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, ~ l l l l lI.lh<\ l \ ( I . \ c ; ~ l l cl3.\'. ~ ~ .\I1 r l g l l l \ rc\cr\<>'l t 1 ~ 1 1 1 ~ 1 10 /~' ~. \1~~~ 1~ ;1 . 1 r 0 ~ ~ . ~ 1 2~ 1~i /d1kd111o11. 0 / ~ 7 ~ 1 , \.<)I. 2 F.Bnllzr and J. Gr8frn:in (Fds) CHAPTER 10 Memory consolidation, retrograde amnesia, and the temporal lobe Toshikatsu ~ u j i i ' . ~ Morris , ~ o s c o v i t c and h ~ ~Lynn ~ ade el^.* ' ~ e c t i o nof Neuropsychology, Division of Disability Science, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, of Psychology, Erindale College, University of Toronto, Mississauga, ON L5L IC6, Canada, Sendai 980-8575, Japan. 2~epartment 3 ~ o t m a nResearch Institute, Baycrest Centrefor Geriatric Care, Bathurst Street, Toronto, ON M6A 2EI, Canada, and 4~epartment of Psychology and Neural system, Memory and Aging Division. University of Arizona. Tucson, AZ 85721, USA Introduction Memory consolidation refers to the idea that neurophysiological processes occurring after the initial registration of information contribute to the permanent storage of memory (Miiller and Pilzecker, 1900; Burnham, 1903; Glickman, 1961; Squire and Alvarez, 1995; Nadel and Moscovitch, 1997). This idea has been supported by the phenomenon of temporally graded (or temporally limited) retrograde amnesia, in which information acquired recently is more affected than information acquired longer ago. It is an important, yet open issue at present, how memory consolidation occurs in the brain (Murre, 1997). Retrograde amnesia (RA), the inability to retrieve information acquired prior to the onset of brain damage, is sometimes extensive enough to cover a patient's whole lifetime, or sometimes temporally limited. Typically, RA is caused by damage to the medial temporal lobe, the diencephalon, and the basal forebrain (Markowitsch, 1995; O'Connor et al., 1995; Tranel and Damasio, 1995, Yamadori et al., 1996). As far as the temporal lobe is concerned, however, RA results from damage not only to medial temporal regions, but also to other regions in the temporal lobe with or without damage to the medial temporal region. To gain a better understanding of memory consolidation processes and RA after damage to the temporal lobe, we will review studies on amnesia after temporal lobe lesions in terms of lesion profile and the naturelextent of RA. In this chapter, we first review data on RA after damage to the temporal lobe in humans (see Conway and Aikatomi, this volume; and Kapur (in press) for reviews of RA following damage to other structures). Then, we review the relevant literature from the study of memory consolidation in animal models. Finally, we propose a possible model of memory consolidation based on the data available to date. Retrograde amnesia after damage to the temporal lobe in humans We examine data from patients with damage primarily in the temporal lobe, focusing on: (1) the types of memory impaired in RA; (2) the extent of impaired memory in RA; and (3) the relationship between the naturelextent of RA and the lesion profile. We imposed the following restrictions on *Corresponding author. E-mail: [email protected] 223 our review. First, since patients with unilateral temporal lobe lesion typically do not show severe amnesia, we included only patients with bilateral damage to the temporal lobes. Second, we only included patients whose structural damage was confirmed by CT, MRI, or autopsy. Third, we restricted our review to patients who developed amnesia with acute or subacute onset, because assessment of the extent of RA is difficult when the onset of amnesia is unknown, as it often is in degenerative disorders and Korsakoffs syndrome. Finally, we included only those cases which have appeared in the past 20 years, with the exception of case HM, whose resected areas were recently confirmed by MRI (Corkin et al., 1997). Conventionally, memory contents have been fractionated into subtypes, such as episodic, semantic, and non-declarative memory, and more recently, finer distinctions, such as autobiographical episodes, and autobiographical (personal) semantics have been proposed. Although these distinctions may be useful, the relationship or dependency between these memory subtypes remains a controversial issue. In descriptions of the nature of RA in this paper, we refer mainly to the following types of memory: autobiographical episodes which contain experiential information acquired in a specific temporal and spatial context, autobiographical semantics which includes personal facts about one's life, and public knowledge including knowledge of public events and that of personalities. We deal concisely with general semantics in the text: general semantics acquired during adult life to the onset of amnesia (for example, one's professional terms and new vocabulary) and more basic general semantics acquired during childhood (knowledge about the world, knowledge of one's own language, and knowledge about objects, etc.). We will not deal with procedural memory or priming. Data are classified basically in terms of lesion profile. We identified five subtypes with bilateral damage: to the hippocampus proper (group 1); to the hippocampal formation without bilateral involvement of other cortex (group 2); to the hippocampal complex without bilateral involvement of other cortex (group 3); to the hippocampal complex and additional bilateral cortical lesion (group 4); and to the temporal lobes with preservation of at least one hippocampal complex (group 5). The hippocampal formation includes the hippocampus proper (CA fields), the dentate gyrus, and the subicular complex. The hippocampal complex includes the hippocampal formation, and the entorhinal cortex, the perirhinal cortex, and parahippocampal gyrus. The relevant studies are summarized in Tables 1-5. Retrograde amnesia for autobiographical episodes Fig. 1 shows the estimated extent of RA for autobiographical episodes after various lesion subtypes (some cases are not included in the figure because of uncertainty of the extent of RA). If the extent of RA is noted in the article, it was employed as the estimated extent of RA; if extent of RA was not noted clearly, we estimated it using the autobiographical incident schedule (Kopelman et al., 1990). If a patient had impaired autobiographical episodes in early adult life and preserved autobiographical episodes in childhood, we assumed 18 years as the preserved duration of autobiographical episodes. In group 1 (Table l), in two cases whose lesions were confirmed by autopsy, damage limited to the hippocampus proper (CA 1 field) caused no or minimal RA for autobiographical episodes (Zola-Morgan et al., 1986; Rempel-Clower et al. 1996). Another case (Kartsounis et al., 1995) showed RA for autobiographical episodes and autobiographical semantics extending back to his youth, although the lesion was not confirmed by autopsy, but specified by MRI. Later studies showed involvement of regions outside the hippocampal complex, in particular the right thalamus (Kapur et al., 1999). Most recently, Kapur and Brooks (1999) reported two cases with RA extending from about 2 to 10 years. In earlier studies, two cases with lesion limited to the hippocampus proper confirmed by autopsy were reported (Cummings et TABLE 1 Retrograde amnesia after damage to bilateral hippocampus propera Authors (published year) Age at onset (years) RA (autobiographical memory) Zola-Morgan et al. (1986) Kartsounis et al. (1995) 52 67 Rempel-Clower et al. (1996) case G D (see also MacKinnon and Squire, 1989) Kapur and Brooks (1999) case BE 43 Intact PE and F F Intact AE (Crovitz) Impaired AE and AS extending back to Impaired PE for at least 30 years, impaired F F for at least 20 years his youth (AMI, Crovitz) Difficult to judge (PE, FF) because of Intact AE (Crovitz) poor motivation Kapur and Brooks (1999) case LC 36 45 RA (public knowledge) Impaired AE for 2 years, normal AS (AM11 Impaired AE for a few years AA MQ FIQ VIQ PIQ Yes Yes 91 Nd 111 Nd Nd 99 Nd 111 Yes 85 92 Nd Nd Yes 82 128 120 133 Impaired PE for 7 years, probably im- Yes paired FP for 7 years Nd Nd Nd Nd F1 Oc Pa Impaired FP for about 10 years Etiology Lesion profile (lesion specification methods) HP Zola-Morgan et al. (1986) Ischemia (autopsy) Kartsounis et al. (1995) Ischemic attack with seizure (MRI) Rempel-Clower et al. (1996) case G D Ischemia (autopsy) (see also MacKinnon and Squire, 1989) Kapur and Brooks (1999) case BE Encephalitis (MRI) Kapur and Brooks (1999) case LC Encephalitis (MRI) R L R H F HC Am T P FG IT MT ST Fv Others * * * L * R * L * P (*I Abbreviations used inTables 1-5: RA, retrograde amnesia; AA, anterograde amnesia; MQ, memory quotient of the Wechsler Memory Scale (or -Revised); FIQ, full IQ of the Wechsler Intelligence Scale (or -Revised); VIQ, verbal IQ; PIQ, performance IQ; AE. autobiographical episodes; AS, autobiographical semantics; PE, public events; FF, famous faces test; FP, famous people test including the Dead or Alive test (Kapur et al., 1989); FN, famous names test; AMI, Autobiographical Memory Interview (Kopelman et al., 1990), Crovitz, Galton-Crovitz method (Crovitz and Schifmann, 1974); Nd, not described; R, right hemisphere; L, left hemisphere; HP, hippocampus proper; HF, hippocampal formation; HC, hippocampal complex; Am, amygdala; TP, temporal pole; FG, fusiform gyrus; IT, inferior temporal gyrus; MT, middle temporal gyrus; ST, superior temporal gyrus; Fv, ventromedial frontal region; F1, lateral frontal region; Oc, occipital lobe; Pa, parietal lobe; BFB, basal forebrain; p, partial damage; (*), probable damage. a 0\ 9 TABLE2 Retrograde amnesia after damage to bilateral hippocampal formationa \ Authors (published year) Age at onset (years) RA (autobiographical memory) RA (public knowledge) Impaired AE for whole life, preserved AS Schnider et al. (1995) 55 Oxbury et al. (1997) 28 Impaired AE for 10-15 years (on the AMI, impaired AE and relatively preserved AS for early adult life) Impaired AE and borderline AS for early adult life (AMI) No detectable impairment (AMI, Crovitz) Impaired AE and borderline AS for early adult life (AMI) Borderline AE and impaired AS for early adult life (AMI) Impaired AE for whole life (AMI, Crovitz), preserved AS (AMI) Impaired AE and AS for 10 years (on the AMI, poorly elaborated AE for whole life and good AS for early adult life) Eslinger (1998) case PD 40 Hirano and Noguchi (1998) 54 Fujii et al. (1999) 51 ~d 99 93 Yes Nd 91 89 96 Nd Yes Nd 117 106 129 Impaired PE and F F for at most 10 years Nd Yes Yes 69 56 98 Nd 117 Nd Nd Nd 2. Nd Yes 68 91 Nd Nd $ Impaired PE for 10 years Yes 52 94 96 92 Impaired PE and FP for 10 years Mild 93 89 84 96 s% Operated for epilepsy and seizure (onset, 13 years; operation 18 years) (Autopsy) Reed and Squire (1998) case LJ Unknown (MRI) Eslinger (1998) case MR Status epilepticus (MRI) Eslinger (1998) case PD Encephalitis (MRI) Hirano and Noguchi (1998) Encephalitis (MRI) Fujii et al. (1999) Encephalitis (MRI) H F HC Am T P * * * * * I. - * R L R L R L * * * * * * * * * * * * * . 