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The medial temporal lobe and declarative memory
International Congress Series 1250 (2003) 245 – 259
The medial temporal lobe and declarative memory Peter J. Bayley a, Larry R. Squire a,b,c,d,* a
Department of Psychiatry, University of California-San Diego, La Jolla CA 92093, USA b Veterans Affairs Healthcare System, San Diego, CA 92161, USA c Department of Neurosciences, University of California-San Diego, La Jolla, CA 92093, USA d Department of Psychology, University of California-San Diego, La Jolla, CA 92093, USA Received 17 January 2003; accepted 26 February 2003
Abstract The hippocampus is part of a system of anatomically related structures in the medial temporal lobe that supports the capacity for conscious recollection (declarative memory). In three studies, we investigated memory functions in amnesic patients with bilateral damage limited primarily to the hippocampal region and in other patients with larger lesions of the medial temporal lobe. The results support three conclusions about the neurological organization of human memory. First, to a limited degree, nondeclarative memory can substitute for declarative memory, but what is learned and stored in memory is substantially different depending on which memory system is used. Second, damage limited primarily to the hippocampal region impairs the learning of new facts (semantic memory), just as such damage impairs the learning of new events (episodic memory). Remote memory for factual knowledge is spared. Third, damage to the medial temporal lobe spares remote memory for autobiographical events (episodic memory). D 2003 Elsevier Science B.V. All rights reserved. Keywords: Hippocampus; Nondeclarative memory; Amnesia; Retrograde amnesia; Autobiographical memory
The hippocampus is part of a system of anatomically related structures in the medial temporal lobe that supports the capacity for conscious recollection (declarative memory) (Fig. 1A). Declarative memory can be contrasted with a collection of nonconscious, nondeclarative forms of memory, each of which is supported by specific brain systems (Fig. 1B). This chapter considers three issues that have been prominent in recent
* Corresponding author. VA Medical Center (116A), University of California-San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Tel.: +1-858-642-3628; fax: +1-858-552-7457. E-mail addresses: [email protected] (P.J. Bayley), [email protected] (L.R. Squire). 0531-5131/ D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00192-4
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Fig. 1. (A) A schematic view of the medial temporal lobe memory system for declarative memory. The hippocampal region is composed of the dentate gyrus (DG), the CA fields, and the subiculum (S). The medial temporal lobe memory system is composed of the hippocampal region together with the perirhinal, entorhinal, and parahippocampal cortices [38]. (B) A taxonomy of mammalian long-term memory systems. The taxonomy lists the brain structures thought to be especially important for each form of declarative and nondeclarative memory. In addition to its central role in emotional learning, the amygdala is able to modulate the strength of both declarative and nondeclarative memory [39].
discussions of the nature of declarative memory: (1) whether one memory system can substitute for another; (2) whether the hippocampus is important for semantic memory as well as for episodic memory; (3) whether autobiographical remembering is possible after medial temporal lobe damage.
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1. Learning facts with nondeclarative memory It is an under-appreciated feature of the memory systems of the brain that the memory system that is engaged depends not so much on what task must be learned as on the strategy that is implemented during learning. Some tasks, such as motor skill learning, are difficult to acquire except by the gradual practice and trial-and-error repetition that engage nondeclarative memory systems. Other tasks can be learned in more than one way. For example, consider the task of eight-pair concurrent discrimination learning, which involves repeatedly presenting eight different pairs of objects one at a time. One member of the pair is always correct, and the learner tries to select the correct object each time it appears (for example, during daily training sessions of 40 trials in which each object pair appears five times). Patients with memory impairment due to bilateral medial temporal lobe or diencephalic lesions had severe difficulty learning this task [1]. Further, their learning score was correlated with their ability to answer questions about the task. Indeed, the difficulty that the patients had in attempting to memorize the correct object in each pair was entirely consistent with the difficulty they had in learning other kinds of verbal and nonverbal material. Remarkably, monkeys with hippocampal lesions [2] as well as monkeys with larger lesions involving the hippocampus together with adjacent medial temporal lobe cortex [3] learned the eight-pair concurrent task at a normal rate. In contrast, monkeys were impaired on this task, and on similar versions of the task, when the damage included either inferotemporal cortex (area TE) [3,4], or when the damage included the tail of the caudate nucleus, which is a striatal target of projections from area TE [2,5]. These observations can be understood by supposing that the monkeys approached the eight-pair concurrent task as a task of habit learning, a task that can be acquired gradually through trial-and-error and that results in a set of dispositions to select the correct object in each pair. Thus, while humans approach the eight-pair concurrent task as a task of memorization, that is, as a task of declarative memory that depends on the medial temporal lobe, for monkeys the eightpair concurrent task is a task of nondeclarative memory that depends on the integrity of the caudate nucleus. This set of findings raises the question whether a patient with profoundly impaired declarative memory might nevertheless be able to use an alternative memory system to acquire factual information, that is, information that is ordinarily acquired as declarative knowledge. If so, would the knowledge that is acquired have different properties than declarative memory? Or, are humans governed to such an extent by particular strategies operating within specific domains that one memory system cannot easily substitute for another? We have had the opportunity to address these questions in studies of a patient (E.P.) who became profoundly amnesic in 1992 at the age of 70 as the result of viral encephalitis [6]. E.P.’s memory is so impaired that he still fails to recognize the examiner after more than 150 visits to his house. Further, E.P. has not acquired the conscious knowledge that he in fact has memory impairment. It appears that he has not been able to record his many memory failures so as to bring about an altered estimate of his own abilities. In the laboratory, E.P. has demonstrated no ability to form new declarative memories. For example, in one series of studies, E.P. and five controls took 42 different two-choice tests
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of recognition memory. The five controls averaged 81.1% correct; E.P. averaged 49.3% correct, about what would be expected by chance. E.P. has extensive, virtually complete bilateral damage to the hippocampus, amygdala, entorhinal cortex, and perirhinal cortex, as well as damage to the anterior parahippocampal cortex and anterior fusiform gyrus [6]. We studied E.P.’s capacity to learn new semantic information in the form of novel three-word sentences (e.g., shark killed octopus; venom caused fever [7]) that were presented on a computer screen [8]. The training procedure followed a study-only method, in which 48 sentences were studied during training without an opportunity to make errors. This procedure has been found to facilitate learning in memory-impaired patients, and for such patients, to be superior to conventional study-test methods [7,9 – 11]. After a pretest (shark killed ???; venom caused ???) to eliminate the one or two sentences that could be completed correctly by guessing, study sessions were given in which participants saw each of the 48 training sentences twice. E.P. was given a total of 24 study sessions on 24 different days (two sessions per week for 12 weeks for a total of 48 training trials). Controls were given a total of two study sessions (one session per week for 2 weeks for a total of four training trials). E.P.’s retention of the sentences was tested on both the 3rd and 4th day after the eighth study session (T1, T2), on the 4th and 5th day after the 16th study session (T3, T4), and on the 3rd and 4th day after the 24th study session (T5, T6). The retention tests assessed memory for the last word of the sentence when the first two words were given as a cue (e.g., shark killed ???). On each day of retention testing, a cued-recall test was presented first. The cued-recall test was followed by a two-alternative, forced-choice test in which the first two words of each sentence were presented together with two possible completions, and participants were asked to select the correct word. Seven days after their final study session, the control group recalled an average of 49.5% F 11.9% of the 48 target words (Fig. 2A). In contrast, E.P. was markedly impaired at learning the target words. After 4 weeks of study (eight sessions), he recalled one word on the first retention test (T1) and two words on the second retention test (T2). Thus, across these two tests, his recall score (3.2%) was far below the 49.5% score that controls were able to achieve after only two study sessions. Nevertheless, despite E.P.’s inability to learn scarcely anything during the first 4 weeks of study, he demonstrated unmistakable improvement as the study sessions continued. Thus, he averaged 11.5% correct on T3 and T4 after 8 weeks of study, and 18.8% correct (9 items correct out of 48) on T5 and T6 after a total of 12 weeks of study. His improvement across the three study-test intervals (T1 and T2, T3 and T4, T5 and T6) was significant (linear trend, F(1,5) = 17.2, p < 0.02). Ten controls took the forced-choice test in the absence of prior study and identified 46.9 F 2.9% of the target words. This value was taken as a baseline score against which to compare the performance of E.P. and his controls. Fig. 2B shows that controls correctly identified 89.6 F 5.6% of the target words after their two study sessions. In contrast, E.P. scored 58.3% correct after eight study sessions (T1 and T2), 64.6% correct after 16 study sessions (T3 and T4), and 64.6% correct after 24 study sessions (T5 and T6). His performance was much poorer than that of the controls, though he did score measurably above chance at each study-test interval (binomial test, p’s < 0.02; the results were the same when 50.0% was taken as chance performance, except that in this case E.P. did not score above chance in sessions T1 and T2). In earlier testing with similar material [11],
