40on storing representations about facts and episods Non ther nesic patier anges in s avior and the ire a subset of a aand mem ects an as her kindof ix amr nd pati one 00 nemory,but performanc anges v g a vers on of the 1960 1993 any p ngs of common obj ts and anin tion.and classical cor ning. are phylo enetically an do not have a oral lobe or d to inte sive study In ied examp e of nonc show cor sid (1968 ving,Dan and or an analogous sin ee lists picture 1 we 1990 and ng the d to the age. amed co group bu as p ete ofthe tm and anticipated th tho H for the ed in the te endency to complete the word frag at s at ic pa redu ed his that had been nre ented re e by 489 did not n nber se ve be 1968 ong? a sitions or te cies lled"perceptual lear n instanc of what is vives hippocampal da age in hu ans and r skill and pr his or in fear na is dependent on the e Declarative and Nondeclarative mount has b and Larry Squire sh learning,partic studies in v ed that amne larly from sic patients could leamn th k of re ding -pote 19 the of nat am patie ant fore rning in humans (Da the way all of us proces s and store information abou n als noncon ry sy (Fiaure 3)is os me the enn hancer nt by the termn on the integrity arousal (Adolph s et al,.199刀 ple of nondecla ative cious rec ections about facts and e mammals is classical P ndit 9 false.It is involved in modelling the external world and ated in the early 19805 by richard thompson and his
Neuron 450 reality of multiple memory systems. This later work made storing representations about facts and episodes. Nonit clear that the spared memory capacities of H. M. and declarative memory is neither true nor false. It underlies other amnesic patients with bilateral medial temporal- changes in skilled behavior and the ability to respond lobe lesions are not limited to motor skills. Motor skills appropriately to stimuli through practice, as the result of are a subset of a large collection of learning and memory conditioningor habit learning. It also includes changes in abilities, all of which are spared in amnesia and indepen- the ability to detect or identify objects as the result of dent of the medial temporal lobe. In 1968, Warrington recent encounters, a phenomenon known as priming. and Weiskrantz demonstrated what turned out to be In the case of nondeclarative memory, performance another kind of preserved learning ability in a group of changes as the result of experience, which justifies the six amnesic patients, one after a right temporal lobec- term memory, but performance changes without providtomy and five with alcoholic Korsakoff’s psychosis. Us- ing conscious access to any prior episodes (Squire et ing a version of the Gollin Figures task (Gollin, 1960), al., 1993; Schacter and Tulving, 1994). Many forms of Warrington and Weiskrantz asked their patients to try nondeclarative memory, such as habituation, sensitizato identify line drawings of common objects and animals tion, and classical conditioning, are phylogenetically an- (such as a chair or an elephant) from which most of the cient and well developed in invertebrate animals that contour lines had been removed. This is initially quite do not have a medial temporal lobe or hippocampus. difficult with the most fragmented drawings, but over A number of nondeclarative forms of memory have successive presentations the contour is gradually filled been subjected to intensive study. In humans, perhaps in until the subject can name the item depicted. On a the best studied example of nondeclarative memory is second presentation of the task, 1 hour later, normal priming, first explored by Warrington and Weiskrantz subjects show considerable savings, requiring fewer (1968) and by Milner et al. (1968). Endel Tulving, Daniel contour cues to name the items. On this incomplete Schacter, Larry Squire, and others have explored several figures task and on an analogous fragmented words paradigms in which subjects see lists of words, pictures task, Warrington and Weiskrantz found marked savings of objects, or nonverbal material such as novel objects in their amnesic patients, with good retention 4 weeks or designs (Weiskrantz, 1990; Tulving and Schacter, later, although the patients did not remember doing the 1990). Subsequently, subjects are tested with both old tasks before. It is true that the amnesic group showed and new items and asked to name words or objects as less savings than the age-matched control group, but quickly as possible, to complete fragments to form this was only to be expected, given that the control whole items, or to make rapid decisions about items. subjects could recall most of the items and anticipated For example, when the first few letters (MOT__) of a seeing them again. recently studied word (MOTEL) are presented, priming Milner subsequently replicated the findings for the is