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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.

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."

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."

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.

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.

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.

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.

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.

The hippocampus- the aptly named seahorse-shaped structure located in the medial temporal lobe of the human brain- has been central to the study of memory for over fifty years. Over this time period, memory research in humans and rodents has focused on the hippocampus’ role in memory differently, with the human work focused on declarative memories for events and facts while rodent work has emphasized the spatial nature of memories. While these two views are not necessarily incompatible, there are still many open questions as to why the rodent hippocampus appears to rely upon spatial aspects of memory far more than its human counterpart. This dissertation was designed to bridge these two traditions using a spatial navigation task, path integration, which was first described in both humans and animals by Charles Darwin. We approached this first by studying whether working memory could support path integration. Working memory is independent of the hippocampus; however, its capacity is limited by the amount and complexity of information needed for recall. If the paths the subjects needed to recall were short and simple, presumably working memory could support them. Indeed, we found that patients with hippocampal damage were able to path integrate as well as normal subjects. However, rats with hippocampal damage were impaired relative to controls regardless of path complexity. This finding may reflect the limited capacity of rodent working memory; it may not be possible for rodents to path integrate without using long-term memory. Rats with lesions of the hippocampus and the medial prefrontal cortex (the region commonly associated with working memory) were tested on a variety of spatial and nonspatial memory tasks. We concluded that the hippocampus is needed for spatial memory in rodents not because it is dedicated to spatial processing, but because spatial tasks inherently exceed the capacity of rodent working memory. These studies, in addition to a third study on extra

The hippocampus- the aptly named seahorse-shaped structure located in the medial temporal lobe of the human brain- has been central to the study of memory for over fifty years. Over this time period, memory research in humans and rodents has focused on the hippocampus’ role in memory differently, with the human work focused on declarative memories for events and facts while rodent work has emphasized the spatial nature of memories. While these two views are not necessarily incompatible, there are still many open questions as to why the rodent hippocampus appears to rely upon spatial aspects of memory far more than its human counterpart. This dissertation was designed to bridge these two traditions using a spatial navigation task, path integration, which was first described in both humans and animals by Charles Darwin. We approached this first by studying whether working memory could support path integration. Working memory is independent of the hippocampus; however, its capacity is limited by the amount and complexity of information needed for recall. If the paths the subjects needed to recall were short and simple, presumably working memory could support them. Indeed, we found that patients with hippocampal damage were able to path integrate as well as normal subjects. However, rats with hippocampal damage were impaired relative to controls regardless of path complexity. This finding may reflect the limited capacity of rodent working memory; it may not be possible for rodents to path integrate without using long-term memory. Rats with lesions of the hippocampus and the medial prefrontal cortex (the region commonly associated with working memory) were tested on a variety of spatial and nonspatial memory tasks. We concluded that the hippocampus is needed for spatial memory in rodents not because it is dedicated to spatial processing, but because spatial tasks inherently exceed the capacity of rodent working memory. These studies, in addition to a third study on extra

Neurocomputational models hold that sparse distributed coding is the most efficient way for hippocampal neurons to encode episodic memories rapidly. We investigated the representation of episodic memory in hippocampal neurons of nine epilepsy patients undergoing intracranial monitoring as they discriminated between recently studied words (targets) and new words (foils) on a recognition test. On average, single units and multiunits exhibited higher spike counts in response to targets relative to foils, and the size of this effect correlated with behavioral performance. Further analyses of the spike-count distributions revealed that (i) a small percentage of recorded neurons responded to any one target and (ii) a small percentage of targets elicited a strong response in any one neuron. These findings are consistent with the idea that in the human hippocampus episodic memory is supported by a sparse distributed neural code.

This grant provided partial support for the Fourth Conference on the Neurobiology of Learning and Memory which was held at Irvine, California on October 17-20, 1990. The conference was organized and sponsored by the Center for the Neurobiology of Learning and Memory of the University of California, Irvine. The aim of the conference was to review current fact and theory concerning three research issues in the neurobiology of learning and memory: (1) the features and loci of patterns of brain activity induced by learning, (2) the roles of different brain systems in mediating learning and memory, and (3) cellular modifications underlying learning and memory. The presentations and discussions represented all levels of analysis from molecular neurobiology through systems/behavioral studies. There were 20 principal speakers, 98 poster presentations and over 300 registered participants representing 20 countries. A book based on the proceedings of the conference, Memory: Organization and Locus of Change (Larry R. Squire, Norman M. Weinberger, Gary Lynch and James L. McGaugh, Editors) is in press. Neurobiology of Learning and Memory, Neuroscience, Neuroplasticity.