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Fig. 2. Controls (CON, black bars, n = 4) and E.P. (open bars) studied 48 three-word sentences (e.g., shark killed octopus). Retention tests were given to controls after four training trials (one session in each of 2 weeks, two training trials per session) and to E.P. on two consecutive days (T1 – T6) after 16, 32, and 48 training trials (two sessions per week, two training trials per session). (A) Percentage of correct cued recall of target words in response to the first two words in each sentence. Performance is shown for the pretest (Pre, before study) and after each study period. (B) Percentage of correct forced-choice recognition when the first two words of each sentence were presented together with two possible target words. Performance is shown after each study period. The dashed line shows the score obtained by a group (n = 10) that received no study. Brackets show mean standard error. Asterisks indicate significant difference vs. the no-study group ( p < 0.05).
E.P. failed to demonstrate learning, but he received considerably less repetition of the study material in those tests than in the present case (8 training trials vs. 48 training trials). It has been reported that factual information acquired gradually by amnesic patients after extended training can be somewhat inflexible and hyperspecific [12 –15]. These findings might reflect the operation of nondeclarative (skill-like) memory, residual declarative (fact-like) memory, or some combination. To investigate what kind of memory E.P. had acquired, other tests were given. First, at T6 we tested the flexibility of what he had learned, that is, how well he could access his knowledge in novel circumstances. In this test, the second word of each sentence was replaced by a synonym (e.g., ‘‘venom caused ???’’ was changed to ‘‘venom induced ???). Fig. 3 shows the results. Substituting a synonym for the second word in each sentence frame markedly disrupted E.P.’s performance. He scored 20.7% correct when the original sentence frames were used as cues (on T5 and T6), but he could recall correctly only one of the target words after the sentences were changed. In contrast, the control group performed almost as well in the synonym condition (24.7% correct) as in the standard condition (28.7%). Thus, the controls were able to use their knowledge flexibly. In contrast, E.P. could sustain his performance only when the words in the sentence frame were exactly the same words that he had previously studied. When the second word in the sentence frame was
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Fig. 3. Cued-recall performance of target words by controls (black bars, n = 12) and E.P. (open bars) in response to the first two words of previously studied three-word sentences. The score for E.P. is the average of two tests (T5 and T6, see Fig. 2). Data are for 29 of 48 studied sentences that were given to both E.P. and controls (control data, n = 12, from Ref. [11]). In the Standard Test given to E.P. after 48 training trials and to controls after two training trials, the same two words were presented that had been previously studied (e.g., venom caused ???), and participants tried to respond with the target word (fever). In the Synonym Test for E.P., the second word of each sentence frame was replaced by a synonym (e.g., venom induced ???). For the controls, the same synonyms were used for 16 of the sentence frames as were used for E.P. For the remaining 13 sentence frames, both words of the sentence frame were replaced by synonyms (e.g., ‘Venom caused ???’ was replaced by ‘Poison induced ???’). Brackets show standard error of the mean.
replaced by a synonym, his performance (one correct response) was no better than during the pretest (Fig. 1A) before he had studied any sentences. Thus, in the absence of declarative memory, E.P. was gradually able to acquire knowledge, but what was learned was inflexible and accessible only when the test items appeared exactly as they had at study. It is noteworthy that E.P.’s learning was not inflexible in every respect. On T6, E.P. was given a cued-recall test with the sentence frames read aloud instead of presented on a computer screen. He was able to recall 16.7% of the target words (eight words). This score is similar to the 18.8% average score he obtained on the standard test when the sentence frames were presented on the computer (see T5 and T6, Fig. 2A). Thus, what E.P. had learned was able to accommodate either visual or spoken presentation of the test material. The quality of what E.P. learned was also unusual in two other respects. First, in the forced-choice test, E.P.’s response times were nearly identical for correct and incorrect responses (mean = 4.1 F 0.1 s vs. mean = 4.3 F 0.1 s), despite the fact that his performance was unequivocally above chance. These findings suggest that E.P. was unaware of when he was making correct and incorrect choices. In contrast, the controls responded faster when they made correct choices (mean = 3.0 F 0.5 s) than when they made incorrect choices (mean = 5.5 F 1.2 s) (t(2)=3.8, p=0.06), consistent with previous
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findings of faster response times for correct vs. incorrect responses in forced-choice recognition memory tasks [16]. The second observation concerned how much confidence E.P. had in his correct and incorrect answers. On the cued-recall test at T6, E.P. rated how confident he was in his answers using a five-point scale. His mean confidence rating for correct answers was 3.2 F 0.1 and for incorrect answers was 3.3 F 0.3. Thus, E.P. was no more confident of his correct answers than of his incorrect answers. These results for E.P. contrast with what is typically observed in less severely impaired amnesic patients and in healthy controls; namely, that confidence ratings are higher for correct answers than incorrect answers [17,18]. These findings provide evidence for the acquisition of knowledge by nondeclarative memory, knowledge that would ordinarily be learned declaratively (as conscious factual knowledge) by normal individuals. What E.P. learned was not experienced as factual knowledge. It was outside of awareness, it could be expressed only through performance, and it was relatively inflexible, such that it was accessible only when the word cues used to test memory were the same as had been used during study. We proposed previously [8] that E.P.’s learning depended on a process akin to perceptual learning and occurred within the neocortex. One way to view the issue is that in those cases when factual information is acquired as consciously accessible, declarative knowledge by amnesic patients, then structures that remain intact within the medial temporal lobe support the learning. In contrast, when factual information is acquired as nondeclarative knowledge, as in the case of E.P., the learning in these circumstances occurs directly within the neocortex. An interesting comparison can be made between our findings with E.P. and earlier studies of fact learning in patient K.C. [7,10]. K.C. developed memory impairment after a head injury, which damaged his medial temporal lobe bilaterally (more on the left than on the right). However, his damage also involved left frontal, left parietal, left retrosplenial, and left occipital cortex, and there is a small lesion in the right parietal cortex. K.C. demonstrated considerable capacity for learning novel phrases, using a very similar procedure as in the present study [10]. After 4 weeks of training and 16 training trials, K.C. scored 83% correct on a cued-recall test, whereas E.P. scored only 2.1% correct after 4 weeks of training and 16 training trials (see Fig. 2A, T1). Thus, E.P.’s learning ability is much poorer than K.C.’s ability. This difference is likely to be related to E.P.’s more extensive medial temporal lobe damage. If so, K.C.’s medial temporal lobe damage cannot explain instances when he performs more poorly than E.P. For example, it is notable that K.C. is reported to be able to recall few, if any, autobiographical episodes from his life before his injury [10,19,20]. In contrast, E.P. can recall autobiographical episodes from his early life in considerable detail, as discussed below [21,22]. Thus, the findings from K.C. and E.P. represent a double dissociation with respect to autobiographical recollection (better for E.P.) and the ability to acquire new factual information (better for K.C.). These findings suggest that the difficulties reported for K.C. in autobiographical recollection are not related to his medial temporal lobe damage (because E.P. has extensive medial temporal lobe damage and yet can recollect autobiographical episodes better than K.C.).