4 HP Oxbury et al. (1997) - ~d (lesion specification methods) * 2. Yes Lesion profile Warrington and Duchen (1992) Operated for epilepsy (onset, 25 years; opera- R tion 54 years) (autopsy) L Schnider et al. (1995) Systemic lupus erythematosus (MRI) R r--. - 0 Impaired PE for at least 30 years, impaired F F for at least 15 years Impaired FP for 10-15 years Etiology " See Table 1 for list of abbreviations. MQ FIQ VIQ PIQ 3 Warrington and Duchen (1992) 54 Reed and Squire (1998) case LJ 51 Eslinger (1998) case MR 40 AA * * * * * * FG IT MT ST Fv F1 Oc Pa Others 2 $ a h TABLE 3 Retrograde amnesia after damage to bilateral hippocampal complexa Authors (published year) Age at onset (years) RA (autobiographical memory) RA (public knowledge) AA MQ FIQ VIQ PIQ Warrington and McCarthy (1988), McCarthy and Warrington (1992) ~ o n e d et a al. (1994) case 2 53 Impaired AE at least encompassing entire adult life, relatively preserved AS Impaired PE for at least 15 years, Impaired F F for at least 25 years Yes Nd Nd 128 110 55 Impaired for 5 years (no information about impaired memory type) Impaired AE for 25 years (Crovitz) Yes 70 97 105 87 Impaired PE and F F for 15 years Yes 89 109 Nd Nd Impaired AE for 35 years (Crovitz) Impaired PE and FF for 25 years Yes 67 113 Nd Nd Impaired AE for whole life (AMI), moderately impaired AS (AMI) Impaired PE for at least 30 years Mild 104 94 Rempel-Clower et al. (1996) 54 case LM (see also Beatty et a]., 1987; MacKinnon and Squire, 1989) Rempel-Clower et al. (1996) 64 case WH (see also Salmon et al. 1988; MacKinnon and Squire, 1989) 46 Kapur et al. (1996) case SP Warrington and McCarthy (1 988), McCarthy and Warrington (1992) Yoneda et al. (1994) case 2 Rempel-Clower et al. (1996) case LM Rempel-Clower et al. (1996) case WH Kapur et al. (1996) case SP Etiology Lesion profile (lesion specification methods) HP H F HC Am TP Encephalitis (CT) R L * * * * + * Encephalitis (MRI) R L R * * * * * * * * * T * Epilepsy andlor ischemia (autopsy) L Unknown (probable ischemia) (autopsy) Severe traumatic brain injury (MRI) " See Table 1 for list of abbreviations. R L R L * * P P * * * FG IT MT ST * + * * * * * * * * * P P * * P P Fv F1 Oc 92 Pa 98 Others N N TABLE4 Retrograde amnesia after damage to bilateral hippocampal complex and additional bilateral cortical lesionsa Authors (published year) Age at onset (years) Scovile and Milner (1957), Cor- 27 kin (1984), Corkin et al. (1997) Cermak and O'Connor (1983), 50 O'Connor et al. (1995) Damasio et al. (1985a) 55 Tulving et al. (1988), Tulving et 30 al. (1991) O'Connor et al. (1992) 18 37 Yoneda et al. (1994) case 1 66 Schnider et al. (1994) Reed and Squire (1998) case EP 70 Reed and Squire (1998) case GT 54 RA (autobiographical memory) RA (public knowledge) AA MQ FIQ VIQ PIQ Impaired AE for 11 years Impaired PE and FP Yes 67 Impaired AE for whole life, AS relatively preserved Impaired AE for whole life, AS relatively preserved Impaired AE for whole life Impairment PE and FP for at least 40 years Yes 90 Impaired F F for whole life Yes 62 Impaired F F Yes 80 Impaired AE for whole life (Test like AMI, Impaired PE for 5 years Crovitz), relatively preserved AS (Test like AMI) Impaired for 10 years (no information about impaired memory type) Impaired PE and FP for whole life Impaired AE for whole life (Interview) Impairment of AE and AS extending back to Impaired PE and F F for at least 40 years early adult life (AMI, Crovitz) Impaired AE (AMI, Crovitz), impaired AS Impaired PE and F F for at least 40 years for whole life (AMI) Etiology Lesion profile (lesion specification methods) HP H F HC Am TP FG IT Scovile and Milner (1957). Cor- Operated for epilepsy (onset, 16 years; kin (1984), Corkin et al. operation 27 years) (MRI) (1997) Cermak and O'Connor (1983), Encephalitis (CT) O'Connor et al. (1995) Encephalitis (CT) Damasio et al. (1985a,b) Tulving et al. (1988),Tulving et Severe traumatic brain injury al. (1991) O'Connor et al. (1992) Encephalitis (MRI) Yoneda et al. (1994) case 1 Schnider et al. (1994) Encephalitis (MRI) Infarct (MRI) R L R * * * * * * (*) * * * * * L * * * * * R P j l j l L * (*I R * * * * L R * * jl * L * * * * R * * I. * * * * MT ST Fv (*I * ( * * (*I * * ) * * * * * * * * FI * * * ( * * (*I * * * * * * * Yes Yes Yes 72 Nd 61 Yes 150 Oc Pa Others B. insula, Basal ganglia, L. BFB * * Mild 84 * (*) ** * B.insula, anterior cingulate, BFB L. insula * Reed and Squire (1998) case EP Encephalitis (MRI) Reed and Squire (1998) case GT Encephalitis (MRI) " See Table 1 for list of abbreviations. B. insula, cingulate I (1) (2) (3) Group (4) (5) Fig. 1. Estimated extent of retrograde amnesia (impaired years) for autobiographical episodes in five subgroups classified by lesion profile. Preserved years is number of years since birth over which memory was normal. Broken line shows an uncertainty of the duration. al., 1984; Duyckaerts et al., 1985). They appeared to show temporally limited RA with severe anterograde amnesia, but the precise extent and nature of RA could not be judged from the descriptions. In group 2 (Table 2), the extent of RA for autobiographical episodes varied considerably, ranging from no RA (Reed and Squire, 1998) to R A covering the patient's whole life (Warrington and Duchen, 1992; Hirano and Noguchi, 1998).The remaining five cases showed RA for 10-22 years. We do not include two studies in which lesions were confirmed by autopsy (Woods et al., 1982; Victor and Agamanolis, 1990), because we could not judge either the extent of RA or which types of memory were impaired. In group 3 (Table 3), the extent of RA was described as 5,25,35, over 35 years, and the patient's whole life (Warrington and McCarthy, 1988;Yoneda et al., 1994; Kapur et al., 1996; Rempel-Clower et al., 1996). In group 4 (Table 4), the extent of RA was more extensive than in groups 2 and 3. Five out of eight cases had RA covering their whole life period. Group 5 (Table 5) consists of many cases reported as isolated or focal RA, i.e. severe retrograde amnesia in combination with relatively mild or absent anterograde amnesia (see Kapur, 1993, in press; De Renzi et al., 1997; Fujii et al., 1999). Estimated RA was extensive in most of the cases, and sometimes encompassed the patient's whole W 0 Retrograde amnesia after damage to bilateral temporal lobe lesion with preservation of at least one hippocampal complexa Authors (published year) Age at onset RA (autobiographical memory) (years) Kapur et al. (1992) Impaired AE for whole life (Interview, Crovitz), somewhat impaired AS Impaired AE for whole life (AMI), less impaired AS Impaired AE for early adult life (AMI, Crovitz), normal AS Impaired AE for whole life (AMI), Norma1 AS (AMI) Impaired AE for at least 20-30 years (AMI, Crovitz), less severely impaired AS (AMI) Impaired AE for early adult life (AMI, Crovitz), impaired AS for whole life (AM11 Probably impaired AE (difficult to check because of confabulation), good AS Impaired AE for whole life except for early childhood Impaired AE in childhood and borderline in early adult life, impaired AS for whole life (AMI) Markowitsch et al. (1993) Kapur et al. (1994) Kapur et al. (1996) case GR Calabrese et al. (1996) Kroll et al. (1997) case AA Kroll et al. (1997) case BB Carlesimo et al. (1998) Eslinger (1998), Eslinger et al. (1996) case EK Kapur et al. (1992) RA (public knowledge) AA Impaired PE and FP for whole life Mild Impaired F F for 30 years, impaired FN Mild Moderately impaired PE and impaired FP Mild for at least 20 years Impaired PE, FF, and FN for whole life Mild Impaired F F for at least 35 years Mild Impaired PE and F F for whole life Mild Moderately impaired PE and FF for whole Mild life Impaired PE for about 10 years Mild Impaired PE and FN for at least 30 years, Poor verbal memory good for F F Etiology Lesion profile (lesion specification methods) HP H F HC Am TP FG IT Severe traumatic brain injury (MRI) R P Severe traumatic brain injury (MRI) Kapur et al. (1994) Radiation necrosis (MRI) Kapur et al. (1996) case GR Severe traumatic brain injury (MRI) Calabrese et al. (1996) Encephalitis (MRI) Kroll et al. (1997) case AA Severe traumatic brain injury (MRI) Kroll et al. (1997) case BB Severe traumatic brain injury (MRI) R L R L R L R L R L R L P P P P P P P P P P P * P MT ST Fv F1 * * * (*I * (*I * * * * * * (*I * * (*) * * * L Markowitsch et al. (1993) MQ FIQ VIQ PIQ * * * Others * * * * + * * * * * * * (*I * * * * * * * * * * * * * * * Oc Pa + (*) + * L. fornix, anterior perforated substance Metizory consoliclation,retrogrude un~nesicz,and tlze temporal lobc C/7. 10 life. The extent of RA for autobiographical episodes in group 5 is somewhat shorter than those in group 4, but may be related to the mean age of onset, which is younger in group 5 than in group 4. The same is true of RA for public knowledge, which will be described later. Retrograde amnesia for autobiographical semantics It is difficult to determine the extent of RA for autobiographical semantics because many of the reports provide insufficient descriptions of this kind of memory. However, in reports that refer to both autobiographical episodes and autobiographical semantics, autobiographical semantics tends to be less impaired than autobiographical episodes (16 out of 22 cases). This tendency does not seem to be related to lesion profile in any obvious way. Of the remaining six cases, three showed impaired memory for both autobiographical episodes and autobiographical semantics over the same period. In the remaining three cases, one showed impaired autobiographical semantics with borderline impairment of autobiographical episodes for early adult life (case PD in Eslinger, 1998), another case showed impaired autobiographical semantics for the whole life period with preserved autobiographical episodes for childhood (case AA in Kroll et al., 1997); and the last showed impaired autobiographical semantics for the whole life period with borderline impairment of autobiographical episodes for early adult life (case EK in Eslinger, 1998). McCarthy and Warrington (1992) pursued this issue and found that their severely amnesic patient was able to discriminate familiar acquaintances' names from unknown names and to provide information about personal acquaintances when presented with their names. This report showed that, at least in some cases after bilateral damage to the hippocampal complex, autobiographical semantics can be shown to be preserved if adequate tests are used. former groups showed RA for public knowledge extending between 10 and 30 years. Two exceptional cases described by Zola-Morgan et al. (1986) and by Reed and Squire (1998) showed either no RA or at most a 10-year impairment of public knowledge with no RA for autobiographical episodes. The cases in groups 4 and 5 tended to show more extensive RA for public knowledge, ranging from 5 years to the patient's whole lifetime. Fig. 3 shows the relationship between the extent of impaired autobiographical episodes and the extent of impaired public knowledge in the patients in Tables 1-5 whose deficits were described for both types of memories. RA for public knowledge is not as extensive as for autobiographical episodes Retrograde umnesia for public kno~vledge (public events and personalities) Fig. 2 shows the estimated extent of RA for public knowledge after various lesion subtypes (some cases are not included in the figure because of uncertainty of the extent of RA). Tests of personalities include identification from their photographs, identification from people's names, and occasionally, the Dead or Alive test (Kapur et al., 1989). In some cases, the precise extent could not be judged since memory was impaired over the entire period that was sampled. On the whole, the extent of RA for public knowledge is shorter for the cases in groups 1-3 than for those in groups 4 and 5. The (2) (3) Group (4) Fig. 2. Estimated extent of RA (impaired years) for public knowledge in five subgroups classified by lesion profile. Preserved years is number of years since birth over which memory was normal. Broken line shows an uncertainty of the duration. 