LR Squire

During the past 100 years clinical studies of amnesia have linked memory impairment to damage of the hippocampus. Yet the damage in these cases has not usually been confined to the hippocampus, and the status of memory functions has often been based on incomplete neuropsychological information. Thus, the human cases have until now left some uncertainty as to whether lesions limited to the hippocampus are sufficient to cause amnesia. Here we report a case of amnesia in a patient (R.B.) who developed memory impairment following an ischemic episode. During the 5 years until his death, R.B. exhibited marked anterograde amnesia, little if any retrograde amnesia, and showed no signs of cognitive impairment other than memory. Thorough histological examination revealed a circumscribed bilateral lesion involving the entire CA1 field of the hippocampus. Minor pathology was found elsewhere in the brain (e.g., left globus pallidus, right postcentral gyrus, left internal capsule), but the only damage that could be reasonably associated with the memory defect was the lesion in the hippocampus. To our knowledge, this is the first reported case of amnesia following a lesion limited to the hippocampus in which extensive neuropsychological and neuropathological analyses have been carried out.

Across three experiments, PET scans were obtained while subjects performed different word-stem completion and FIXATION control tasks designed to study the functional anatomy of memory retrieval. During each of three different word-stem completion scans, word-stem cues were visually presented in uppercase letters. The RECALL task required explicit retrieval of study words presented prior to the PET scan. The PRIMING task addressed the implicit effects of the prior study words without requiring intentional recall. The BASELINE task encouraged retrieval of information from a general knowledge store. Across experiments, the similarity between study words and word stems was manipulated by presenting prescan study words in either uppercase letters identical to the stems, in lowercase letters, or auditorily. The PRIMING task was not studied with auditory presentation. Many activations were consistent across experiments. The BASELINE task activated several regions in response to the reading and verbal-response demands of the task (visual, motor, and premotor cortices, cerebellum), as well as a left prefrontal region. The RECALL task additionally activated regions in anterior right prefrontal cortex. Bilateral occipitotemporal regions showed blood flow reductions during the PRIMING task as compared to the BASELINE task. Activation in the right hippocampal/parahippocampal region was observed only in one experiment, and no experiment showed activation in the left medial temporal lobe. These experiments suggest that areas of frontal cortex play a role in explicit recall and that an effect of priming may be to require less activation of perceptual regions for the processing of recently presented information.

Research in humans and monkeys has demonstrated a system of anatomically related structures in the medial temporal lobe that is important for memory function. This system is comprised of the hippocampal region (i.e., the dentate gyrus, hippocampus proper and subicular complex) and the entorhinal, perirhinal, and parahippocampal cortices. While the hippocampal region has long been thought to be important in memory, there are few systematic studies in primates of the effects on memory of damage limited to the hippocampal region. We have used magnetic resonance imaging techniques, together with a stereotaxic approach, to produce bilateral lesions limited to the hippocampal region (the H lesion). Damage to the adjacent perirhinal, entorhinal, and parahippocampal cortex was minimal. Monkeys with the H lesion exhibited significant and long-lasting impairment on the delayed non-matching to sample task. At the same time, on this and other amnesia-sensitive tasks, monkeys with the H lesion performed better overall than monkeys with lesions of the hippocampal region that also included damage to the adjacent entorhinal and parahippocampal cortices (the H+ lesion). These findings show that, first, the hippocampal region itself is essential for normal memory function; and second, the adjacent entorhinal and parahippocampal cortices, either alone or in combination, are also an essential component of the medial temporal lobe memory system.

In an effort to bring into correspondence the findings from human amnesic patients and the findings from monkeys with surgical lesions of those brain regions thought to be affected in the human cases, we have addressed in three experiments the implication of findings that human amnesia spares motor and cognitive skills. In the first experiment, monkeys with conjoint lesions of hippocampus and amygdala (H-A), which reproduced the surgical removal sustained by the noted amnesic case H.M., were only mildly impaired in learning relatively difficult pattern discrimination tasks. Monkeys with lesions of temporal stem matter (TS) were severely impaired on the same tasks, due to an apparent deficiency in visual information processing. In the second experiment, monkeys with H-A lesions were severely impaired at learning relatively easy discrimination tasks that could be acquired rapidly by normal monkeys. Monkeys with TS lesions were not impaired. In the third experiment, monkeys with H-A lesions exhibited normal acquisition of two motor skill tasks. These data can be understood in the light of a distinction between kinds of memory, founded in recent studies of the neuropsychology of human amnesia. These studies have led to a distinction between the learning of skills or procedures, which is spared in human amnesia, and the learning of facts and episodes, which is impaired. Monkeys with H-A lesions are normal at skill learning like human amnesic patients with similar lesions. This conclusion depends in part on the argument developed here that pattern discrimination learning, as accomplished by monkeys, has a large skill-like component. These results bring into correspondence the behavioral data from human amnesic patients and operated monkeys and set the stage for identifying precisely what brain structures must be damaged to produce amnesia.