MEMORY AND THE HIPPOCAMPUS 201 Zola-Morgan et al 1989a).The finding that Ha*lesi plex but spared adiacent cortex (the a lesion).Monkeys with the A lesion performed normally on four tasks(delaye rrent diser sample. ed res e (Zola-Mo why H.M.is Squire,&Amaral,1989b).I s with Hor R.B.H.M.sustained an HA es but R.B sustained a monkey i ch tures are damaged in the HA'lesion but not i n th abgmpairedontear mory tasks but their impairmen he (Mishkin.1978:Murra &Mishkin.1985 ne did not im oair me Sau ory impair 2 ing cortex At the same These findings e severe r ve and th of the to the ight b the ala.This r supposing that it shoud sibility was tested dicetyintwodiferentwas. t of study to includ theant and much of the pe rhinal cortex (theH tion in th al cortex was re sibly cooled (Horel d nonmatching to sample,the n surg ere a had a le were prod e3)and ex(Horel,Pytko- ere than th imairmentfolov ing either Hor HA lesions rito m neuroe mic elt d memory impa an,1987 The ent rtex wa already known to be also as impai on le of the idea that the ampal gyrus provide ear important for mer was mo inal and parahippoca nal co for between the cnipandaa9ccoTeieume2。 cribed al and pa ippocam ith th natomi amygdala Substantial eto perirhina that spared the hippoc mpus,theam and the 1989)On the hasis of this obs le that d age to peri cortex ad ent to the other cortica nput to ent ninal cor to make more limited ns di cted at the eda r ks they tching t nle ob that con ala her to test the rol d foll nd H lesions.Histolog d. that on anato onty to the rahip ctions to the orbitofrontal cortex separate co s to is u the severe mem ory def on memo oftheMEMORY AND THE HIPPOCAMPUS 201 Zola-Morgan et al., 1989a). The finding that H*A+ lesions pro￾duce more severe memory impairment than H*" lesions (Figure 3) implies that some of the damage produced by the tPA"1 " le￾sion, which is not included in the H+ lesion, are important for memory functions. Herein lies the explanation for why H. M. is more amnesic than other amnesic study patients, including R. B. H. M. sustained an H+A + lesion, but R. B. sustained a lesion involving only a portion of the hippocampus. Considerable effort has been directed toward identifying which structures are damaged in the EPA"1 " lesion but not in the H* lesion. The early evidence on this point seemed to point to the amygdala (Mishkin, 1978; Murray & Mishkin, 1985; Saunders, Murray, & Mishkin, 1984). However, all these early studies were based on surgical groups in which the amygdala was removed together with underlying cortex. At the same time, the cytoarchitectonics and connectivity of the underlying cortex were incompletely understood, and there was little basis for supposing that it should contribute to memory function. The underlying cortex was only incidentally involved in these surgical procedures, not a target of study. An early hint that the underlying cortex might play a role in memory came from behavioral studies of monkeys in which anteroventral temporal cortex was reversibly cooled (Horel & Pytko, 1982). When surgical lesions of this area were produced, the most affected animal had a lesion that involved perirhinal cortex (Horel, Pytko-Joiner, Voytko, & Salsbury, 1987). The pos￾sibility of studying this cortical region improved considerably when the territory of the perirhinal cortex was denned by mod￾ern neuroanatomical methods, and its connectivity with the hippocampal formation was established (Insausti, Amaral, & Cowan, 1987). The entorhinal cortex was already known to be the source of the major afferent projection to the hippocampus and dentate gyms. The important newer finding was that the adjacent perirhinal and parahippocampal gyrus provide nearly two thirds of the cortical input to the entorhinal cortex. Peri￾rhinal and parahippocampal cortex are therefore essential for the normal exchange of information between the neocortex and the hippocampal formation. With these anatomical facts in mind, we reexamined a group of H*A+ monkeys (Zola-Morgan, Squire, & Mishkin, 1982) that had been prepared with the standard surgical approach to the amygdala. Substantial damage to perirhinal cortex had oc￾curred in all the animals (see Zola-Morgan, Squire, Amaral, & Suzuki, 1989). On the basis of this observation, it