232 Impaired years of memory for autobiographical episodes Fig. 3. Relationship between the extent of impaired autobiographical episodes and the extent of impaired public knowledge in amnesic patients with temporal lobe lesions. The number in each circle designates the group we classified in terms of the lesion profile. Lines with an arrow show the possible extent of RA. Open circles show cases whose memory for public knowledge was tested for both public events and personalities. Dotted circles show the cases whose memory for public knowledge was tested only for personalities. Circles with oblique lines show cases whose memory for public knowledge was tested only for public events. in some cases and is the same as for autobiographical episodes in others. Cases with medial temporal lobe lesions (groups 1-4) tended to show less extensive RA for public knowledge than for autobiographical episodes, while cases in group 5 appeared to have the same extent of RA for both public knowledge and autobiographical episodes. Within the realm of public knowledge, the extent of RA for public events and personalities is similar in most of the cases in our review. However, the patient reported by McCarthy and Warrington (1992) and Warrington and McCarthy (1988) again showed a clear dissociation. Thus, the patient showed evidence for well-preserved name vocabu- lary and information about personalities despite showing no evidence for knowledge of the events associated with them. Within the domain of knowledge of personalities, one patient (Eslinger et al., 1996) showed a dissociation in the ability to identify people from names and from photographs, with the former impaired and the latter preserved. This case can be thought of as a comprehension deficit restricted to people's names rather than memory impairment for personalities. Though not the focus of this review, we note briefly some studies of patients with lesions outside the temporal lobe to underscore the point that memory for autobiographical episodes and public knowledge are dissociable one from the other. Dalla Barba et al. (1 990) described a patient with alcoholic Korsakoff syndrome who showed a severe RA for autobiographical episodes with prominent confabulation, but preserved knowledge of public events and famous people. Hodges and McCarthy (1993) described a patient with both anterograde and retrograde amnesia after bilateral thalamic infarction. Their patient's knowledge of public events, and especially of personalities, was surprisingly spared despite a grave deficit of autobiographical memory. Another case (Evans et al., 1996) showed impaired memory for autobiographical episodes for the entire life though memory of public events and famous faces was normal. This case suffered from a rather rare etiology (vasculitis) and showed marked bilateral atrophy of the frontal lobe, the left parietal lobe, and the left temporal pole. An amnesic patient described by Van der Linden et al. (1996) was able to identify famous personalities who became prominent during a period when the patient had severe RA for autobiographical episodes. His amnesia was caused by bilateral infarction in the territory of the posterior cerebral artery resulting from transtentorial herniation. Unfortunately, it is not clear whether the hippocampal complex is involved or not by descriptions on CT findings, although his severe anterograde amnesia suggests the involvement of the medial temporal lobe or diencephalon bilaterally. Similarly, a patient with transient amnesia reported by Venneri and Caffarra (1 998) showed a striking dissociation between a detailed knowledge of public events and famous people and a severe impairment of autobiographical information. During the attack, EEG showed bilateral frontotemporal slow wave and SPECT showed hypoperfusion in the right temporal and parietal lobes. Ross and Hodges (1997) described a patient, following prolonged cardiac arrest, whose amnesia was characterized by severely impaired autobiographical memory and knowledge of public events with well-preserved knowledge of famous people. A CT scan was normal. To sum up, amnesic patients after bilateral tem- poral lobe lesion showed RA for public events although the extent of it was shorter than that for autobiographical episodes in some cases. Most of the cases also showed RA for personalities, but this form of memory was preserved in a thoroughly examined case (Warrington and McCarthy, 1988; McCarthy and Warrington, 1992). Some amnesic cases with damage to regions other than the temporal lobe showed preserved memory for public events and personalities, in contrast to what was typically observed after temporal lobe lesion. Retrograde amnesia for general semantics Unlike the general semantic memory impairment reported in some cases (Warrington, 1975; Yamadori et al., 1992; Hodges et al., 1994), most of the patients do not show any apparent impairment of language, object recognition, and intelligence measured by WAIS-R (see Tables 1-5). Therefore, basic semantic knowledge acquired during childhood is preserved. In many studies, however, it is unclear whether general semantic knowledge acquired during adult life to the onset of amnesia is preserved or not. In this respect, Warrington and McCarthy (1988) reported a postencephalitic patient who retained knowledge of words introduced into the lexicon during the retrograde period for both autobiographical episodes and public events. The postencephalitic patient (Cermak and O'Connor, 1983) appeared to have intact knowledge about physics and laser technology (his profession), though he was amnesic for autobiographical episodes and public knowledge. In contrast, Beatty et al. (1987) described a case (case LM in RempelClower et al., 1996) who showed impaired knowledge of terms commonly employed in his profession in the past 20 years. During this period, he showed retrograde amnesia for both autobiographical episodes and public knowledge tapped by public events test and famous faces test as well as periodic grand ma1 seizures. Preserved or impaired general semantics acquired during adult life to the onset of amnesia has been demonstrated in patients with other lesions and etiologies. Verfaellie et al. (1995) reported an effect similar to the findings by Warrington and McCarthy (1988) in a group of seven nonKorsakoff amnesic patients with mixed etiologies, although the severity and extent of their RA for autobiographical episodes and precise anatomical localization of their lesions were not given. Their patients performed normally (not significantly worse than normal controls) on both recall and recognition tasks regarding memory for words that entered into the vocabulary in the past 25 years. In contrast, Korsakoff amnesic patients in Verfaellie et al. (1995) did show a temporally graded RA for new words. The Korsakoff patient with severe autobiographical episodic impairment described by Butters and Cermak (1986) also was unable to define professional terms once well known to him. Preserved memory for autobiographical episodes along with impairment in other types of memory after bilateral damage to the temporal lobes There have been five reports describing patients who showed preserved autobiographical memory with impaired semantic memory (De Renzi et al., 1987; Grossi et al., 1988; Alexander, 1997; Yasuda et al., 1997; Markowitsch et al., 1999). Among these reports, cases described by De Renzi et al. (1987) and by Yasuda, et al. (1997) are worth considering in some detail because these two patients had bilateral anterior temporal lesions. De Renzi et al. (1987) reported a postencephalitic patient who displayed a severe impairment of semantic knowledge including knowledge of public events and personalities as well as of more general semantics, such as word meaning and object meaning, despite normal memory for autobiographical episodes and autobiographical semantics. An MRI scan showed a wide and irregular area of increased intensity extending over the inferior and anterior part of the left temporal lobe, involving the amygdala, the uncus, the hippocampal formation, the parahippocampal gyrus, the anterior part of the fusiform gyrus, external capsule, and the in- sular white matter. On the right there were minimal signs of increased signal density in the white matter of the inferior temporal lobe. Yasuda, et al. (1997) described a similar patient following several surgeries and radiation therapy for a meningioma. The patient showed severe impairment of memory for public events, personalities, historical figures, cultural items, knowledge of low frequency words and technical terms relevant to her profession despite preserved memory for autobiographical episodes and autobiographical semantics. The T2 weighted MRI revealed lesions due to multiple surgeries in the anteroinferior temporal lobe and the basal frontal lobe in the right hemisphere. Regarding the left hemisphere, the TI weighted MRI with Gadolinium enhancement showed a lesion in the anterior half of the middle temporal gyrus with relative sparing of the temporal pole and the posterior inferior temporal region, although T2 weighted MRI showed more extensive abnormal signal intensity. Both medial temporal lobe structures seemed relatively undamaged. Which lesions are criticalfor emergence of retrograde amnesia for autobiographical episodes in cases with preservation of at least one hippocampal complex? As shown in Table 5, bilateral damage to the medial temporal is not necessary for severe RA to occur. If so, damage to which area other than the hippocampal complex is critical for RA in these cases? Of the nine patients in Table 5, seven had unilateral involvement of either hippocampal formation or complex. Their lesions in the opposite hemisphere were in the temporal pole (6/7), the fusiform gyrus (2/7), the inferior temporal gyrus (2/7), the middle temporal gyrus (2/7), the superior temporal gyrus (1 / 7), ventromedial frontal region (3 / 7), and lateral frontal region (217). One is tempted to conclude that the damage to the temporal polar region is important for RA in these cases. In the remaining two cases, one (Markowitsch et al., 1993) had bilateral damage to the temporal pole as well as the frontal lobe. The other postencephalitic patient (Carlesimo et al., 1998) showed atypical lesions in the bilateral white matter in the temporo-occipitoparietal lobes. In two cases with preserved autobiographical memory and impaired semantic memory (De Renzi et al., 1987; Yasuda et al., 1997), it is of interest that their lesions spared both the hippocampal complex and the temporal pole in either hemisphere. A recent neuroimaging study using PET confirmed that the temporal pole