Stuart M. Zola

Three Cases of Enduring Memory Impairment after Bilateral Damage Limited to the Hippocampal Formation

Patient RB (Human amnesia and the medial temporal region: enduring memory impairment following a bilaterial lesion limited to field CA1 of the hippocampus, S. Zola-Morgan, L. R. Squire, and D. G. Amaral, 1986, J Neurosci 6:2950–2967) was the first reported case of human amnesia in which detailed neuropsychological analyses and detailed postmortem neuropathological analyses demonstrated that damage limited to the hippocampal formation was sufficient to produce anterograde memory impairment. Neuropsychological and postmortem neuropathological findings are described here for three additional amnesic patients with bilateral damage limited to the hippocampal formation. Findings from these patients, taken together with the findings from patient RB and other amnesic patients, make three important points about memory. (1) Bilateral damage limited primarily to the CA1 region of the hippocampal formation is sufficient to produce moderately severe anterograde memory impairment. (2) Bilateral damage beyond the CA1 region, but still limited to the hippocampal formation, can produce more severe anterograde memory impairment. (3) Extensive, temporally graded retrograde amnesia covering 15 years or more can occur after damage limited to the hippocampal formation. Findings from studies with experimental animals are consistent with the findings from amnesic patients. The present results substantiate the idea that severity of memory impairment is dependent on locus and extent of damage within the hippocampal formation and that damage to the hippocampal formation can cause temporally graded retrograde amnesia.

Episodic memory, semantic memory, and amnesia

Episodic memory and semantic memory are two types of declarative memory. There have been two principal views about how this distinction might be reflected in the organization of memory functions in the brain. One view, that episodic memory and semantic memory are both dependent on the integrity of medial temporal lobe and midline diencephalic structures, predicts that amnesic patients with medial temporal lobe/diencephalic damage should be proportionately impaired in both episodic and semantic memory. An alternative view is that the capacity for semantic memory is spared, or partially spared, in amnesia relative to episodic memory ability. This article reviews two kinds of relevant data: 1) case studies where amnesia has occurred early in childhood, before much of an individuals semantic knowledge has been acquired, and 2) experimental studies with amnesic patients of fact and event learning, remembering and knowing, and remote memory. The data provide no compelling support for the view that episodic and semantic memory are affected differently in medial temporal lobe/diencephalic amnesia. However, episodic and semantic memory may be dissociable in those amnesic patients who additionally have severe frontal lobe damage. Hippocampus 1998;8:205–211. Published 1998 Wiley‐Liss, Inc. This article is a US Government work and, as such, is in the public domain in the United States of America.

fMRI of Monkey Visual Cortex

While functional magnetic resonance imaging (fMRI) is now used widely for demonstrating neural activity-related signals associated with perceptual, motor, and cognitive processes in humans, to date this technique has not been developed for use with nonhuman primates. fMRI in monkeys offers a potentially valuable experimental approach for investigating brain function, which will complement and aid existing techniques such as electrophysiology and the behavioral analysis of the effects of brain lesions. There are, however, a number of significant technical challenges involved in using fMRI with monkeys. Here, we describe the procedures by which we have overcome these challenges to carry out successful fMRI experiments in an alert monkey, and we present the first evidence of activity-related fMRI signals from monkey cerebral cortex.

A reexamination of the concurrent discrimination learning task: the importance of anterior inferotemporal cortex, area TE.

For 30 years, the concurrent discrimination learning task has figured prominently in studies used to determine the effects of medial temporal lobe damage in monkeys. However, the findings from these studies have been contradictory. We explored the contribution to concurrent discrimination performance of inadvertent damage to area TE by reexamining the behavioral data and histological material from monkeys with medial temporal lobe lesions previously tested in our laboratory. The amount of inadvertent damage to area TE was more predictive of impaired performance on the concurrent discrimination learning task than was the amount of damage to any medial temporal lobe structure, including the perirhinal cortex. These findings resolve earlier inconsistent findings regarding the concurrent discrimination learning task by demonstrating that performance on this task depends on area TE and not on perirhinal cortex or other medial temporal lobe structures.