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2. Impaired fact learning when damage is limited primarily to the hippocampal region As described in the previous section, a large lesion involving much of the medial temporal lobe (patient E.P.) impairs declarative memory rather completely. In contrast, when damage is limited to the hippocampal region itself, memory is less severely affected. We have had the opportunity to study a group of patients who, from radiological evidence, have damage restricted primarily to the hippocampal region. They have a moderately severe memory impairment (Fig. 4), as has been observed in other patients whose restricted hippocampal lesions have been demonstrated neurohistologically [23,24]. Recent discussions of human hippocampal function have considered whether the hippocampus is especially important for learning about single events (episodic memory) and the adjacent cortex is important for fact learning (semantic memory), or whether the hippocampus supports both episodic and semantic memory (for reviews, see Refs. [25 – 28]). A recent study assessed the capacity of five of these patients to learn new facts as well as to remember facts they had learned before they developed memory impairment [29] (patient G.W. is referred to elsewhere as patient G.R.W.). These patients had become amnesic at a known time during the interval 1976– 2001. They took a test that
Fig. 4. Performance on a test of nonverbal memory (the Rey – Osterrieth figure). Participants were asked to copy the figure illustrated in the small box in the upper left panel, and 10 – 15 min later without forewarning, to reproduce it from memory. The reproduction by a representative healthy control is shown below the target figure. The left panel also shows the reproduction by amnesic patient R.B., who had bilateral lesions involving the CA1 field of the hippocampus [23]. Patient E.P., who has large medial temporal lobe lesions, did not recall copying a figure and declined to attempt a reproduction (lower left panel). The right panel shows reproductions by six other amnesic patients, who have bilateral damage thought to be limited primarily to the hippocampal region.
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asked about 251 news events that had occurred from 1950 to early 2002. A free recall test was given first, followed by a four-alternative multiple-choice test. Fig. 5 shows the results for five patients and 12 age- and education-matched controls. The data for each patient (and for two to three controls matched to each patient) were aligned according to the year when the patient became amnesic, so that an average score could be calculated for the period of anterograde amnesia (AA), the period up to 5 years before the onset of amnesia, the period 6 –10 years before the onset of amnesia, and so on. Thus, for patient A.B., who became amnesic in 1976, most of the questions (n = 196) assessed his anterograde amnesia. For patient G.W. who became amnesic in 2001, only 28 of the questions assessed his anterograde amnesia. The results were that the patients exhibited a significant impairment in learning about news events that occurred after they became amnesic. In addition, the free recall scores demonstrated a temporally limited retrograde amnesia extending back (at most) perhaps 10 years prior to the onset of amnesia. News events that occurred longer than 10 years prior to the onset of amnesia were remembered equally well by patients and controls. The findings for anterograde amnesia indicate that damage limited primarily to the hippocampal region impairs the acquisition of semantic knowledge. Thus, the impairment after hippocampal damage is not restricted to episodic memory. Further, the finding of temporally limited retrograde amnesia is consistent with what has been described previously for damage limited to the hippocampal region [21,23, 24,30].
Fig. 5. Recall and recognition performance on a test of news events that occurred from 1950 to early 2002. Performance is shown separately for events that occurred after the onset of amnesia (AA, anterograde amnesia) and for events that occurred during 5-year periods preceding the onset of amnesia. The patients became amnesic in different years from 1976 to 2001. Standard errors ranged from 2% to 12% for the patients and controls. H = patients with damage limited primarily to the hippocampal region; CON = controls.