as well as the hippocampal formation play an important role in retrieving autobiographical episodes (Maguire and Mummery, 1999). In that study, enhanced activity was observed for retrieval of autobiographical episodes (i.e. personally relevant, time-specific memories in their conceptualization) in the left hippocampus, medial prefrontal cortex, and temporal pole. The observation that the temporal polar region is implicated in recovering autobiographical memories is consistent with Markowitsch's (1995) proposal that this region plays a central role in this process by virtue of its rich anatomical connections to a network of memory structures. These include the amygdala and hippocampus in the medial temporal lobes, the posterior neocortex, the thalamus, and the prefrontal cortex. Markowitsch places particular emphasis on the right temporal polar region and its connection to the right frontal cortex via the uncinate fasciculus (see also Levine et al., 1998). Despite reports that some patients with extensive and dense RA have lesions in the right temporal pole or uncinate fasciculus, it is not yet certain whether the corollary is true: that right temporal polar lesions produce dense RA. For example, unilateral surgical excisions for the relief of temporal-lobe epilepsy almost always include the temporal pole on the affected side, yet reports of extensive RA in people with right temporal lobectomy are rare, though evidence of moderate remote memory loss for faces (Warrington and James, 1967) and autobiographical episodes (Viskontas, MacAndrews and Moscovitch (1999) cited in Moscovitch et al., 1999) has been reported. At the moment, the evidence for the centrality of the tempo- ral polar region, and in particular the one on the right, for recovery of autobiographical memory is certainly provocative, but not conclusive. Summary of the evidencefrom studies of humans From the data we have reviewed, several points regarding RA after temporal lobe damage emerge. (1) Damage to the hippocampus proper does not necessarily cause RA for both autobiographical episodes and public knowledge despite always giving rise to anterograde amnesia (Table 1). Firm conclusions on this point, however, are unwarranted because only a few cases with such lesions have been reported. In particular, the cases showing a lack of RA had damage restricted to just a portion (CAI field) of the hippocampus proper. It remains to be determined what effect damage including, but restricted to, all the CA fields would have on memory for autobiographical episodes and public knowledge. The few existing cases suffice to demonstrate that measurable anterograde amnesia can occur in the absence of any RA, but only as measured by current tests. The last proviso is important since recent studies have shown that when autobiographical memories are scored in terms of the total number of details provided (Moscovitch and Melo, 1997; Moscovitch et al., 1999), measurable, and quite extensive RA, is found even in cases where patients score normally on more traditional tests such as the AM1 (Kopelman et al., 1990) and the Crovitz test (Crovitz and Schiffman, 1974). Indeed, the results from those studies suggest that amnesic patients retain the gist and major aspects of autobiographical episodes, but not a richness of detail that characterizes these memories in normal people (Moscovitch et al., 1999). (2) If the hippocampal formation or hippocampal complex are damaged bilaterally (Tables 2 and 3), RA for autobiographical episodes can extend for 10-50 years. In many cases who have additional bilateral lesions (Table 4), RA encompasses the patient's whole lifetime. Thus, the duration of RA for autobiographical episodes appears to be related to the extent of medial temporal lobe damage. iMmmoy.c~oi7.solidrrtior~, ~.ctr.ogr.ucleut7zi7c~.sin,criirl the ttvripo/.~I lobe (3) Autobiographical semantics seem to be less impaired than autobiographical episodes across various lesion profiles when both types of memory were evaluated (Tables 2-5). (4) Bilateral lesions, including the hippocampal formation or the hippocampal complex (Tables 24), result in RA for public knowledge. The extent of RA for public knowledge also depends on the extent of medial temporal lobe damage. It is not as extensive as RA for autobiographical episodes in many cases, but is parallel to that for autobiographical episodes in some. It is worth noting that the relation between RA for autobiographical episodes and public knowledge is asymmetric; while the former may be more severely impaired than the latter, the reverse pattern is rarely reported after damage to the medial temporal lobe (Fig. 3). (5) Basic semantic knowledge (language, knowledge about objects, general intelligence, and the like) acquired during childhood is unscathed in temporal lobe amnesia (Table 1-5). At this time, we cannot draw firm conclusions about the fate of general semantics acquired during adulthood prior to the onset of amnesia, because of inconsistent results and a dearth of relevant information. (6) Extensive RA for autobiographical episodes and for public knowledge can occur after bilateral temporal lobe lesions even if the hippocampal complex in either hemisphere is undamaged (Table 5). Anterograde amnesia is minimal in these cases. The relation between RA for autobiographical episodes and public knowledge appears to be less asymmetric than that in cases with bilateral medial temporal lobe lesions (Fig. 3). In these cases, RA appears to occur when lesions affect the temporal polar region in one hemisphere in which the hippocampal complex is spared. Animal studies of retrograde amnesia and memory consolidation Recognizing the inherent limitations of studies involving human subjects, a number of investigators have examined retrograde amnesia and memory consolidation in animal models, typically rodents, C.71. I 0 but occasionally primates. In general, such studies have three kinds of advantages: first, one can, in principle, test subjects with lesions targeted at specific brain regions, although this is not quite as simple as it sounds; second, one can exert virtually complete control over what is learned, and which experiences experimental subjects have in the interim between learning and any retention test; finally, one can carefully and systematically manipulate the learning-retention interval. It is difficult, if not impossible, to match these features in studies with human subjects. On the other hand, there is a signal disadvantage in working with animals; namely, it remains quite difficult to compare animal and human memory, feature by feature and type by type. How, for example, can we characterize the difference between episodic and semantic memory in rats, or monkeys? What in animals could possibly count as autobiographical semantics? Nonetheless, animal studies can contribute important insights, and in what follows, we briefly discuss this literature and what it tells us about memory consolidation. In particular, we focus on several questions already brought to the fore in the literature on humans: (1) which brain structures are critical to memory formation, consolidation and storage; (2) does the shape of the RA gradient change as a function of the extent of damage in critical brain regions; (3) are there different RA gradients for different kinds of learned material? In a recent review, Murray and Bussey (in press) have carefully evaluated all of the studies investigating the role of medial temporal lobe structures in consolidation in animals. Rather than repeat their effort, we will refer to it several times below. Brain structures involved in memory There is considerable support in the animal literature for the notion that there are multiple memory systems, supported by distinct brain structures. Indeed, some of the earliest suggestions about multiple memory systems came from work with rats (Hirsh, 1974; Nadel and O'Keefe, 1974) and monkeys (Gaffan, 1974). In parallel with the human lit- Ch. 10 7: Fujii, M. Moscovitcll and L. Nude1 erature, much of the animal work has focused on the hippocampus, and its neighbors in the temporal lobe. Murray and Bussey (in press) considered the central question of whether the group of structures we have referred to as the hippocampal complex are functionally equipotential with regard to consolidation. Murray and Bussey (in press) pointed out that there is now considerable evidence against this univocal view. For example, data demonstrating rather different roles for hippocampus and perirhinal cortex have been provided by Zola-Morgan and Squire (1990) and Thornton et al. (1997), using comparable tasks (object discrimination) and retention intervals. Murray and Bussey conclude, in general, that different parts of the hippocampal complex play crucial roles in the consolidation of different kinds of memory. As we see below, there is no single answer to the question of what structures are critical to consolidation: it depends upon the nature of the memory being consolidated. The shape of the RA gradienl Given that there would appear to be multiple consolidation processes in different brain regions concerned with different kinds of memory, there cannot be a single answer to the question of the shape of the RA gradient. As Murray and Bussey point out, the gradient can be either graded or flat, depending on the kind of learning involved, and the brain structures damaged. Murray and Bussey tabulated 15 studies of retrograde amnesia after hippocampal complex lesions since 1990. Of these, five studies employed maze learning of one kind or another (Cho et al., 1993, 1995, 1996; Bolhuis et al., 1994), five utilized object or scene discriminations (Salmon et al., 1985; Zola-Morgan and Squire, 1990; Gaffan, 1993; Wiig et al., 1996; Thornton et a]., 1997), three used fear of both contexts and specific tone stimuli (Kim and Fanselow, 1992; Maren et al., 1997; Anagnostaras et al., 1999;), while the remaining two used a socially acquired food preference (Winocur, 1990) and trace eyeblink conditioning (Kim et al., 1995). Of the five studies using spatial maze learning, three employed lesions to the hippocampal formation, while four included groups with damage in the entorhinal cortex. After hippocampal formation lesions, flat RA gradients were seen in 213 cases. After lesions restricted to the entorhinal cortex graded RA was observed in 414 cases. In the studies using discrimination tasks, a more complicated picture emerged. Gaffan (1993) employed a scene discrimination task (with clear spatial components) and relatively restricted fornix lesions, reporting a flat gradient. Several studies using concurrent object discriminations and large aspiration lesions, including several components of the hippocampal complex, also reported flat RA gradients (Salmon et al., 1985; Thornton et al., 1997). However, two other studies using object discriminations reported either graded RA (ZolaMorgan and Squire, 1990, who used extensive hippocampal complex lesions in monkeys; and Wiig et al., 1996, who used fornix lesions in rats) or a flat gradient (Wiig et al., 1996, in groups with perirhinal lesions). In the three studies using context and tone fear conditioning, the typical result has been an absence of RA for tone conditioning, and