196 LARRY R.SQUIRE 1982)e othe ely amnesic (Cohen,1984 Squire Indeed,in the absence of the hippo mpus.sev nitive function were rene dly evaluated and his m pairment was d ented.The only cognitive deficit that was the tion of R.B's brain after his deathn revealed a d that the role fthe hinr in memo is time limited.Amne patients.includ campal dal extent of the hippocar asonably b SRk然2S uire,Haist,& of retro cas thus showed that to th hippocampusi ent to cause and cl mesia in the monkey (2 gan Squi 199% rage is only t rary Memory is gradually reo pp learn ng M ris initial bl duces selective neuronal loss in the ed later,bilateral CAl damage and f the Medial foun e that the at and mor ey pro ing e ntial for ncxDerimcnta memory The strongly supported b and studies of the effects of selective lesions in rats. 89 Memory-Impaired Patients The ding rats are dise ussed more fully in a later s ovided val Additional confir ation for the idea that the human hippo 1987) have been thosc where the amnesia occurs against a back Robninneiomicalinomatioanvingpgticas pocampus was developed tha permits visualization of the hir rofound forgetful pocamp det nes a)and o Until re 89).con campus were demonstr ated in 4 pati en with circu be at neur path patients being studied.S case studies attribu the mbria. damage sizel.In contrast,the area of the e temp et al1985;Victor.Ang call.6 damage in patients with a selective m nory disorde and othe truct matter on firme ound.Patient B.became the severity of H.M.s memory impairment resulted from dam 97 at the age earuyo-Morg.quire. age be structu 196 LARRY R. SQUIRE affected by hippocampal damage accumulated in demonstra￾tions of entirely intact learning and memory abilities in patients who were otherwise severely amnesic (Cohen, 1984; Squire, 1982). The important implication was that memory is not a single entity. Indeed, in the absence of the hippocampus, sev￾eral other kinds of learning can still be accomplished, includ￾ing the learning of skills and habits, simple conditioning, and the phenomenon of priming. Third, the idea is developed that the role of the hippocampus in memory is time limited. Amnesic patients, including pa￾tients with confirmed hippocampal damage, have difficulty recalling the recent past but can recall remote events as well as normal subjects (MacKinnon & Squire, 1989; Squire, Haist, & Shimamura, 1989). Recently, the significance of this observa￾tion has been illuminated by a prospective study of retrograde amnesia in the monkey (Zola-Morgan & Squire, 1990c). The findings indicate that the role of the hippocampal formation in memory storage is only temporary. Memory is gradually reor￾ganized as time passes after learning. Memory is initially de￾pendent on the hippocampus formation, but its role diminishes as a more permanent memory is gradually established else￾where, probably in neocortex. Identification of the Components of the Medial Temporal Lobe Memory System Information about which structures and connections are im￾portant for memory (and that when damaged produce amnesia) comes from three sources: studies of neurological patients with circumscribed memory impairment, systematic experimental work with an animal model of human amnesia in the monkey, and studies of the effects of selective lesions in rats. Memory-Impaired Patients Cognitive studies of memory impairment have provided valu￾able information about the organization of memory functions (Baddeley, 1982; Cermak, 1982; Milner, 1972; Schacter, 1985; Squire, 1986; Weiskrantz, 1987). The most informative cases have been those where the amnesia occurs against a back￾ground of normal intellectual function and intact immediate memory. The hallmark of the disorder is profound forgetful￾ness for new material (anterograde amnesia) and some loss of previously acquired information (retrograde amnesia). Until re￾cently, comparatively little was known about what neuropatho￾logical changes in the medial temporal lobe had occurred in the patients being studied. Several single-case studies attributed memory impairment to hippocampal damage (Cummings, Tomiyasu, Read, & Benson, 1984; DeJong, Itabashi, & Olson, 1968; Duyckaerts et al., 1985; Victor, Angevine, Mancall, & Fisher, 1961), but the assessment of memory functions ia these cases was often informal or incomplete. In addition, the dam￾age was often not restricted to the hippocampus but extended into the amygdala, the parahippocampal gyrus, and other structures. The findings from a carefully studied single case have placed the matter on firmer ground. Patient R. B. became amnesic in 1978 at the age of 52 as the result of an ischemic event that occurred following open-heart surgery (Zola-Morgan, Squire, & Amaral, 1986). Ischemia (ISC) refers to a condition during which the blood supply to the brain is insufficient. In R. B.'s case, a tear occurred in the atrium of the heart. R. B. survived for 5 years after the ischemic event, during which time his cog￾nitive functions were repeatedly evaluated and his memory im￾pairment was documented. The only cognitive deficit that was noted was moderately severe memory impairment. Examina￾tion of R. B.'s brain after his death in 1983 revealed a lesion in the CA1 region of the hippocampus (Zola-Morgan et al., 1986, Figure 1). The lesion was bilateral and extended the full rostro￾caudal extent of the hippocampus. There was some other minor pathology, but the only finding that could reasonably be associated with the amnesia was hippocampal damage. This case thus showed that damage limited to the hippocampus is sufficient to cause easily detectable and clinically significant memory impairment. Recently, another case has been reported of memory impairment associated with a bilateral lesion of the hippocampus (Victor & Agamanolis, 1990). The CA1 region of the hippocampus is especially vulnerable to ischemic damage. Thus, global ischemia in the rat also pro￾duces selective neuronal loss in the CA1 region together with memory impairment (Auer, Jensen, & Whishaw, 1989; Davis & Volpe, 1990). Also, as discussed later, bilateral CA1 damage and memory impairment can be found after global ischemia in the monkey (Zola-Morgan & Squire, 1990a; Zola-Morgan et al., in press). The findings from R. B., and the observed effects of global ischemia in the rat and monkey, provide compelling evi￾dence that the hippocampus proper is essential for mammalian memory. The same conclusion is now strongly supported by findings of memory impairment in rats following surgical dam￾age limited to the hippocampus when appropriate tasks are used (Barnes, 1988; Eichenbaum, Mathews, & Cohen, 1989; Olton et al., 1979; Sutherland & Rudy, 1989). The findings with rats are discussed more fully in a later section. Additional confirmation for the idea that the human hippo￾campus is important for memory has come from recent im￾provements in magnetic resonance (MR) imaging, which make it possible to obtain anatomical information in living patients (Figure 1). A high-resolution protocol for imaging human hip￾pocampus was developed that permits visualization of the hip￾pocampal formation in considerable detail (Press, Amaral, & Squire, 1989). Using this protocol, abnormalities in the hippo￾campus were demonstrated in 4 patients with circumscribed memory impairment (Squire, Amaral, & Press, 1990). Specifi￾cally, in the patients, the region of the hippocampus (defined as the fimbria, dentate gyrus, hippocampus proper, and subicu￾lum) appeared markedly shrunken and atrophic (57% of normal size). In contrast, the area of the temporal lobe excluding the hippocampal region was normal. Thus, the MR technique has been able to provide direct visual evidence of hippocampal damage in patients with a selective memory disorder. One important finding was that neither patient R. B. nor the 4 other amnesic patients studied with MR imaging were as severely memory impaired as the well-studied surgical patient H. M. (Scoville & Milner, 1957). This observation suggests that the severity of H. M.'s memory impairment resulted from dam￾age to medial temporal lobe structures other than or in addi￾tion to the region of the hippocampus itself. Recently, it has