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3. Spared memory for remote autobiographical events following damage to the medial temporal lobe The work summarized in the previous section demonstrated that remote factual information is spared following damage limited primarily to the hippocampal region. This section summarizes recent work that has assessed the status of remote autobiographical memory after hippocampal damage and after larger medial temporal lobe lesions (for review of previous work, see Ref. [31]). Memories of autobiographical events are often complex, richly detailed narratives, and have the defining characteristic of being unique to a particular time and place. Earlier studies suggested that autobiographical memory could be intact after damage to the hippocampal region. For example, patient R.B., who had histologically identified bilateral lesions restricted to the CA1 field of the hippocampus [23], was asked to recall 10 autobiographical memories from any time in his life. On the basis of a 0– 3 scoring system for each recollection, R.B. appeared to be as good as controls at recalling past events. Similarly, remote autobiographical memories appeared to be intact (again, on the basis of a 0– 3 scoring system) in patients L.M. and W.H. [32]. These two patients had histologically identified damage to all the CA fields of the hippocampus, as well as damage to the dentate gyrus, the subiculum (W.H. only), and some cell loss in the entorhinal cortex [24]. In contrast to these findings, some patients have been described who appear to have difficulty recalling any autobiographical episodes from the period before they became amnesic, even when they are asked to recall episodes from their early life [20,33]. These reports raise the possibility that autobiographical memory does not become independent of medial temporal lobe structures with the passage of time and that these structures are always necessary for recollecting the richness of detail that characterizes well-formed autobiographical episodes. There appear to be two ways to understand the available data. First, it is possible that the 0– 3 scoring system used in the early studies was not sufficiently sensitive to detect impaired recollection. A patient’s recollection might receive a full score of 3 but nevertheless contain less detail and context than the recollection of a healthy control. Second, it is possible that those patients reported to be deficient at autobiographical recollection might have significant damage in addition to damage within the medial temporal lobe. In the earlier studies, the locus and extent of damage was known through detailed neurohistological analysis. Less is known about the patients in the more recent studies. One of these studies included patient K.C. (see first section of this chapter), together with four other patients for whom little or no anatomical information was available [20]. The four patients included one reported to have a medial temporal lobe lesion as the result of encephalitis, one with a diencephalic lesion caused by astrocytoma, one with early Alzheimer’s disease, and one with basal forebrain damage following an anterior communicating artery aneurysm. A second study involved a patient with quantitative MRI evidence of volume loss in the hippocampal region and the parahippocampal gyrus [33]. No damage outside the medial temporal lobe was reported. We have assessed remote autobiographical memory in eight well-characterized amnesic patients who have damage limited primarily to the hippocampal region (n = 6, Fig. 4, [34]; two patients [22] courtesy of Ramona Hopkins, PhD]) or who have more extensive
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damage to the medial temporal lobe (n = 2; patients E.P. and G.P. [6,35]). The eight patients and 24 age-matched control subjects were each asked to recollect memories from the first third of their lives (on average, from before 16 years of age). Each participant was given 24 cue words one at a time (e.g., river, bottle, nail) and asked to recollect a unique memory involving the cue word that was specific in time and place [36]. All participants were encouraged to provide as much information as they could, in order to demonstrate that they were recollecting a specific event. The responses were tape-recorded, and those responses that contained a specific recollection were subsequently scored according to how many details were provided for each narrative. Both the patients and their controls were able to provide specific recollections in response to most of the cue words (eight patients, 89.2%; 24 controls, 95.3%; U = 67, p>0.10). The quantitative analysis of these recollections resulted in two kinds of content: episodic details and semantic details. An episodic detail was unique to the recollection (e.g., the outcome of a particular sporting event played at school one day). A semantic detail was a fact contained within the narrative (e.g., the name of the school). Fig. 6
Fig. 6. The number of details contained in narrative reports of remote autobiographical memories. Participants were given 24 cue words (e.g., river, bottle, nail). For each cue word, they were asked to recollect a specific event from the first third of their life that involved the word. Data were collected in two separate studies by different interviewers. Panels A (first study) and B (second study) show the mean number of details per narrative that described specific autobiographical events (episodic memory). Panels C (first study) and D (second study) show the mean number of details per narrative that were recounted as part of the recollections but were not unique to a specific episode (semantic memory). Each participant is represented by a filled circle, and patients are identified by their initials. H = patients with lesions thought to be limited primarily to the hippocampal region; MTL + = post-encephalitic patients with large medial temporal lobe lesions; CON = controls.
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shows the results, presented as two separate studies (A and C; B and D). (The studies differed only in that they were conducted by different interviewers. The interviewer for the second study did not question and probe for details as extensively as the interviewer for the first study, with the result that both the patients and the controls produced somewhat fewer details in the second study than in the first study). Overall, the patients and the controls provided recollections that contained a similar number of episodic and semantic details. Approximately two-thirds of the total details that were recalled were scored as episodic details (one-third were semantic details), and this distribution was observed across both patients and controls. The results indicate that amnesic patients, even patients with large medial temporal lobe lesions (E.P. and G.P.) are able to recall detailed autobiographical memories from their early life. To assess the reliability of the scoring, all the narratives from 10 of the participants (four amnesic patients and six controls) were scored by two raters. Although one rater credited the narratives with more details than the other rater (mean difference = 5.5 F 1.1 details/narrative), both raters credited the amnesic patients and the controls with a similar number of details (for both raters, < 1.0 details/narrative separated the patients and the controls). The narratives provided by the patients and controls were not identical in every respect, as indicated by the finding that the patients but not the controls tended to repeat details within a narrative (Fig. 7). These repeated details were not credited towards the patients’ scores. The tendency to repeat is likely to be a function of anterograde amnesia. Indeed, it is notable that repetition of narrative detail was most frequent in the two most severely impaired patients (E.P. and G.P.) who have the most extensive medial temporal lobe damage (Fig. 7). For all eight of the amnesic patients and for six controls, who were available for follow-up and for six controls, an effort was made to determine the accuracy of the recollections. After the initial interview (median = 14 months), we provided a few cues for each recollection and asked whether participants could then produce the same recollection as before. The patients reproduced 88.0% of their recollections (controls, 93.4%; t(12)=1.3, p>0.1).
Fig. 7. The number of times that patients and controls repeated the same detail in their narrative recollections of remote autobiographical memories. Data were collected in two separate studies (A and B) by different interviewers. Abbreviations as in Fig. 6.
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The eight amnesic patients and 13 new controls were also assessed with the autobiographical memory interview (AMI; [37]). This standardized test quantifies the recall of autobiographical incidents and personal facts from childhood, early adult life, and recent life. We summarize here the results for childhood memories (up to 18 years old). For autobiographical incidents, participants were asked to recall three unique events from childhood (maximum score = 9). For personal facts, participants were asked 12 factual questions about their childhood (e.g., names and places, maximum score = 21). The patients performed similarly to controls in all respects. For the patients, the mean score for autobiographical incidents was 8.9 (controls, 7.9), and for personal facts the score was 18.9 (controls, 19.3). The findings from the AMI are consistent with what was found in the analysis of narrative recollections; namely, amnesic patients with medial temporal lobe lesions were able to recall remote autobiographical memories. The results taken together suggest that the hippocampal region and adjacent medial temporal lobe cortex are not essential for the recall of remote autobiographical events. It is important to qualify this conclusion in two ways. First, it is not possible to conclude that remote autobiographical memory was entirely intact in the patients studied here. Although we were unable to distinguish qualitatively or quantitatively the recollections of the patients from those of the controls, it is possible that the patients differed from the controls in some way that escaped our analysis. At the same time, the results clearly rule out the notion that patients with medial temporal lobe lesions are grossly deficient at autobiographical remembering. Second, it is not possible to determine to what extent the stories told by the patients were episodic memories in the same sense as the rich and unique recollections that intact individuals can recover from their recent past. Yet, it is also true that it is not possible to make this determination in the case of the remote recollections reported by the controls. From the data presented here, it is possible only to conclude that whatever qualities are present in the remote recollections of controls also appear to be present in the recollections of amnesic patients. We suggest that patients who are reported to have impaired autobiographical recollections [20,33] will eventually prove to have damage in addition to damage within the medial temporal lobe. It will be an important topic for future study to identify the locus and extent of damage that is necessary and sufficient to impair autobiographical remembering.
4. Conclusion The studies described here support three conclusions about the neurological organization of human memory. First, to a limited degree, nondeclarative memory can substitute for declarative memory, but what is learned and stored in memory is substantially different depending on which memory system is used. Second, damage limited primarily to the hippocampal region impairs the learning of new facts (semantic memory), just as such damage impairs the learning of new events (episodic memory). Remote memory for factual knowledge is spared. Third, damage to the declarative memory system spares remote memory for autobiographical events (episodic memory).
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Acknowledgements This study was supported by the Medical Research of the Department of Veterans Affairs, National Institute of Mental Health (NIMH) Grant MH24600, and the Metropolitan Life Foundation. We thank Dr. Ramona Hopkins, Brigham Young University, Provo Utah, for her collaboration and for permission to test her study patients.