graded RA for context conditioning. The same pattern of graded RA was reported in the two other studies utilizing non-spatial tasks. While there are no obvious generalizations that capture this pattern of results, the following might hold: when relatively complete lesions are placed in the appropriate region for a given task, flat gradients will typically (but not always) be observed. This seems to hold for spatial tasks and hippocampus proper lesions, and for object discrimination tasks and perirhinal cortex lesions. Additional considerations Two very recent studies raise some critical questions (Land et al., 1998; Kubie et al., 1999). The Land et al. study probed the traditional view of graded RA by inserting a simple manipulation just prior to testing rats for retention of a Y-maze sig- naled avoidance task (this is a task typically assumed to not require an intact hippocampus for solution, given the use of a signal to indicate the correct arm on each trial). They reasoned as follows: the traditional interpretation of graded RA is that if one waits long enough before making a lesion in the hippocampal formation, the memory no longer depends upon the hippocampus, and that is why lesions are ineffective. In their situation, hippocampal lesions made 3 h after training severely impaired retention, while lesions made 30 days after Y-maze training had little effect on performance, indicating that the memory had survived. However, if the animals received a 'reminder' of the experimental situation (rats were simply placed on the Ymaze and a cue light was turned on and off - no training was allowed) just prior to the hippocampal lesion 30 days after initial training, then severe RA was observed. Somehow, the reminder activated the memory in such a way that hippocampal lesions were now effective in inducing RA. This result cannot readily be accommodated within the traditional model of consolidation. It is, however, consistent with the view that the hippocampus remains important for retrieval of memories long after the 'consolidation' period is complete. Kubie et al. (1 999) tested rats in a dry version of the Morris maze, and obtained a graded RA after excitotoxic lesions to the hippocampus proper (CA fields and dentate gyrus). However, more careful analysis of the data indicated that performance in the animals lesioned after long retention intervals was not entirely normal. Their result is similar to that reported by Cho et al. (1993), who also concluded that medial temporal lobe lesions after long retention intervals yield animals who are not as severely impaired, but who are also not normal. Cho et al. suggested that performance in animals receiving lesions after a long retention interval might demonstrate shifts in behavioral strategy rather than in the locus of the memory trace (i.e. from hippocampal formation to neocortex). Kubie et al. offer an intriguing explanation of their results. They suggest that the hippocampal formation and cortex are capable of forming two different kinds of spa- tial representations, each of which can support performance on a previously learned maze. In their view, the hippocampus is essential to the storage of a true map-like representation, while the cortex can store 'vector-field' representations that are impoverished compared to the hippocampal map, but nonetheless sufficient to perform a previously learned maze task. What is particularly appealing about this notion is that it fits rather well the data recently obtained in a human patient with extensive hippocampal damage (Rosenbaum et al., 1999 cited in Moscovitch et al., 1999).This patient demonstrated considerably preserved remote spatial memory, but was not normal when looked at in careful detail. This finding parallels what has been observed with remote autobiographical memory, as noted above: apparently normal performance has been shown to be deficient when more precise tests measuring memory in finer detail are employed. In summary, the work with animals generally confirms the impressions obtained in work with humans. Retrograde amnesia can cover very long time periods, depending on the nature of the task and the extent and location of the lesion. Damage within the hippocampal complex, if sufficiently extensive, can yield flat RA gradients when spatial tasks are used, or graded RA that upon closer examination reveals subtle defects even at retention intervals where performance can appear normal by some measures; damage in areas of neocortex can yield flat gradients in other kinds of tasks. Although results to date do not allow firm conclusions, they converge with the human data in suggesting that the standard model of memory consolidation has potentially serious shortcomings. Models of memory consolidation and the temporal lobe In an excellent, extensive review of retrograde amnesia that includes neurological and psychological causes, Kapur (in press) concludes by proposing three main factors, each with multiple levels, that determine the temporal extent, severity, and type Ch. 10 7: Fujii, M. Moscovitch and L. Nadel of retrograde amnesia. Those factors are the initial strength of the experience, lesion characteristics, and retention testing. Although we agree with Kapur's more parametric analysis that each of these factors is important, we would like to take a more theoretical approach in this last section and speculate about the neural mechanisms that can support normal remote memory when they are intact and give rise to the different types of retrograde amnesia when they are damaged. In light of the data we reviewed, we evaluate two models, the standard consolidation model and the multiple trace theory (MTT), and propose that a modified version of the latter can accommodate most of the available evidence. The standard model According to what we have termed the standard model, memory consolidation begins when information, initially registered by the neocortex, is bound into a cohesive memory trace by the hippocampus and related structures in the medial temporal lobes and diencephalon. In the early stage, the hippocampus and related structures are needed for the storage and retrieval of the memory trace, but their contribution is diminished as the consolidation process proceeds, until the neocortex alone can maintain the memory trace and mediate its retrieval. Long-term declarative memory results from continuous, gradual strengthening of neural connections in the neocortex that were formed initially (but very weakly) at encoding. Thus, the medial temporal lobes play a time-limited role in memory until long-term consolidation is complete and a permanent memory is established in the neocortex (Squire and Zola-Morgan, 1991; Squire, 1992; Alvarez and Squire, 1994; Squire and Alvarez, 1995). Relatively brief RA for declarative memory supports this standard model of consolidation, by showing that the hippocampal complex can play a temporary role in memory storage and retrieval. The data on humans singles out the hippocampus proper for this role. Once damage extends beyond the hippocampus proper, this model, however, has considerable difficulty explaining the temporally limited, yet extensive RA for declarative memory that occurs even if damage is limited to the bilateral hippocampal complex, unless it assumes that consolidation processes continue over many decades. Furthermore, for the standard model to succeed, it must posit that tight connections are formed among memory fragments corresponding to perceptual aspects of the initial event, and coded by distinct, geographically separate modality- and category-specific association areas. From what we know of the anatomy of these domain-specific regions, binding them into a cohesive network without recourse to regions outside these areas, such as the hippocampal complex, is unlikely to occur. Moreover, to contribute a true autobiographical memory, the information in the network needs to be constrained by specific temporal and spatial contexts. Indeed, explaining the latter, context-specific retrieval of remote memories demands not only that dispersed memory fragments be bound together, but that contextual codes previously formed within hippocampal regions somehow be reconstructed outside this system. Finally, because the standard model as articulated by Squire and colleagues refers to 'declarative memory' as a whole, it cannot explain dissociations within RA among different types of 'declarative' memory after damage to medial temporal lobe structures. Nadel and Moscovitch (1997) proposed an alternative to the standard consolidation theory, which they called the multiple-trace theory of memory (MTT) (see also Moscovitch and Nadel, 1998; Nadel and Moscovitch, 1998; Moscovitch and Nadel, 1999). MTT focused on RA for autobiographical episodes following hippocampal complex lesions. Initially, the MTT was formulated to account for the various temporal gradients and extent of RA that had been reported for patients with such lesions. Little attempt was made to deal with cases in which damage occurred to regions of the temporal lobe other than the hippocampal complex (but see Moscovitch and Nadel (1999) for application of MTT to semantic dementia, a degenerative dis- order that spares the hippocampal complex, but damages the lateral surface of the temporal lobes, particularly the superior temporal gyrus). Nor was MTT formulated to deal with RA for other types of information, such as knowledge of public events and personalities or of personal (autobiographical) semantics, though it was suggested how MTT could accommodate such evidence (Nadel and Moscovitch, 1997, pp. 223-224). By and large, the MTT accounts well for the additional evidence gathered in this review, though some modifications may be necessary to address the following three issues more fully. (1) The different effects that subregions of the hippocampal complex and other areas of the anterior temporal lobe have on RA. As we noted, iesions confined to the hippocampus proper, and restricted even to the CAI region, produce a temporally limited RA as compared to the far more temporally extensive RA once lesions include other parts of the hippocampal complex. (2) The dissociation between anterograde and retrograde amnesia, particularly the dramatic effects observed following bilateral lesions to the temporal pole in which extensive RA co-exists with relatively mild AA. (3) The differences in RA for autobiographical episodes as compared to knowledge of public events and personalities, and autobiographical semantics. We first present the MTT as it was most recently formulated and then consider what modifications, if any, might be necessary in light of the evidence gathered in this review. The multiple trace theory (1) According to MTT, the hippocampal complex (and related diencephalic structures) rapidly and obligatorily encodes all information that is attended or consciously apprehended (Moscovitch, 1995; Nadel and Moscovitch, 1997; Fukatsu et al., 1998). The process entails the formation of a code embodied in a sparse and distributed set of hippocampal complex neurons which bind neurons in unimodal and heteromodal association areas that represent the attended information (Teyler and DiScenna, 1986; McLelland et al., 1995; Moscovitch, 