MEMORY, MEMORY IMPAIRMENT, AND THE MEDIAL TEMPORAL LOBE

The cognitive and neuroanatomical work described here should be viewed as a first step in analyzing how the brain has organized its memory functions, which can open the door to more detailed neurobiological analysis. With respect to declarative memory, it should soon be possible to study representations directly in neocortex with the technique of single-cell recording, to observe directly the development of neuronal plasticity important for declarative memory, and to determine how the medial temporal lobe interacts with neocortex during learning, consolidation, and retrieval. In this regard, the paradigms developed by Miyashita and his colleagues appear to hold particular promise (Sakai and Miyashita 1991; Higuchi and Miyashita 1996). With respect to nondeclarative memory, it is now possible to identify particular brain systems that are essential for particular kinds of memory. An important next step will be to determine whether these systems are essential for the acquisition, storage, or expression of memory, and to identify exactly where the synaptic changes occur that support each kind of memory.

Neural Correlates of Knowledge: Stable Representation of Stimulus Associations across Variations in Behavioral Performance

Behavioral responses to a sensory stimulus are often guided by associative memories. These associations remain intact even when other factors determine behavior. The substrates of associative memory should therefore be identifiable by neuronal responses that are independent of behavioral choices. We tested this hypothesis using a paired-associates task in which monkeys learned arbitrary associations between pairs of visual stimuli. We examined the activity of neurons in inferior temporal cortex as the animals prepared to choose a remembered stimulus from a visual display. The activity of some neurons (22%) depended on the monkeys behavioral choice; but for a novel class of neurons (54%), activity reflected the stimulus that the monkey was instructed to choose, regardless of the behavioral response. These neurons appear to represent memorized stimulus associations that are stable across variations in behavioral performance. In addition, many neurons (74%) were modulated by the spatial arrangement of the stimuli in the display.

Trace eyeblink classical conditioning in the monkey : A nonsurgical method and behavioral analysis

Classical eyeblink conditioning has been used extensively to study the neurobiology of associative learning and memory in rabbits and in humans. During the last several years, new developments have renewed interest in the possibility of studying classical conditioning in monkeys. Specifically, it is now known that impaired conditioning can be observed in humans with various neurologic problems, including amnesia, and thus there is now considerable interest in the neurobiology of human eyeblink conditioning. Research involving monkeys, in which discrete lesions of anatomically defined neural structures can be produced, has the potential to provide information that might not be readily available from work in humans. Here, the authors present a simple, nonsurgical method for classically conditioning the eyeblink response in monkeys and report behavioral results using a trace conditioning paradigm that is sensitive to hippocampal damage in both rabbits and humans. This method is reliable and effective for recording eyeblinks and shows that robust eyeblink classical conditioning can be readily established in the monkey.

Declarative Memory, Neural Basis of

An important finding of neuropsychological studies is that memory is not a single entity but is composed of several different forms that rely on separate brain systems. The major distinction is between conscious knowledge of facts and events, referred to as declarative or explicit memory, and nonconscious knowledge systems that provide for the capacity of skill learning, habit formation, the phenomenon of priming, and certain other ways of interacting with the world, collectively referred to as nondeclarative or implicit memory. Declarative memory is dependent on the integrity of the hippocampus and anatomically related structures in the medial temporal lobe and diencephalon. It seems to be especially good at associating the various aspects of a context that are present at a particular time and place, thereby creating a memory of an episode. A particularly good example of declarative memory involves the ability to identify a recently encountered item as familiar, a capacity termed as recognition memory. Declarative memory is the kind of memory impaired in amnesia. Other characteristics of this form of memory have emerged from studies with experimental animals. Declarative memory is fast and is flexible in the sense that it is accessible to multiple response systems. It is especially suited for one-trial learning, and for forming and maintaining associations between arbitrarily different pieces of material.