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The medial temporal lobe and declarative memory Peter J. Bayley a, Larry R. Squire a,b,c,d,* a
Department of Psychiatry, University of California-San Diego, La Jolla CA 92093, USA b Veterans Affairs Healthcare System, San Diego, CA 92161, USA c Department of Neurosciences, University of California-San Diego, La Jolla, CA 92093, USA d Department of Psychology, University of California-San Diego, La Jolla, CA 92093, USA Received 17 January 2003; accepted 26 February 2003
Abstract The hippocampus is part of a system of anatomically related structures in the medial temporal lobe that supports the capacity for conscious recollection (declarative memory). In three studies, we investigated memory functions in amnesic patients with bilateral damage limited primarily to the hippocampal region and in other patients with larger lesions of the medial temporal lobe. The results support three conclusions about the neurological organization of human memory. First, to a limited degree, nondeclarative memory can substitute for declarative memory, but what is learned and stored in memory is substantially different depending on which memory system is used. Second, damage limited primarily to the hippocampal region impairs the learning of new facts (semantic memory), just as such damage impairs the learning of new events (episodic memory). Remote memory for factual knowledge is spared. Third, damage to the medial temporal lobe spares remote memory for autobiographical events (episodic memory). D 2003 Elsevier Science B.V. All rights reserved. Keywords: Hippocampus; Nondeclarative memory; Amnesia; Retrograde amnesia; Autobiographical memory
The hippocampus is part of a system of anatomically related structures in the medial temporal lobe that supports the capacity for conscious recollection (declarative memory) (Fig. 1A). Declarative memory can be contrasted with a collection of nonconscious, nondeclarative forms of memory, each of which is supported by specific brain systems (Fig. 1B). This chapter considers three issues that have been prominent in recent
* Corresponding author. VA Medical Center (116A), University of California-San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Tel.: +1-858-642-3628; fax: +1-858-552-7457. E-mail addresses: [email protected] (P.J. Bayley), [email protected] (L.R. Squire). 0531-5131/ D 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0531-5131(03)00192-4
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Fig. 1. (A) A schematic view of the medial temporal lobe memory system for declarative memory. The hippocampal region is composed of the dentate gyrus (DG), the CA fields, and the subiculum (S). The medial temporal lobe memory system is composed of the hippocampal region together with the perirhinal, entorhinal, and parahippocampal cortices [38]. (B) A taxonomy of mammalian long-term memory systems. The taxonomy lists the brain structures thought to be especially important for each form of declarative and nondeclarative memory. In addition to its central role in emotional learning, the amygdala is able to modulate the strength of both declarative and nondeclarative memory [39].
discussions of the nature of declarative memory: (1) whether one memory system can substitute for another; (2) whether the hippocampus is important for semantic memory as well as for episodic memory; (3) whether autobiographical remembering is possible after medial temporal lobe damage.
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1. Learning facts with nondeclarative memory It is an under-appreciated feature of the memory systems of the brain that the memory system that is engaged depends not so much on what task must be learned as on the strategy that is implemented during learning. Some tasks, such as motor skill learning, are difficult to acquire except by the gradual practice and trial-and-error repetition that engage nondeclarative memory systems. Other tasks can be learned in more than one way. For example, consider the task of eight-pair concurrent discrimination learning, which involves repeatedly presenting eight different pairs of objects one at a time. One member of the pair is always correct, and the learner tries to select the correct object each time it appears (for example, during daily training sessions of 40 trials in which each object pair appears five times). Patients with memory impairment due to bilateral medial temporal lobe or diencephalic lesions had severe difficulty learning this task [1]. Further, their learning score was correlated with their ability to answer questions about the task. Indeed, the difficulty that the patients had in attempting to memorize the correct object in each pair was entirely consistent with the difficulty they had in learning other kinds of verbal and nonverbal material. Remarkably, monkeys with hippocampal lesions [2] as well as monkeys with larger lesions involving the hippocampus together with adjacent medial temporal lobe cortex [3] learned the eight-pair concurrent task at a normal rate. In contrast, monkeys were impaired on this task, and on similar versions of the task, when the damage included either inferotemporal cortex (area TE) [3,4], or when the damage included the tail of the caudate nucleus, which is a striatal target of projections from area TE [2,5]. These observations can be understood by supposing that the monkeys approached the eight-pair concurrent task as a task of habit learning, a task that can be acquired gradually through trial-and-error and that results in a set of dispositions to select the correct object in each pair. Thus, while humans approach the eight-pair concurrent task as a task of memorization, that is, as a task of declarative memory that depends on the medial temporal lobe, for monkeys the eightpair concurrent task is a task of nondeclarative memory that depends on the integrity of the caudate nucleus. This set of findings raises the question whether a patient with profoundly impaired declarative memory might nevertheless be able to use an alternative memory system to acquire factual information, that is, information that is ordinarily acquired as declarative knowledge. If so, would the knowledge that is acquired have different properties than declarative memory? Or, are humans governed to such an extent by particular strategies operating within specific domains that one memory system cannot easily substitute for another? We have had the opportunity to address these questions in studies of a patient (E.P.) who became profoundly amnesic in 1992 at the age of 70 as the result of viral encephalitis [6]. E.P.’s memory is so impaired that he still fails to recognize the examiner after more than 150 visits to his house. Further, E.P. has not acquired the conscious knowledge that he in fact has memory impairment. It appears that he has not been able to record his many memory failures so as to bring about an altered estimate of his own abilities. In the laboratory, E.P. has demonstrated no ability to form new declarative memories. For example, in one series of studies, E.P. and five controls took 42 different two-choice tests
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of recognition memory. The five controls averaged 81.1% correct; E.P. averaged 49.3% correct, about what would be expected by chance. E.P. has extensive, virtually complete bilateral damage to the hippocampus, amygdala, entorhinal cortex, and perirhinal cortex, as well as damage to the anterior parahippocampal cortex and anterior fusiform gyrus [6]. We studied E.P.’s capacity to learn new semantic information in the form of novel three-word sentences (e.g., shark killed octopus; venom caused fever [7]) that were presented on a computer screen [8]. The training procedure followed a study-only method, in which 48 sentences were studied during training without an opportunity to make errors. This procedure has been found to facilitate learning in memory-impaired patients, and for such patients, to be superior to conventional study-test methods [7,9 – 11]. After a pretest (shark killed ???; venom caused ???) to eliminate the one or two sentences that could be completed correctly by guessing, study sessions were given in which participants saw each of the 48 training sentences twice. E.P. was given a total of 24 study sessions on 24 different days (two sessions per week for 12 weeks for a total of 48 training trials). Controls were given a total of two study sessions (one session per week for 2 weeks for a total of four training trials). E.P.’s retention of the sentences was tested on both the 3rd and 4th day after the eighth study session (T1, T2), on the 4th and 5th day after the 16th study session (T3, T4), and on the 3rd and 4th day after the 24th study session (T5, T6). The retention tests assessed memory for the last word of the sentence when the first two words were given as a cue (e.g., shark killed ???). On each day of retention testing, a cued-recall test was presented first. The cued-recall test was followed by a two-alternative, forced-choice test in which the first two words of each sentence were presented together with two possible completions, and participants were asked to select the correct word. Seven days after their final study session, the control group recalled an average of 49.5% F 11.9% of the 48 target words (Fig. 2A). In contrast, E.P. was markedly impaired at learning the target words. After 4 weeks of study (eight sessions), he recalled one word on the first retention test (T1) and two words on the second retention test (T2). Thus, across these two tests, his recall score (3.2%) was far below the 49.5% score that controls were able to achieve after only two study sessions. Nevertheless, despite E.P.’s inability to learn scarcely anything during the first 4 weeks of study, he demonstrated unmistakable improvement as the study sessions continued. Thus, he averaged 11.5% correct on T3 and T4 after 8 weeks of study, and 18.8% correct (9 items correct out of 48) on T5 and T6 after a total of 12 weeks of study. His improvement across the three study-test intervals (T1 and T2, T3 and T4, T5 and T6) was significant (linear trend, F(1,5) = 17.2, p < 0.02). Ten controls took the forced-choice test in the absence of prior study and identified 46.9 F 2.9% of the target words. This value was taken as a baseline score against which to compare the performance of E.P. and his controls. Fig. 2B shows that controls correctly identified 89.6 F 5.6% of the target words after their two study sessions. In contrast, E.P. scored 58.3% correct after eight study sessions (T1 and T2), 64.6% correct after 16 study sessions (T3 and T4), and 64.6% correct after 24 study sessions (T5 and T6). His performance was much poorer than that of the controls, though he did score measurably above chance at each study-test interval (binomial test, p’s < 0.02; the results were the same when 50.0% was taken as chance performance, except that in this case E.P. did not score above chance in sessions T1 and T2). In earlier testing with similar material [11],