1995; Squire and Alvarez, 1995; Nadel and Moscovitch, 1997; Mesulam, 1998). These areas are usually considered to be in posterior neocortex, but can also include other regions, such as the amygdala, in the medial temporal lobe, which contribute to emotional aspects of the conscious experience. We should be clear that the hippocampal complex codes are not necessary for mediating the conscious experience of the event while it is occurring, but are needed instead for the rapid creation of memory traces of the experience and for later retrieval of those traces. We refer to this rapid binding process as short-term consolidation or cohesion and believe it is hippocampally dependent, probably with little engagement of basal forebrain structures (Fukatsu et al., 1998). (2) These codes, which bind fragments of information that occurred more or less simultaneously and in the same spatial context, are initially laid down and stored in distributed ensembles of neurons in the hippocampal complex. They correspond to Conway's (1993, this volume) phenomenological records, each of which can be considered a near sensory record of a 'scene' in a temporally extended episode event. During any single episode, several such codes or phenomenological records are created and stored. (3) The entire ensemble of binding codes in the hippocampal complex, and fragments of information in association areas, constitutes the memory trace for a specific episode (e.g. dinner with X on the last night of a conference in Arcachon). (4) The binding codes in the hippocampus act as a pointer or index to neurons in association cortex (and elsewhere) that represent the attended information which forms the content of the memory trace. It is via these codes that autobiographical episodes are retrieved. (5) After initial encoding, each reactivation of these memory traces during retrieval may occur in an altered neuronal and experiential context. Because the extended hippocampal encoding system automatically creates codes binding information that is attended, the reactivation of pre-existing memory traces results in the creation of new codes in the hippocampal complex which are also sparse and distributed. (6) In the course of time, autobiographical episodes will either have been lost, or if reactivation occurs, will have benefited from the formation of multiple traces in the hippocampal complex and links between it and association areas. The older the memory, the greater the number of codes in the hippocampal complex and of links to association cortex. In contrast to the standard model, MTT postulates no long-term consolidation process which slowly strengthens neural connections in geographically separate modality- and category-specific association areas, with a resulting shift of storage from the hippocampal complex to neocortex. Instead, this model proposes that the maintenance and reconstruction of memory for autobiographical episodes involves the continued participation of posterior association cortices and hippocampal complex. Thus, remembering of autobiographical episodes is achieved by means of activating via the hippocampal complex many independent, geographically separate, but interconnected memory traces in various brain regions. Evaluation of MTT This MTT is consistent with much of the evidence in this review. The extent of RA and the shape of the gradient varies according to the size of the lesion to the hippocampal complex. When lesions are confined to the hippocampus proper, RA is very short. As more regions of the hippocampal complex are damaged, RA for autobiographical episodes extends further in time, encompassing the entire life in those cases where lesions cover the entire complex. The temporal gradient, too, would appear to be flatter with more extensive damage, but the evidence is too poor to permit a firm conclusion on this matter. In general, the model also accounts for differences in RA among different types of memory. According to our prediction, 'differences in the extent of RA would also be determined by the complexity or richness of the trace that is to be recovered. Because the full details of an autobiographical episode are not likely to be re-activated often, these details would be most vulnerable to disruption. On the other hand, the gist of an episode, partial information about it, or facts about one's personal life - those things that constitute personal semantic memory [autobiographical semantics] - are more likely to be reactivated and hence would be multiply represented. The same would be true of semantic memory for public events and personalities, as for personal semantic memories, ... unless extremely detailed information about semantic memory were required (Moscovitch and Melo, 1997)' (Nadel and Moscovitch, 1997, pp. 23-24). The relative preservation of autobiographical semantics and knowledge of public events and personalities, in comparison to autobiographical episodes, is consistent with these predictions. Despite the general agreement between the evidence reviewed in this chapter and the MTT, there are some unexpected observations and some apparent discrepancies which need to be examined more closely. Efects of lesions to dzferent regions ofthe hippocampal complex As we noted earlier, lesions confined to the hippocampus proper, or restricted even to the CAI fields, produce a very temporally limited RA with moderate AA. A possible interpretation of this finding is that the hippocampus proper is crucial only for short-term consolidation or cohesion, but not for storage or retrieval, more in keeping with the role assigned to it by the standard consolidation model than by MTT. To reconcile MTT with this interpretation, the theory would have to be modified to state that the hippocampus proper contributes to the formation of the binding codes but that the codes themselves are mediated by neurons in other parts of the hippocampal complex. There are, however, alternative interpretations of the effects of restricted, hippocampal lesions. Except for a study by Reed and Squire (1998), the evidence is based on tests of remote memory that are not particularly sensitive to the richness of the memory that is recovered. In most of those tests, between 0 and 3 points are awarded for each episode that is recalled with the maximum allotted if the time and place of the event is stated and some detail is provided. In short, the tests may assess one's memory of the gist of an event. Even Reed and Squire, who evaluated the quality of the memory in terms of various categories, relied on the subjective impressions of the examiners. New tests that emphasize the number of details that are recovered have shown that RA is extensive even in amnesic people who displayed minimal RA when assessed using more traditional tests (Moscovitch, 1997; Moscovitch et al., 1999). Until people with lesions restricted to the hippocampus are submitted to tests that are scored in terms of total details, one cannot discount the possibility that the hippocampus proper may be needed not only for cohesion, but also for storage and recovery of phenomenological records, the detailed near-sensory content of memory for autobiographical episodes. As predicted by MTT, memory for the gist of an episode can survive such small lesions1 Correspondence between human and animal studies Because lesions confined to a single region of hippocampal complex rarely occur in people, our knowledge of the function each of these regions depended, until recently, primarily on animal models and, to a lesser extent, on extrapolation from studies in humans in which lesions to a particular area were included in a larger area of damage. More recently, functional neuroimaging techniques have allowed investigators to focus on these small regions of interest. The difficulty in comparing animal with human ' An intriguing possibility is that memory for gist, the abstracted essence of an episode, may be encoded separately from the details. Whereas phenomenological records are encoded and stored by the hippocampus, gist may be encoded and stored in other regions of the complex (see below) studies is that the categories used to investigate human memory, such as autobiographical episodes and semantics, and knowledge of public events and persons, have no natural counterpart in animals. Instead, animal studies deal with categories related to specific domains of information such as space, objects, and their interaction. Even so, studies of remote memory loss after lesions to various medial temporal lobe subregions in animal models are few in number. As we noted, the results could be summarized as follows: complete lesions in an area specialized for acquisition of domain-specific information typically leads to extensive RA for that information. The findings from animal studies, however, do not always correspond exactly to those suggested by the literature in humans when similar tests are administered. Thus, hippocampal damage in rats is associated with extensive RA for allocentric spatial memory. Humans with large lesions to the hippocampus and adjacent cortex, however, retain remote allocentric spatial memories or cognitive maps of large-scale natural environments, such as a neighborhood or a house (Rosenbaum et al., 1999). Retrograde topographical amnesia in humans is often associated, instead, with parahippocampal, parietal, or posterior cingulate lesions (Aguirre and D'Esposito 1999, De Renzi, 1982). While the recent work of Kubie et al. (1999) offers a possible rapprochement, more work is needed to determine if there has been some shift in the responsibility of different regions within the medial temporal lobe with regard to the storage of longterm spatial information. There is as yet no human counterpart to loss of remote memory for objects following perirhinal lesions in rats and monkeys. Although object agnosia is a possible candidate, it is a fundamentally different disorder produced by lesions to inferotemporal, rather than perirhinal, cortex. The imperfect correspondence between animal and human studies of remote memory following lesions to subregions of the medial temporal lobe stands in contrast to the excellent correspondence in studies of anterograde memory. Probably the main reasons for the discrepancy are that the study knowledge, whether autobiographical or general. Vargha-Khedem et al. (1997) demonstrated that acquisition, maintenance, and retrieval of semantic information is relatively spared in peoplc with neonatal lesions to the hippocampal formation despite their severely impaired episodic memory. Nonetheless, other reports (Ostergaard, 1987; Broman et al., 1997; DeLong and Heinz, 1997) suggest that acquisition may not be as rapid or knowledge may not be as detailed, especially for semantic knowledge acquired in adulthood. Limitations of the MTT MTT was not intended to be an all-encompassing theory of memory. It was devised to address what we believed were the shortcomings of traditional consolidation theory, and to offer an alternative explanation of RA after medial temporal lobe lesions. As a theory of memory, and even of RA observed after damage to other structures, MTT is incomplete. It needs to be supplemented by consideration of how the medial temporal lobes interact with other