evidenced in the tendency to complete the word fragGollin figures with H. M. Interestingly, H. M.’s initial per- ment to form the study word instead of other possible formance on the firstexposure to thematerial was above words. Severely amnesic patients exhibit fully intact the control mean, illustrating his superior perceptual priming, despite being unable to recognize as familiar abilities. On retesting, 1 hour later, he reduced his error the items that had been presented previously. score by 48%, although he did not remember seeing any Other forms of nondeclarative memory also have been of the drawings before. Moreover, he showed residual studied. These include habit memory, which refers to savings 4 months later (Milner et al., 1968). This long- gradually acquired dispositions or tendencies that are term effect of a prior visual experience, which Milner specific to a set of stimuli and that guide behavior. Habit called “perceptual learning,” is an instance of what is learning survives hippocampal damage in humans and now known as priming, a form of learning distinct from experimental animals but is impaired by damage to motor skill and which, in this case, is probably mediated the caudate nucleus (Packard et al., 1989; Knowlton et by higher visual cortical areas. al., 1996). Emotional learning, as in the development of phobias or in fear conditioning, is dependent on the amygdala. Anenormous amount has beenlearned about The Declarative and Nondeclarative the essential structures and connections involved in Memory Systems emotional learning, particularly from studies in which In 1980, Neal Cohen and Larry Squire showed that amne- rats learn to fear a neutral stimulus such as a tone (fear sic patients could learn the task of reading mirror- conditioning and fear-potentiated startle) (LeDoux, 1995; reversed print as wellas normal subjects.These findings Davis et al., 1997). The amygdala has also been shown to broadened further the scope of what amnesic patients beimportant for emotional learning in humans (Damasio, could do and suggested a fundamental distinction in 1995; Cahill et al., 1996). Moreover, the amygdala is the way all of us process and store information about essential not only for emotional learning itself; it also the world. The major distinction is between declarative exerts modulatory effects on other memory systems memory and a collection of nondeclarative, noncon- (McGaugh et al., 1996). For example, the amygdala is scious forms of memory. responsible for the enhancement of declarative, conDeclarative memory (Figure 3) is what is ordinarily scious memory, which normally occurs with emotional meant by the term memory. It depends on the integrity arousal (Adolphs et al., 1997). of the medial temporal lobe and affords the capacity for Perhaps the best studied example of nondeclarative conscious recollections about facts and events. Declar- memory in mammals is classical Pavlovian conditioning ative memory is propositional—it can be either true or of discrete behavioral responses. A body of work initifalse. It is involved in modelling the external world and ated in the early 1980s by Richard Thompson and his
iw:Mier.Squre,and Kande LONG-TERN MEMOR David Amaral has reviewed tone:unconditioned stimulus ditioned re 1997).He finds that Scoville's removal I was in fac h ce that the of th 8 cm origina th h ded th ain ste ircuitry and that ory traces nd th nt he p and Krupa,1994).To date,eyeblink condi spard.Mostimp rtantly,the ter of a within the mam the localiza me died y h ude adap Prir nas H.M.was describe h1959 monkey. con cept of onscious knowle dge about categories in ntal animals？Se e the ms th nory to mic (Squire et al. 1993 all reas re on e t Part s of the Medial poral Lobe rpola Are i ortant for Memory te rtan e of specific structur region fo which memory tasks were apr priate to other bra ugh So in 1978 when Mort M shkin eir paper,th r exper the sult in an r obje ching to sia they n vith th by single-tria delayed
Review: Milner, Squire, and Kandel 451 Figure 3. A Taxonomy of Mammalian Memory Systems This taxonomy lists the brain structures and connections thought to be especially important for each kind of declarative and nondeclarative memory. colleagues has focused on basic delay conditioning of David Amaral has recently reviewed the results of a the rabbit eyeblink response (conditioned stimulus 5 magnetic resonance imaging study of H. M. (Corkin et tone; unconditioned stimulus 5 airpuff; conditioned re- al., 1997). He finds that Scoville’s removal was in fact sponse 5 eyeblink). Based on anatomical findings, elec- exactly as he had described it, except that the resection trical stimulation, and reversible lesion techniques, the only extends about 5 cm posteriorly in both hemiresults provide strong evidence that the essential mem- spheres, instead