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Fig. 2. Controls (CON, black bars, n = 4) and E.P. (open bars) studied 48 three-word sentences (e.g., shark killed octopus). Retention tests were given to controls after four training trials (one session in each of 2 weeks, two training trials per session) and to E.P. on two consecutive days (T1 – T6) after 16, 32, and 48 training trials (two sessions per week, two training trials per session). (A) Percentage of correct cued recall of target words in response to the first two words in each sentence. Performance is shown for the pretest (Pre, before study) and after each study period. (B) Percentage of correct forced-choice recognition when the first two words of each sentence were presented together with two possible target words. Performance is shown after each study period. The dashed line shows the score obtained by a group (n = 10) that received no study. Brackets show mean standard error. Asterisks indicate significant difference vs. the no-study group ( p < 0.05).
E.P. failed to demonstrate learning, but he received considerably less repetition of the study material in those tests than in the present case (8 training trials vs. 48 training trials). It has been reported that factual information acquired gradually by amnesic patients after extended training can be somewhat inflexible and hyperspecific [12 –15]. These findings might reflect the operation of nondeclarative (skill-like) memory, residual declarative (fact-like) memory, or some combination. To investigate what kind of memory E.P. had acquired, other tests were given. First, at T6 we tested the flexibility of what he had learned, that is, how well he could access his knowledge in novel circumstances. In this test, the second word of each sentence was replaced by a synonym (e.g., ‘‘venom caused ???’’ was changed to ‘‘venom induced ???). Fig. 3 shows the results. Substituting a synonym for the second word in each sentence frame markedly disrupted E.P.’s performance. He scored 20.7% correct when the original sentence frames were used as cues (on T5 and T6), but he could recall correctly only one of the target words after the sentences were changed. In contrast, the control group performed almost as well in the synonym condition (24.7% correct) as in the standard condition (28.7%). Thus, the controls were able to use their knowledge flexibly. In contrast, E.P. could sustain his performance only when the words in the sentence frame were exactly the same words that he had previously studied. When the second word in the sentence frame was
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Fig. 3. Cued-recall performance of target words by controls (black bars, n = 12) and E.P. (open bars) in response to the first two words of previously studied three-word sentences. The score for E.P. is the average of two tests (T5 and T6, see Fig. 2). Data are for 29 of 48 studied sentences that were given to both E.P. and controls (control data, n = 12, from Ref. [11]). In the Standard Test given to E.P. after 48 training trials and to controls after two training trials, the same two words were presented that had been previously studied (e.g., venom caused ???), and participants tried to respond with the target word (fever). In the Synonym Test for E.P., the second word of each sentence frame was replaced by a synonym (e.g., venom induced ???). For the controls, the same synonyms were used for 16 of the sentence frames as were used for E.P. For the remaining 13 sentence frames, both words of the sentence frame were replaced by synonyms (e.g., ‘Venom caused ???’ was replaced by ‘Poison induced ???’). Brackets show standard error of the mean.
replaced by a synonym, his performance (one correct response) was no better than during the pretest (Fig. 1A) before he had studied any sentences. Thus, in the absence of declarative memory, E.P. was gradually able to acquire knowledge, but what was learned was inflexible and accessible only when the test items appeared exactly as they had at study. It is noteworthy that E.P.’s learning was not inflexible in every respect. On T6, E.P. was given a cued-recall test with the sentence frames read aloud instead of presented on a computer screen. He was able to recall 16.7% of the target words (eight words). This score is similar to the 18.8% average score he obtained on the standard test when the sentence frames were presented on the computer (see T5 and T6, Fig. 2A). Thus, what E.P. had learned was able to accommodate either visual or spoken presentation of the test material. The quality of what E.P. learned was also unusual in two other respects. First, in the forced-choice test, E.P.’s response times were nearly identical for correct and incorrect responses (mean = 4.1 F 0.1 s vs. mean = 4.3 F 0.1 s), despite the fact that his performance was unequivocally above chance. These findings suggest that E.P. was unaware of when he was making correct and incorrect choices. In contrast, the controls responded faster when they made correct choices (mean = 3.0 F 0.5 s) than when they made incorrect choices (mean = 5.5 F 1.2 s) (t(2)=3.8, p=0.06), consistent with previous
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findings of faster response times for correct vs. incorrect responses in forced-choice recognition memory tasks [16]. The second observation concerned how much confidence E.P. had in his correct and incorrect answers. On the cued-recall test at T6, E.P. rated how confident he was in his answers using a five-point scale. His mean confidence rating for correct answers was 3.2 F 0.1 and for incorrect answers was 3.3 F 0.3. Thus, E.P. was no more confident of his correct answers than of his incorrect answers. These results for E.P. contrast with what is typically observed in less severely impaired amnesic patients and in healthy controls; namely, that confidence ratings are higher for correct answers than incorrect answers [17,18]. These findings provide evidence for the acquisition of knowledge by nondeclarative memory, knowledge that would ordinarily be learned declaratively (as conscious factual knowledge) by normal individuals. What E.P. learned was not experienced as factual knowledge. It was outside of awareness, it could be expressed only through performance, and it was relatively inflexible, such that it was accessible only when the word cues used to test memory were the same as had been used during study. We proposed previously [8] that E.P.’s learning depended on a process akin to perceptual learning and occurred within the neocortex. One way to view the issue is that in those cases when factual information is acquired as consciously accessible, declarative knowledge by amnesic patients, then structures that remain intact within the medial temporal lobe support the learning. In contrast, when factual information is acquired as nondeclarative knowledge, as in the case of E.P., the learning in these circumstances occurs directly within the neocortex. An interesting comparison can be made between our findings with E.P. and earlier studies of fact learning in patient K.C. [7,10]. K.C. developed memory impairment after a head injury, which damaged his medial temporal lobe bilaterally (more on the left than on the right). However, his damage also involved left frontal, left parietal, left retrosplenial, and left occipital cortex, and there is a small lesion in the right parietal cortex. K.C. demonstrated considerable capacity for learning novel phrases, using a very similar procedure as in the present study [10]. After 4 weeks of training and 16 training trials, K.C. scored 83% correct on a cued-recall test, whereas E.P. scored only 2.1% correct after 4 weeks of training and 16 training trials (see Fig. 2A, T1). Thus, E.P.’s learning ability is much poorer than K.C.’s ability. This difference is likely to be related to E.P.’s more extensive medial temporal lobe damage. If so, K.C.’s medial temporal lobe damage cannot explain instances when he performs more poorly than E.P. For example, it is notable that K.C. is reported to be able to recall few, if any, autobiographical episodes from his life before his injury [10,19,20]. In contrast, E.P. can recall autobiographical episodes from his early life in considerable detail, as discussed below [21,22]. Thus, the findings from K.C. and E.P. represent a double dissociation with respect to autobiographical recollection (better for E.P.) and the ability to acquire new factual information (better for K.C.). These findings suggest that the difficulties reported for K.C. in autobiographical recollection are not related to his medial temporal lobe damage (because E.P. has extensive medial temporal lobe damage and yet can recollect autobiographical episodes better than K.C.).