structures, such as the prefrontal cortex, which clearly play an important role in episodic memory, self, and consciousness in humans and possibly in non-human species. We noted briefly what the nature of those interactions might be (see Nadel and Moscovitch, 1997, 1998; Moscovitch and Nadel, 1998) and we refer the interested reader to more recent work on this topic (Moscovitch, 1992, 1995, 1999; Wheeler et al., 1997; Conway and Fthenaki, this volume). Even within its own frame of reference, the MTT provides at best a sketchy account of the function of the various components of the hippocampal complex, with respect to episodic memory. A fuller account will emerge when one can isolate these components in humans, hopefully with the aid of functional neuroimaging studies, and apply the lessons learned from animal models. Summary The evidence reviewed in this paper challenges tra- ditional consolidation theory which states that the hippocampal complex or medial temporal lobes play a time-limited role in memory, being needed for storage and recovery of memories only until they are fully consolidated in other structures. The review of the literature showed that bilateral lesions to the medial temporal lobes that include other regions in addition to the hippocampus produce extensive RA, the severity and length of which increases as more regions are implicated, often leading to a RA that covers an individual's entire life. In humans, RA is most severe for autobiographical episodes, but is also substantial for knowledge of public figures and events. When damage is limited to the hippocampus proper in humans, the period of RA is very short, though it may be shown to extend further if more sensitive tests were used. In animals, as in humans, RA can be extensive with temporal gradients of varying degree, but the type of memory that is affected depends on the region of the hippocampal complex that is damaged. This evidence reviewed in this chapter is consistent with a multiple trace theory of memory. According to that theory, the episodic memory trace consists of an ensemble of neurons in the hippocampal complex cohesively bound to neurons in the neocortex (and elsewhere) which mediate a consciously experienced event. Binding of the elements occurs during a short-term consolidation period typically lasting seconds or minutes, but no more than a few days. The evidence suggests, but is not conclusive, that the hippocampus proper may be needed for short-term consolidation, after which the trace depends on extra hippocampal neurons in the hippocampal complex. There is no need to postulate a long-term consolidation process that strengthens existing memory traces outside the hippocampal complex. Instead, as memory traces are reactivated over time, multiple related traces are formed in the hippocampal complex and dispersed over wider areas of the system. Hippocampal complex neurons, however, remain an integral part of the memory trace as long as it exists. As a result, damage to the hippocampal complex always produces a retrograde amnesia, but more extensive lesions are required to eradicate more remote memories. By virtue of its postulates, MTT provides a good account of the pattern of RA following temporal lobe damage. As such, it can form the core of a more complete theory of episodic memory that will take its hierarchical structure and temporal sequencing into account. References Agguirre GK, D'Esposito M: 1999 Alexander MP: Specific semantic memory loss after hypoxic-ischemic injury. Neurology: 48, 165-173, 1997. Alvarez P, Squire LR: Memory consolidation and the medial temporal lobe: A simple network model. Proc. Natl. Acad. Sci. USA: 91,7041-7045, 1994. Anagnostaras SG, Maren S, Fanselow MS: Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. J. Neurosci.: 19, 1106-1 114, 1999. Beatty WW, Salmon DP, Bernstein N, Butters N: Remote memory in a patient with amnesia due to hypoxia. Psychol. Med.: 17,657665, 1987. Bolhuis JJ, Stewart CA, Forrest EM: Retrograde amnesia and memory reactivation in rats with ibotenate lesions to the hippocampus or subiculum. Q. % Exp. Psychol.: 47B, 129-150, 1994. Broman M, Rose AL, Hotson G, Casey CM: Severe anterograde amnesia with onset in childhood as a result of anoxic encephalopathy. Brain: 120,417433, 1997. Burnham WH: Retroactive amnesia: illustrative cases and a tentative explanation. Am. J. Psychol.: 14, 1 18-1 32, 1903. Butters N, Cermak LS: A case study of forgetting of autobiographical knowledge: Implication for the study of retrograde amnesia. In: Rubin D (Editor), Autobiographical Memory. New York: Cambridge University Press, pp. 253-272, 1986. Calabrese P, Markowitsch HJ, Durwen HF, Widlitzek H, Haupts M, Holinka B, Gehlen W: Right temporofrontal cortex as critical locus for the ecphory of old episodic memories. J. Neurol. Neurosurg. Psychiatry: 61, 3 0 4 3 10, 1996. Carlesimo GA, Sabbadini M, Loasses A, Caltagirone C: Analysis of the memory impairment in a post-encephalitic patient with focal retrograde amnesia. Cortex: 34,449-460, 1998. Cermak LS, O'Connor M: The anterograde and retrograde retrieval ability of a patient with amnesia due to encephalitis. Neuropsychologia: 21,213-234, 1983. Cho YH, Kesner RP: Involvement of entorhinal cortex or parietal cortex in long-term spatial discrimination memory in rats: retrograde amnesia. Behav. Neurosci.: 110, 4 3 H 4 2 , 1996. Cho YH, Berawchea D, Jaffard R: Extended temporal gradient for the retrograde and anterograde amnesia produced by ibotenate entorhinal wrtex lesions in mice. J. Neurosci.: 13, 1759-1766, 1993. Cho YH, Kesner RP, Brodale S: Retrograde and anterograde amnesia for spatial discrimination in rats: role of hippocampus, entorhinal cortex, and parietal cortex. Psychobiology: 23, 185-194, 1995. Conway MA: Impairments of autobiographical memory. In: Boller F, Grafman J (Editors), Handbook of Neuropsychology, Amsterdam, Elsevier, Vol. 8. pp. 175-191, 1993. Corkin S: Lasting consequences of bilateral medial temporal lobectomy: clinical course and experimental findings in H.M. Semin. Neurol.: 4,249-259, 1984. Corkin S, Amaral DG, Gonzalez RG, Johnson KA, Hyman BT: H.M.'s medial temporal lobe lesion: finding from magnetic resonance imaging. J. Neurosci.: 17,39643979, 1997. Crovitz HF, Schifmann H: Frequency ofepisodic memories as a function of their age. Bull. Psychonom. Soc.: 4,5 17-6 18, 1974. Cummings JL, Tomiyasu U, Read S, Benson F: Amnesia with hippocampal lesions after cardiopulmonary arrest. Neurology: 34,679-68 1, 1984. Dalla Barba G, Cipolotti L, Denes G: Autobiographical memory loss and confabulation in Korsakoffs syndrome: a case report. Cortex: 26, 525-534, 1990. Damasio AR: Time-locked multiregional retroactivation: a systems-level proposal for the neural substrates of recall and recognition. cognition: 33,2542, 1989. Damasio AR, Eslinger PJ, Damasio H, Van Hoesen GW: Multimodal amnesic syndrome following bilateral temporal and basal forebrain damage. Arch. Neurol.: 42,252-259, 1985a. Damasio AR, Graff-Radford NR, Eslinger PJ, Damasio H, Kassell N: Amnesia following basal forebrain lesions. Arch. Neurol.: 42,263-271, 1985b. Damasio H, Grabowski TJ, Tranel D, Hichwa RD, Damasio AR: A neural basis for lexical retrieval. Nature: 380, 499-505, 1996. De Renzi E, Liotti M, Nichelli P: Semantic amnesia with preservation of autobiographic memory. A case report. Cortex: 23, 575-597, 1987. De Renzi E, Lucchelli F, Muggia S, Spinnler H: Is memory loss without anatomical damage tantamount to a psychogenic deficit? The case of pure retrograde amnesia. Neuropsychologia: 35,78 1-794,1997. DeLong GR, Heinz ER: The clinical syndrome of early-life bilateral hippocampal sclerosis. Ann. Neurol.: 42, 11-17, 1997. Duyckaerts C , Derouesne C, Signoret JL, Gray F, Escourolle R, Castaigne P: Bilateral and limited amygdalohippocampal lesions causing a pure amnestic syndrome. Ann. Neurol.: 18, 314319, 1985. Ellis AW, Young AW, Critchley EMR: Loss of memory for people following temporal lobe damage. Brain: 112, 1469-1483, 1989. Eslinger PJ: Autobiographical memory after temporal lobe lesions. Neurocase: 4,481495, 1998. Eslinger PJ, Easton A, Grattan LM, van Hoesen GW: Distinctive forms of partial retrograde amnesia after asymmetric temporal lobe lesions: possible role of the occipitotemporal gyri in memory. Cerebral cortex: 6,530-539, 1996. Evans JJ, Heggs AJ, Antoun N, Hodges JR: Progressive proso- Ch. 10 1: Ftljii, M. Moscovitch and L. Nadel pagnosia associated with selective right temporal lobe atrophy. Brain: 118, 1-13, 1995. Evans JJ, Breen EK, Antoun N, Hodges JR: Focal retrograde amnesia for autobiographical events following cerebral vasculitis: a connectionist account. Neurocase: 2, 1-1 1, 1996. Fujii T,Yamadori A, Endo K, Suzuki K, Fukatsu R: Disproportionate retrograde amnesia in a patient with herpes simplex encephalitis. Cortex: 35, 599-614, 1999. Fukatsu R, Yamadori A, Fujii T: Impaired recall and preserved encoding in prominent amnesic syndrome: a case of basal forebrain amnesia. Neurology: 50, 539-541, 1998. Fukatsu R, Fujii T, Tsukiura T, Yamadori A, Otsuki T: Proper name anomia after left temporal lobectomy: a patient study. Neurology: 52, 1096-1099, 1999. Gaffan: 1974. Gaffan D: Additive effects of forgetting and fornix transaction in the temporal gradient of retrograde amnesia. Neuropsychologia: 31, 1055-1066, 1993. Glickman SE: Perseverative neural processes and consolidation of the memory trace. Psychol. Bull.: 58,218-233, 1961. Grafman: 1989. Grossi D, Trojano L, Grasso A, Orsini A: Selective 'semantic amnesia' after closed-head injury. A case report. Cortex: 24, 457-464, 1988. Hirano M, Noguchi K: Dissociation between specific personal episodes and other aspects of remote memory in a patient with hippocampal amnesia. Percept. Motor Skills: 87, 99-107, 1998. Hirsh: 1974. Hodges JR, McCarthy RA: Autobiographical amnesia resulting from bilateral paramedian thalamic infarction. A case study in cognitive neurobiology. Brain: 116,921-940, 1993. Hodges JR, McCarthy RA: Loss of remote memory: a cognitive neuropsychological perspective. Curr. Opin. Neurobiol.: 5, 178-183, 1995. Hodges JR, Patterson K, Tyler LK: Loss of semantic memory: implication for the modularity of mind. Cogn. Neuropsychol.: 11,505-542, 1994. Kapur N, Brooks DJ: Temporally-specific retrogade amnesia in two cases of discrete bilateral hippocampal pathology. Hippocampus: 9,247-254,1999. Kapur N: Focal retrograde amnesia in neurological disease: a critical review. Cortex: 29, 2 17-234, 1993. Kapur N: Syndromes of retrograde amnesia. Psychol. Bull.: (in press). Kapur N, Brooks DJ: Temporally-specificretrograde amnesia in two cases of discrete bilateral hippocampal pathology. Hippocampus: 9,247-254, 1999. Kapur N et al.: 1999. Kapur N, Ellison D, Smith MP, McLellan DL, Burrows EH: Focal retrograde amnesia following bilateral temporal lobe pathology. Brain: 115,73-85, 1992. Kapur N, Young A, Bateman D, Kennedy P: Focal retrograde amnesia: A long-term clinical and neuropsychological follow-up. Cortex: 25,387-402, 1989. Kapur N, Ellison D, Parkin AJ: Bilateral temporal lobe pathology with sparing of medial temporal lobe structures: lesion profile and pattern of memory disorder. Neuropsychologia: 32,23-38, 1994. Kapur N, Scholey K, Moore E, Barker S, Brice J, Thompson S: