study. Our patients produced marginally fewer episodic details than controls. Patients from the earlier study were more impaired than our patients. Patients in both groups had difficulty in returning to their narratives after going on tangents, suggesting that anterograde memory impairment may have interfered with narrative construction. In experiment 2, the experimenter used supportive questioning to help keep participants on task and reduce the burden on anterograde memory. This procedure increased the number of details produced by all participants and rescued the performance of our patients for the distant past. Neither of the two patient groups had any special difficulty in producing spatial details. The findings suggest that constructing narratives about the remote past and the future does not depend on MTL structures, except to the extent that anterograde amnesia affects performance. The results further suggest that different findings about the status of autobiographical memory likely depend on differences in the location and extent of brain damage in different patient groups.

Learning and remembering real-world events after medial temporal lobe damage.

The hippocampus is important for autobiographical memory, but its role is unclear. In the study, patients with hippocampal damage and controls were taken on a 25-min walk on the University of California, San Diego, campus during which 11 planned events occurred. Memory was tested directly after the walk. In addition, a second group of controls took the same walk and were tested after 1 mo. Patients with hippocampal damage remembered fewer details than controls tested directly after the walk but remembered a similar number of details as controls tested after 1 mo. Notably, the details that were reported by patients had the characteristics of episodic recollection and included references to particular places and events. Patients exhibited no special difficulty remembering spatial details in comparison with nonspatial details. Last, whereas both control groups tended to recall the events of the walk in chronological order, the order in which patients recalled the events was unrelated to the order in which they occurred. The findings illuminate the role of the hippocampus in autobiographical memory and in the spatial and nonspatial aspects of episodic recollection.

Preserved capacity for scene construction and shifts in perspective after hippocampal lesions.

The hippocampus has long been recognized as important for the formation of long-term memory. Recent work has suggested that the hippocampus might also be important for certain kinds of spatial operations, as in constructing scenes, shifting perspective, or perceiving the geometry of scenes and their boundaries. We explored this proposal using a task similar to one used previously that related hippocampal activity to scenes and their boundaries. In our study, participants viewed scenes from above that displayed walls and towers. After viewing each scene, participants saw a scene from ground level and judged whether it was the same as or different from the scene just presented. The number of towers and walls in each scene was manipulated so that it was possible to assess how the structure of the scene affected performance. Patients with hippocampal lesions performed similarly to controls in all task conditions and had no special difficulty as a function of the layout of a scene and its boundaries. In contrast, a patient with large medial temporal lobe (MTL) lesions was impaired. Taken together, our findings suggest that the hippocampus is not needed for scene construction, shifts in perspective, or perceiving the geometry of scenes. The impairment associated with large MTL lesions may result from damage in or near parahippocampal cortex.

The beneficial effect of prior experience on the acquisition of spatial memory in rats with CA1, but not large hippocampal lesions: a possible role for schema formation.

Prior experience has been shown to improve learning in both humans and animals, but it is unclear what aspects of recent experience are necessary to produce beneficial effects. Here, we examined the capacity of rats with complete hippocampal lesions, restricted CA1 lesions, or sham surgeries to benefit from prior experience. Animals were tested in two different spatial tasks in the watermaze, the conventional watermaze task and delayed match-to-position. The two lesions impaired performance in both tasks when rats had no prior experience. However, when given prior training with one task, CA1 lesions had no effect on performance in the other task. In contrast, rats with hippocampal lesions did not benefit from prior training. The findings show that prior experience can benefit learning even when the previously learned task and a new task are quite different. The concept of schema may be useful for understanding the benefits of prior experience.

Spared perception of object geometry and object components after hippocampal damage.

We tested the proposal that medial temporal lobe (MTL) structures support not just memory but also high-level object perception. In one task, participants decided whether a line drawing could represent an object in three-dimensional space and, in another task, they saw the components of an object and decided what object could be formed if the components were assembled. Patients with hippocampal lesions were intact, indicating that the hippocampus is not needed for perceiving the structural coherence of objects or appreciating the relations among object parts. Patients with large MTL lesions were moderately impaired, likely due to damage outside the MTL.

Memory, scene construction, and the human hippocampus.

We evaluated two different perspectives about the function of the human hippocampus--one that emphasizes the importance of memory and another that emphasizes the importance of spatial processing and scene construction. We gave tests of boundary extension, scene construction, and memory to patients with lesions limited to the hippocampus or large lesions of the medial temporal lobe. The patients were intact on all of the spatial tasks and impaired on all of the memory tasks. We discuss earlier studies that associated performance on these spatial tasks to hippocampal function. Our results demonstrate the importance of medial temporal lobe structures for memory and raise doubts about the idea that these structures have a prominent role in spatial cognition.

When eye movements express memory for old and new scenes in the absence of awareness and independent of hippocampus.

Eye movements can reflect memory. For example, participants make fewer fixations and sample fewer regions when viewing old versus new scenes (the repetition effect). It is unclear whether the repetition effect requires that participants have knowledge (awareness) of the old-new status of the scenes or if it can occur independent of knowledge about old-new status. It is also unclear whether the repetition effect is hippocampus-dependent or hippocampus-independent. A complication is that testing conscious memory for the scenes might interfere with the expression of unconscious (unaware), experience-dependent eye movements. In experiment 1, 75 volunteers freely viewed old and new scenes without knowledge that memory for the scenes would later be tested. Participants then made memory judgments and confidence judgments for each scene during a surprise recognition memory test. Participants exhibited the repetition effect regardless of the accuracy or confidence associated with their memory judgments (i.e., the repetition effect was independent of their awareness of the old-new status of each scene). In experiment 2, five memory-impaired patients with medial temporal lobe damage and six controls also viewed old and new scenes without expectation of memory testing. Both groups exhibited the repetition effect, even though the patients were impaired at recognizing which scenes were old and which were new. Thus, when participants viewed scenes without expectation of memory testing, eye movements associated with old and new scenes reflected unconscious, hippocampus-independent memory. These findings are consistent with the formulation that, when memory is expressed independent of awareness, memory is hippocampus-independent.