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2. Impaired fact learning when damage is limited primarily to the hippocampal region As described in the previous section, a large lesion involving much of the medial temporal lobe (patient E.P.) impairs declarative memory rather completely. In contrast, when damage is limited to the hippocampal region itself, memory is less severely affected. We have had the opportunity to study a group of patients who, from radiological evidence, have damage restricted primarily to the hippocampal region. They have a moderately severe memory impairment (Fig. 4), as has been observed in other patients whose restricted hippocampal lesions have been demonstrated neurohistologically [23,24]. Recent discussions of human hippocampal function have considered whether the hippocampus is especially important for learning about single events (episodic memory) and the adjacent cortex is important for fact learning (semantic memory), or whether the hippocampus supports both episodic and semantic memory (for reviews, see Refs. [25 – 28]). A recent study assessed the capacity of five of these patients to learn new facts as well as to remember facts they had learned before they developed memory impairment [29] (patient G.W. is referred to elsewhere as patient G.R.W.). These patients had become amnesic at a known time during the interval 1976– 2001. They took a test that
Fig. 4. Performance on a test of nonverbal memory (the Rey – Osterrieth figure). Participants were asked to copy the figure illustrated in the small box in the upper left panel, and 10 – 15 min later without forewarning, to reproduce it from memory. The reproduction by a representative healthy control is shown below the target figure. The left panel also shows the reproduction by amnesic patient R.B., who had bilateral lesions involving the CA1 field of the hippocampus [23]. Patient E.P., who has large medial temporal lobe lesions, did not recall copying a figure and declined to attempt a reproduction (lower left panel). The right panel shows reproductions by six other amnesic patients, who have bilateral damage thought to be limited primarily to the hippocampal region.
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asked about 251 news events that had occurred from 1950 to early 2002. A free recall test was given first, followed by a four-alternative multiple-choice test. Fig. 5 shows the results for five patients and 12 age- and education-matched controls. The data for each patient (and for two to three controls matched to each patient) were aligned according to the year when the patient became amnesic, so that an average score could be calculated for the period of anterograde amnesia (AA), the period up to 5 years before the onset of amnesia, the period 6 –10 years before the onset of amnesia, and so on. Thus, for patient A.B., who became amnesic in 1976, most of the questions (n = 196) assessed his anterograde amnesia. For patient G.W. who became amnesic in 2001, only 28 of the questions assessed his anterograde amnesia. The results were that the patients exhibited a significant impairment in learning about news events that occurred after they became amnesic. In addition, the free recall scores demonstrated a temporally limited retrograde amnesia extending back (at most) perhaps 10 years prior to the onset of amnesia. News events that occurred longer than 10 years prior to the onset of amnesia were remembered equally well by patients and controls. The findings for anterograde amnesia indicate that damage limited primarily to the hippocampal region impairs the acquisition of semantic knowledge. Thus, the impairment after hippocampal damage is not restricted to episodic memory. Further, the finding of temporally limited retrograde amnesia is consistent with what has been described previously for damage limited to the hippocampal region [21,23, 24,30].
Fig. 5. Recall and recognition performance on a test of news events that occurred from 1950 to early 2002. Performance is shown separately for events that occurred after the onset of amnesia (AA, anterograde amnesia) and for events that occurred during 5-year periods preceding the onset of amnesia. The patients became amnesic in different years from 1976 to 2001. Standard errors ranged from 2% to 12% for the patients and controls. H = patients with damage limited primarily to the hippocampal region; CON = controls.