Long-term retention deficit in two cases of disproportionate retrograde amnesia. J. Cogn. Neurosci.: 8,416-434, 1996. Kapur N, Thompson P, Kartsounis LD, Abbott P: Retrograde amnesia: clinical and methodological caveats. Neuropsychologia: 37,27-30, 1999. Kartsounis LD, Rudge P, Stevens JM: Bilateral lesion of CAI-CA2 fields of the hippocampus are sufficient to cause a severe amnesic syndrome in humans. J. Neurol. Neurosurg. Psychiatry: 59,95-98, 1995. Kim JJ, Fanselow MS: Modality-specific retrograde amnesia of fear. Science: 256,675-677, 1992. Kim JJ, Clark RE, Thompson RF: Hippocampectomy impairs the memory of recently, but not remotely, acquired trace eyeblink conditioned responses. Behav. Neurosci.: 109, 195-203, 1995. Kopelman MD, Wilson BA, Baddeley AD: The Autobiographical Memory Interview. Bury St Edmunds: Thames Valley Test Company, 1990. Kroll NEA, Markowitsch HJ, Knight RT, von Cramon DY: Retrieval ofold memories: the temporofrontal hypothesis. Brain: 120, 1377-1399,1997. Kubie JL, Sutherland RJ, Muller RU: Hippocampal lesions produce a temporally graded retrograde amnesia on a dry version of the Morris swimming task. Psychobiology: 27, 313-330, 1999. Land et al.: 1998. Levine B, Black SE, Cabeza R, Sinden M, McIntosh AR, Toth JP, Tulving E, Stuss DT: Episodic memory and the self in a case of isolated retrograde amnesia. Brain: 121, 1951-1973, 1998. Levine B, Black SE, Cabeza R, Sinden M, Mcintosh AR, Toth JP, Tulving E, Stuss DT: Episodic memory and the self in a case of isolated retrogade amnesia. Brain: 121, 1951-1973, 1998. MacKinnon DF, Squire LR: Autobiographical memory and amnesia. Psychobiology: 17,247-256, 1989. Maguire EA, Mummery CJ: Differential modolation of a common memory retrieval network revealed by positron emission tomography. Hippocampus: 9 , 5 4 4 1, 1999. Maren S, Aharanov G, Fanselow MS: Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav. Brain Res.: 88, 261-274, 1997. Markowitsch HJ: Anatomical basis of memory disorders. In: Gazzaniga MS (Editor), The Cognitive Neurosciences. Cambridge, MA: MIT press, pp. 765-779, 1995. Markowitsch HJ, Calabrese P, Liess J, Haupts M, Durwen HF, Gehlen W: Retrograde amnesia after traumatic injury of the fronto-temporal cortex. J. Neurol. Neurosurg. Psychiatry: 56, 988-992, 1993. Markowitsch HJ, Calabrese P, Neufeld H, Gehlen W, Durwen HF: Retrograde amnesia for world knowledge and preserved memory for autobiographical events. A case report. Cortex: 35,243-252, 1999. McCarthy RA, Warrington EK: Actors but not scripts: The dis- Mrn7or.j. consoli~fation, retrogruck. nn?nesia, ~ ~ the n dtrn?poral lobe sociation of people and events in retrograde amnesia. Neuropsychologia: 30,633-644, 1992. McCarthy RA, Evans JJ, Hodges JR: Topographic amnesia: spatial memory disorder, perceptual dysfunction, or category specific semantic memory impairment? J. Neurol. Neurosurg. Psychiatry: 60, 3 18-325, 1996. McClelland JL, McNaughton BL, O'Reilly RC: Why there are complementary learning systems in the hippocampus and neocortcx: Insights from the successes and failures of connectionist models of learning and memory. Psychol. Rev.: 102, 419-457, 1995. Mesulam M-M: From sensation to cognition. Brain: 121, 1013-1052, 1998. Moscovitch M: 1992. Moscovitch M: Recovered consciousness: a hypothesis concerning modurality and episodic memory. J. Clin. Exp. NeuropsychoL: 17,276290, 1995. Moscovitch M: Theories of memory and consciousness. In E. Tulving, F.I.M. Craik (Editors), The Oxford Handbook of Memory. Oxford: Oxford University Press, 1999. Moscovitch M, Melo B: Strategic retrieval and the frontal lobes: evidence from confabulation and amnesia. Neuropsychologia: 35, 1017-1034, 1997. Moscovitch M, Nadel L: Consolidation and the hippocampal complex revisited: in defence of the multiple-trace model. Curr. Opin. Neurobiol.: 8,297-300, 1998. Moscovitch M, Nadel L: Multiple-trace theory and semantic dementia: response to K.S. Graham (1999). Trends Cogn. Sci.: 3,87-90, 1999. Moscovitch M, Yaschyshyn T, Ziegler M, Nadel L: Remote episodic memory and retrograde amnesia: Was Endel Tulving right all along? In E. Tulving (Editor), Memory Consciousness and the Brain: and The Tallinn Conference. Philadelphia, PA: Taylor and Francis., 1999. Miiller GE, Pilzecker A: Experimentelle beitrage zur lehre vom gedachtniss. Z. Psychol.: Suppl. 1,388-394, 1900. Murray EA, Bussey TJ: Consolidation and the medial temporal lobe revisited. Hippocampu.r (in press). Murre JMJ: Implicit and explicit memory in amnesia: some explanations and predictions by the tracelink model. Memory: 5,213-232, 1997. Nadel L, Moscovitch M: Memory consolidation, retrograde amnesia and the hippocampal complex. Curr. Opin. Neurobiol.: 7,217-227, 1997. Nadel L, Moscovitch M: Hippocampal contributions to cortical plasticity. Neuropharmacology: 37,43 1-439, 1998. Nadel and O'Keefe: 1974. O'Connor M, Butters N, Miliotis P, Eslinger P, Cermak LS: The dissociation of anterograde and retrograde amnesia in a patient with herpes encephalitis. J. Clin. Exp. Neuropsychol.: 14, 159-178, 1992. O'Connor M, Verfaellie M, Cermak LS:Clinical differentiation of amnesic subtypes. In: Baddeley AD, Wilson BA, Watts FN (Editors), Handbook of Memory Disorders. Chichester: John Wiley and Sons, pp. 53-80, 1995. O'Connor MG, Cermak LS, Seidman LJ: Social and emotional characteristics of a profoundly amnesic postencephalitic pa- Clz. 10 tient. In: Campbell R, Conway MA (Editors), Broken Memories: Case Studies in Memory Impairment. Oxford: Blackwell, pp. 45-53, 1995. Ostergaard AL: Episodic, semantic and procedural memory in a case of amnesia at an early age. Neuropsychologia: 25, 341-357, 1987. Oxbury S, Oxbury J, Rcnowden S, Squier W, Carpenter K: Severe amnesia: An unusual late complication after temporal lobectomy. Neuropsychologia: 35,975-988, 1997. Reed JM, Squire LR: Retrograde amnesia for facts and events: Finding from four new cases. J. Neurosci.: 18, 3943-3954, 1998. Rempel-Clower NL, Zola SM, Squire LR, Amaral DG: Three cases of enduring memory impairment after bilateral damage limited to the hippocampal formation. J. Neurosci.: 16, 5233-5255, 1996. Rosenbaum S, Priselac S, Moscovitch M: Remote spatial memory in an amnesic person with extensive bilateral hippocampal lesions. Soc. Neurosci Absrr.: 1999. Ross SJM, Hodges JR: Preservation of famous person knowledge in a patient with severe post anoxic amnesia. Cortex: 33,733-742, 1997. Salmon et al.: 1985. Salmon DP, Lasker BR, Butters N, Beatty WW: Remote memory in a patient with circumscribed amnesia. Brain Cognition: 7,201-21 1, 1988. Schnider A, Regard M, Landis T: Anterograde and retrograde amnesia following bitemporal infarction. Behav. Neurol.: 7, 87-92, 1994. Schnider A, Bassetti C, Gurbrod K, Ozdoba C: Very severe amnesia with acute onset after isolated hippocampal damage due to systemic lupus erythematosis. J. Neurol. Neurosurg. Psychiatry: 59, 644-646, 1995. Scoville WB, Milner B: Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry: 20, 11-21, 1957. Sirigu A, Grafman J: Selective impairments within episodic memories. Cortex: 32, 83-95, 1996. Squire LR: Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol. Rev.: 99, 195-231, 1992. Squire LR, Alvarez P: Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr. Opin. Neurobiol.: 5, 169-1 77, 1995. Squire LR, Zola-Morgan S: The medial temporal lobe memory system. Science: 253, 1380-1386, 1991. Teyler TJ, DiScenna P: The hippocampal memory indexing theory. Behav. Neurosci.: 100, 147-1 54, 1986. Thornton JA, Rothblat LA, Murray EA: Rhinal cortex removal produces amnesia for preoperatively learned discrimination problems but fails to disrupt postoperative acquisition and retention in rhesus monkeys. J. Neurosci: 17,85368549, 1997. Tranel D, Damasio AR: Neurobiological foundations of human memory. In: Baddeley AD, Wilson BA, Watts FN (Editors), Handbook of Memory Disorders. Chichester: John Wiley and Sons, pp. 27-50, 1995. Tulving E, Schacter DL, McLachlan D, Moscovitch M: Priming of semantic autobiographical knowledge: a case study of retrograde amnesia. Brain Cogn.: 8, 3-20, 1988. Tulving E, Hayman CAG, Macdonald CA: Long-lasting perceptual priming and semantic learning in amnesia: a case experiment. J. Exp. Psychol. Learn. Memory Cogn.: 17, 595417, 1991. Van der Linden M, Bredart S, Depoortcr N, Coyette F: Semantic memory and amnesia: a case study. Cogn. Neuropsychol.: 13,391413, 1996. Vargha-Khadem F, Gadian DG, Watkins KE, et al.: Differential effects of early hippocampal pathology on episodic and semantic memory. Science: 277, 376-380, 1997. Venneri A, Caffarra P: Transient autobiographic amnesia. EEG and single-photon emission CT evidence of an organic etiology. Neurology: 50,186-1 9 1,1998. Verfaellie M, Reiss L, Roth HL: Knowledge of new English vocabulary in amnesia: an examination of premorbidly acquired semantic memory. J. Int. Neuropsychol. Soc.: I , 443453, 1995. Victor M, Agamanolis D: Amnesia due to lesions confined to the hippocampus: a clinical-pathologic study. J. Cogn.. Neurosci,: 2, 246-257, 1990. Viskontas I, McAndrews MP, and Moscovitch M. (1999): Remote episodic memory deficits in patients with unilateral temporal lobe epilepsy and excisions. Submitted for publication. Warrington James MK: 1967. Warrington EK: The selective impairment of semantic memory. Q. J. Exp. Psychol.: 27,635457, 1975. Warrington EK, Duchen LW: A re-appraisal of a case of persistent global amnesia following right temporal lobectomy: a clinico-pathological study. Neuropsychologia: 30, 437-50, 1992. Warrington EK, McCarthy RA: The fractionation of retrograde amnesia. Brain Cogn.: 7, 184-200, 1988. Wheeler MA, Stuss DT, Tulving E: Toward a theory of episodic memory: The frontal lobes and autonoetic consciousness. Psychological Bulletin: 121.33 1-354, 1997. Wiig KA, Cooper LN, Bear MF: Temporally graded retrograde amnesia following separatc and combined lesions of the perirhinal cortex and fornix in the rat. Learn. Memory: 3, 31 3-325, 1996. Winocur G: Anterograde and retrograde amnesia in rats with dorsal hippocampal or dorsomedial thalamic lesions. Behav. Brain Res. 38, 145-1 54, 1990. Woods RT, Schoene W, Kneisley L: Are hippocampal lesions sufficient to cause lasting amnesia? J. Neurol. Neurosurg. Psychiatry: 45, 243-247, 1982. Yamadori A, Yoneda Y, Mori E, Yamashita H, Fujii T: Further fractionation of human memory? A problem of retrograde amnesia. In Ono T, McNaughton BL, Molotchnikoff S, Rolls ET, Nishijo H (Editors), Perception, Memory and Emotion: Frontier in Neuroscience. Oxford: Pergamon Press, pp. 137-143, 1996. Yamadori A,Yoneda Y,Yamashita H, Sugiura K: A patient with difficulty of object recognition: semantic amnesia for manipulable objects. Behav. Neurol. 5, 183-187, 1992. Yasuda K, Watanabe 0, Ono Y Dissociation between semantic and autobiographical memory: a case report. Cortex: 1997. YonedaY, Mori E,Yamashita H,Yamadori A: MRI volmetry of medial temporal structures in amnesia following herpes simplex encephalitis. Eur. Neurol. 34, 243-252, 1994. Zola-Morgan S, Squire LR: The primate hippocampal formation: evidence for a time-limited role in memory storage. Science: 250,288-290, 1990. Zola-Morgan S, Squire LR, Amaral DG: Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CAI of the hippocampus. J. Neurosci.: 6, 2950-2967, 1986.