of the radical 8 cm originally reported. ory trace circuit includes the cerebellum and related Thus, in both hemispheres the removal included the brain stem circuitry and that the memory traces them- amygdala, the perirhinal and entorhinal cortex, and the selves are formed and stored in the cerebellum (Thomp- anterior hippocampus. The parahippocampal cortex son and Krupa, 1994). To date, eyeblink conditioning was largely spared. Most importantly, the temporal neoprovides the clearest information about the localization cortex and the temporal stem were spared. If the roles of a memory within the mammalian brain. of these various structures were to be understood, an animal model clearly was needed. In humans, several kinds of nondeclarative memory have been studied, which are likely based on perceptual learning. These include adaptation-level effects, the Nonhuman Primate Models of Declarative Memory ability to resolve random-dot stereograms, the ability to As soon as H. M. was described in 1957, efforts began to establish an animal model of his condition in the rat learn the regularities of “artificial grammars” by studying and monkey. If the concept of conscious recollection lawfully ordered letter strings, and the ability to acquire is central to declarative memory, how can declarative knowledge about categories. In category learning, one memory be studied in experimental animals? Several extracts and stores information about the prototype (or characteristics have been useful in extending the notion representative instance) of a series of items by studying many different items that, when averaged together, de- of declarative memory to mice, rats, and monkeys (Eichenbaum, 1997). These include its flexibility and the scribe the prototype. All these forms of memory are ability to use it inferentially in novel situations. It took intact in amnesic patients (Squire et al., 1993; Squire considerable time to achieve such a model, and the first and Zola-Morgan, 1996). These kinds of memory likely results of lesion studies in the monkey were puzzling. involve changes within the same cortical areas responsi- Animals with bilateral medial temporal-lobe resections ble for perceiving and analyzing the materials that are similar to what was described in H. M. showed normal studied. performance on visual discrimination learning tasks, even when concurrent trials on a different task were What Parts of the Medial Temporal Lobe interpolated as potential “distractors” for the discrimina- Are Important for Memory? tion learning. This led many investigators to question The behavioral studies reviewed above provide compel- either thehuman findings or the validity of cross-species ling evidence that the human declarative memory sys- comparisons. It was not until the early 1980s, with the tem is critically dependent upon the medial temporal concept of multiple memory systems and the idea that region. Yet we still have much to learn about the relative amnesia impaired only one kind of memory, that it beimportance of specific structures within the region for came clearer which memory tasks were appropriate to memory processes and the mode of interaction of these give to experimental animals. The beginning of the solustructures with other brain areas. Although Scoville and tion came in 1978 when Mort Mishkin described severe Milner (1957) drew attention to the hippocampus in the deficits in monkeys with bilateral medial temporal-lobe title to their paper, this was only because in their experi- lesions, when the monkeys were given a one-trial task ence bilateral removals limited to the amygdala and un- of object recognition memory (delayed nonmatching to cus did not result in amnesia; they never claimed that the sample). This finding was consistent with the severe hippocampal lesions alone were responsible for H. M.’s impairment shown by H. M. on single-trial delayed severe memory loss. matching tasks
B The Medial Te ral-Lobe Me System in the Monke B)Schemat urce of p x also receives other direc inputs from orbital frontal cortex,insul The 1978p paper did not settle matters all at once but H.M..as well as the two patients described by Penfield work by te events that occum rs h re their sur del.th 8nieqgegy,ormale tha al which s red he medial temporal important ng up t et al ut inge al components of the nedial temporal-lobe me y(retro sial ca Squire and zola-Morg al temporal-lobe the hippoca npus proper.the d tate memory and ograde amne ethe mpal formati erfect tests past is dif the phenomenon of retr ystem,although it can exert a modulatory action on rade amnes nt st th major nponents at t re bilat ge t this heer n de ry(Figure 5).The cribe (R.B.an to the Zola-M gan t al. t d 1986 o H.M.'s impairment,though quantitativ it was gshnepenashol on his h ghth 994 cs Corkin et al. function is tha ce was at cha ce tha ume po the medial temporal lo e is involy in for a have becn for this idea came from the vation that patient