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3. Spared memory for remote autobiographical events following damage to the medial temporal lobe The work summarized in the previous section demonstrated that remote factual information is spared following damage limited primarily to the hippocampal region. This section summarizes recent work that has assessed the status of remote autobiographical memory after hippocampal damage and after larger medial temporal lobe lesions (for review of previous work, see Ref. [31]). Memories of autobiographical events are often complex, richly detailed narratives, and have the defining characteristic of being unique to a particular time and place. Earlier studies suggested that autobiographical memory could be intact after damage to the hippocampal region. For example, patient R.B., who had histologically identified bilateral lesions restricted to the CA1 field of the hippocampus [23], was asked to recall 10 autobiographical memories from any time in his life. On the basis of a 0– 3 scoring system for each recollection, R.B. appeared to be as good as controls at recalling past events. Similarly, remote autobiographical memories appeared to be intact (again, on the basis of a 0– 3 scoring system) in patients L.M. and W.H. [32]. These two patients had histologically identified damage to all the CA fields of the hippocampus, as well as damage to the dentate gyrus, the subiculum (W.H. only), and some cell loss in the entorhinal cortex [24]. In contrast to these findings, some patients have been described who appear to have difficulty recalling any autobiographical episodes from the period before they became amnesic, even when they are asked to recall episodes from their early life [20,33]. These reports raise the possibility that autobiographical memory does not become independent of medial temporal lobe structures with the passage of time and that these structures are always necessary for recollecting the richness of detail that characterizes well-formed autobiographical episodes. There appear to be two ways to understand the available data. First, it is possible that the 0– 3 scoring system used in the early studies was not sufficiently sensitive to detect impaired recollection. A patient’s recollection might receive a full score of 3 but nevertheless contain less detail and context than the recollection of a healthy control. Second, it is possible that those patients reported to be deficient at autobiographical recollection might have significant damage in addition to damage within the medial temporal lobe. In the earlier studies, the locus and extent of damage was known through detailed neurohistological analysis. Less is known about the patients in the more recent studies. One of these studies included patient K.C. (see first section of this chapter), together with four other patients for whom little or no anatomical information was available [20]. The four patients included one reported to have a medial temporal lobe lesion as the result of encephalitis, one with a diencephalic lesion caused by astrocytoma, one with early Alzheimer’s disease, and one with basal forebrain damage following an anterior communicating artery aneurysm. A second study involved a patient with quantitative MRI evidence of volume loss in the hippocampal region and the parahippocampal gyrus [33]. No damage outside the medial temporal lobe was reported. We have assessed remote autobiographical memory in eight well-characterized amnesic patients who have damage limited primarily to the hippocampal region (n = 6, Fig. 4, [34]; two patients [22] courtesy of Ramona Hopkins, PhD]) or who have more extensive
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damage to the medial temporal lobe (n = 2; patients E.P. and G.P. [6,35]). The eight patients and 24 age-matched control subjects were each asked to recollect memories from the first third of their lives (on average, from before 16 years of age). Each participant was given 24 cue words one at a time (e.g., river, bottle, nail) and asked to recollect a unique memory involving the cue word that was specific in time and place [36]. All participants were encouraged to provide as much information as they could, in order to demonstrate that they were recollecting a specific event. The responses were tape-recorded, and those responses that contained a specific recollection were subsequently scored according to how many details were provided for each narrative. Both the patients and their controls were able to provide specific recollections in response to most of the cue words (eight patients, 89.2%; 24 controls, 95.3%; U = 67, p>0.10). The quantitative analysis of these recollections resulted in two kinds of content: episodic details and semantic details. An episodic detail was unique to the recollection (e.g., the outcome of a particular sporting event played at school one day). A semantic detail was a fact contained within the narrative (e.g., the name of the school). Fig. 6
Fig. 6. The number of details contained in narrative reports of remote autobiographical memories. Participants were given 24 cue words (e.g., river, bottle, nail). For each cue word, they were asked to recollect a specific event from the first third of their life that involved the word. Data were collected in two separate studies by different interviewers. Panels A (first study) and B (second study) show the mean number of details per narrative that described specific autobiographical events (episodic memory). Panels C (first study) and D (second study) show the mean number of details per narrative that were recounted as part of the recollections but were not unique to a specific episode (semantic memory). Each participant is represented by a filled circle, and patients are identified by their initials. H = patients with lesions thought to be limited primarily to the hippocampal region; MTL + = post-encephalitic patients with large medial temporal lobe lesions; CON = controls.
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shows the results, presented as two separate studies (A and C; B and D). (The studies differed only in that they were conducted by different interviewers. The interviewer for the second study did not question and probe for details as extensively as the interviewer for the first study, with the result that both the patients and the controls produced somewhat fewer details in the second study than in the first study). Overall, the patients and the controls provided recollections that contained a similar number of episodic and semantic details. Approximately two-thirds of the total details that were recalled were scored as episodic details (one-third were semantic details), and this distribution was observed across both patients and controls. The results indicate that amnesic patients, even patients with large medial temporal lobe lesions (E.P. and G.P.) are able to recall detailed autobiographical memories from their early life. To assess the reliability of the scoring, all the narratives from 10 of the participants (four amnesic patients and six controls) were scored by two raters. Although one rater credited the narratives with more details than the other rater (mean difference = 5.5 F 1.1 details/narrative), both raters credited the amnesic patients and the controls with a similar number of details (for both raters, < 1.0 details/narrative separated the patients and the controls). The narratives provided by the patients and controls were not identical in every respect, as indicated by the finding that the patients but not the controls tended to repeat details within a narrative (Fig. 7). These repeated details were not credited towards the patients’ scores. The tendency to repeat is likely to be a function of anterograde amnesia. Indeed, it is notable that repetition of narrative detail was most frequent in the two most severely impaired patients (E.P. and G.P.) who have the most extensive medial temporal lobe damage (Fig. 7). For all eight of the amnesic patients and for six controls, who were available for follow-up and for six controls, an effort was made to determine the accuracy of the recollections. After the initial interview (median = 14 months), we provided a few cues for each recollection and asked whether participants could then produce the same recollection as before. The patients reproduced 88.0% of their recollections (controls, 93.4%; t(12)=1.3, p>0.1).
Fig. 7. The number of times that patients and controls repeated the same detail in their narrative recollections of remote autobiographical memories. Data were collected in two separate studies (A and B) by different interviewers. Abbreviations as in Fig. 6.
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The eight amnesic patients and 13 new controls were also assessed with the autobiographical memory interview (AMI; [37]). This standardized test quantifies the recall of autobiographical incidents and personal facts from childhood, early adult life, and recent life. We summarize here the results for childhood memories (up to 18 years old). For autobiographical incidents, participants were asked to recall three unique events from childhood (maximum score = 9). For personal facts, participants were asked 12 factual questions about their childhood (e.g., names and places, maximum score = 21). The patients performed similarly to controls in all respects. For the patients, the mean score for autobiographical incidents was 8.9 (controls, 7.9), and for personal facts the score was 18.9 (controls, 19.3). The findings from the AMI are consistent with what was found in the analysis of narrative recollections; namely, amnesic patients with medial temporal lobe lesions were able to recall remote autobiographical memories. The results taken together suggest that the hippocampal region and adjacent medial temporal lobe cortex are not essential for the recall of remote autobiographical events. It is important to qualify this conclusion in two ways. First, it is not possible to conclude that remote autobiographical memory was entirely intact in the patients studied here. Although we were unable to distinguish qualitatively or quantitatively the recollections of the patients from those of the controls, it is possible that the patients differed from the controls in some way that escaped our analysis. At the same time, the results clearly rule out the notion that patients with medial temporal lobe lesions are grossly deficient at autobiographical remembering. Second, it is not possible to determine to what extent the stories told by the patients were episodic memories in the same sense as the rich and unique recollections that intact individuals can recover from their recent past. Yet, it is also true that it is not possible to make this determination in the case of the remote recollections reported by the controls. From the data presented here, it is possible only to conclude that whatever qualities are present in the remote recollections of controls also appear to be present in the recollections of amnesic patients. We suggest that patients who are reported to have impaired autobiographical recollections [20,33] will eventually prove to have damage in addition to damage within the medial temporal lobe. It will be an important topic for future study to identify the locus and extent of damage that is necessary and sufficient to impair autobiographical remembering.
4. Conclusion The studies described here support three conclusions about the neurological organization of human memory. First, to a limited degree, nondeclarative memory can substitute for declarative memory, but what is learned and stored in memory is substantially different depending on which memory system is used. Second, damage limited primarily to the hippocampal region impairs the learning of new facts (semantic memory), just as such damage impairs the learning of new events (episodic memory). Remote memory for factual knowledge is spared. Third, damage to the declarative memory system spares remote memory for autobiographical events (episodic memory).
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Acknowledgements This study was supported by the Medical Research of the Department of Veterans Affairs, National Institute of Mental Health (NIMH) Grant MH24600, and the Metropolitan Life Foundation. We thank Dr. Ramona Hopkins, Brigham Young University, Provo Utah, for her collaboration and for permission to test her study patients.
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