Neuron 452 Figure 4. The Medial Temporal-Lobe Memory System in the Monkey (A) Ventral view of a monkey brain illustrating the cortical areas underlying the hippocampus that are part of the medial temporal-lobe system. Blue, perirhinal cortex; pink, entorhinal cortex; green, parahippocampal cortex. The periamygdaloid cortex (yellow) is not thought to be a part of the system. (B) Schematic view of the memory system. The entorhinal cortex is a major source of projections to the hippocampal region, which includes the dentate gyrus (DG), the cell fields of the hippocampus, and the subicular complex (S). Nearly two-thirds of the cortical input to entorhinal cortex originates in the adjacent perirhinal and parahippocampal cortices, which in turn receive projections from unimodal and polymodal areas in the frontal, temporal, and parietal lobes. The entorhinal cortex also receives other direct inputs from orbital frontal cortex, insular cortex, and superior temporal gyrus. All these projects are reciprocal. The 1978 paper did not settle matters all at once but H. M., as well as the two patients described by Penfield by the early 1980s, after additional work by Mishkin, and Milner (1958), appeared to have intact memory for Zola-Morgan, and others, an animal model of human remote events that occurred years before their surgery. amnesia in the monkey was established. With this Subsequently, formal tests that asked about past public model, the question of precisely which structures within events also showed amnesic patients to have impaired memory for events leading up to the amnesia but intact the medial temporal lobe were important could be sysmemory for more remote events (Squire et al., 1989; tematically explored. The identification of the anatomical components of the medial temporal-lobe memory Rempel-Clower et al., 1996). This loss of premorbid memory (retrograde amnesia) can cover months or even system required about 10 years of experimental work years, depending on the extent of medial temporal-lobe (Squire and Zola-Morgan, 1991). The important struc- damage (Rempel-Clower et al., 1996). tures are the hippocampus proper, the dentate gyrus, Studies of remote memory and retrograde amnesia the subicular complex, and the entorhinal cortex (which in amnesic patients necessarily rely on retrospective together comprise the hippocampal formation) and the methods and imperfect tests. As a result, it is difficult adjacent, anatomically related cortex: the perirhinal and to compare performance across past time periods. For parahippocampal cortices (Figure 4). The amygdala these reasons, the phenomenon of retrograde amnesia proved not to be a component of the declarative memory has begun to beexamined prospectively inexperimental system, although it can exert a modulatory action on animals. To date, eight different studies have been car- declarative memory. ried out in which equivalent amounts of training were A lesion restricted to any of the major components given at two or more times before bilateral damage to of this system has a significant effect on declarative the hippocampal formation, and retention was assessed memory. Indeed, two amnesic patients have been de- shortly after surgery (Figure 5). The work has involved scribed (R. B. and G. D.) who, following an ischemic mice, rats, rabbits, and monkeys and a variety of mem- event, had bilateral lesions limited to the CA1 region of ory tasks including object discrimination learning, con- the hippocampus (Zola-Morgan et al., 1986; Rempel- text-specific fear conditioning, maze learning, and trace Clower et al., 1996). Their deficit was qualitatively similar conditioning of the eyeblink reflex. In seven of the eight to H. M.’s impairment, though quantitatively it was much studies, clear evidence was obtained for temporally milder. It is now clear that the severity of H. M.’s memory graded retrograde amnesia, which covered a period impairment depends not only on his hippocampal dam- ranging from a few days to about a month before surage but on the fact that his surgery included the hippo- gery. In the eighth study (Bolhius et al., 1994), memory campal region togetherwith theperirhinal and entorhinal was affected similarly at the time points tested, although cortices (Corkin et al., 1997). performance was always at chance levels so that no A key feature of medial temporal-lobe function is that difference between the two time points could have been the medial temporal lobe is involved in memory for a detected. limited period of time after learning. The initial evidence Recent accounts of temporally graded retrograde amfor this idea came from the observation that patient nesia propose that medial temporal-lobe structures