seems plausi￾ble that damage to perirhinal cortex adjacent to the amygdala would also have occurred during the similar surgical approach used to make more limited lesions directed at the amygdala itself or the amygdalofugal pathway (Bachevalier, Saunders, & Mishkin, 1985; Mishkin, 1978). In short, it appears that the lesions in the earlier studies that were intended to test the role of the amygdala had damaged cortex in addition to the amyg￾dala that on anatomical grounds might be expected to have a role in memory function. It thus became important to determine experimentally the separate contributions to memory impairment of amygdala damage and damage to underlying cortex. To evaluate the ef￾fect of amygdala damage itself on memory, we developed a surgical procedure involving bilateral stereotaxic lesions, which damaged virtually all the components of the amygdaloid com￾plex but spared adjacent cortex (the A lesion). Monkeys with the A lesion performed normally on four memory tasks (delayed nonmatching to sample, retention of object discriminations, concurrent discrimination, and delayed response (Zola-Mor￾gan, Squire, & Amaral, 1989b). In contrast, monkeys with H+ or H*A+ lesions were impaired on all four tasks. We also evaluated monkeys who had bilateral lesions of the hippocampal forma￾tion (H*) made conjointly with circumscribed lesions of the amygdaloid complex (the H"A lesion). The H*A monkeys were also impaired on the four memory tasks, but their impairment was no greater than after H* lesions. Thus, amygdala damage alone did not impair memory; nor did it exacerbate the mem￾ory impairment associated with damage to the hippocampal formation (Figure 3). These findings suggested that more severe memory impair￾ment observed after H*A+ lesions might be attributable to dam￾age to the cortical regions that surround the amygdala. This possibility was tested directly in two different ways. First, mon￾keys were prepared with H*" lesions that were brought forward to include the anterior entorhinal cortex and much of the peri￾rhinal cortex (the H1 " 1 " lesion). The intention in this group was to reproduce as much of the H+A+ lesion as possible but to leave the amygdala intact. On delayed nonmatching to sample, the impairment associated with H*4 ' lesions was nearly as severe as that following H"A+ lesions (Figure 3) and significantly more severe than the impairment following either H*" or H*A lesions (Squire & Zola-Morgan, 1991). Thus, lesions of the cortex surrounding the amygdala, but not lesions of the amygdala it￾self, exacerbated memory impairment in monkeys following lesions of the hippocampal formation. The H4 " 1 " monkeys were also as impaired as №A+ monkeys on a second task: object-dis￾crimination learning. The second test of the idea that the cortical regions surrounding the amygdala are important for memory was mo￾tivated by current understanding of the anatomical connec￾tions of the hippocampus and adjacent cortex (Figure 2). In particular, as described earlier, perirhinal and parahippocam￾pal cortex are major routes by which information is exchanged between the neocortex and the hippocampal formation. Ac￾cordingly, monkeys were prepared with bilateral lesions limited to the perirhinal cortex and parahippocampal gyrus (PRPH) that spared the hippocampus, the amygdala, and the entorhinal cortex (Zola-Morgan, Squire, Amaral, & Suzuki, 1989). The white matter underlying perirhinal cortex was also transected in an attempt to remove other cortical input to entorhinal cor￾tex. These monkeys were severely impaired on the three mem￾ory tasks they were given (delayed nonmatching to sample, ob￾ject discrimination, and concurrent discrimination). In gen￾eral, the impairment following PRPH lesions was similar to that observed following tfA+ lesions and H1 " 1 " lesions. Histologi￾cal analysis showed that, as intended, damage had occurred not only to the perirhinal and parahippocampal cortex but also to projections to the entorhinal cortex from orbitofrontal cortex, superior temporal gyrus, insula, and cingulate gyrus. It is unlikely that the severe memory deficit after either PRPH lesions or H^ lesions resulted from indirect effects of these lesions on the function of the amygdala. This possibility merits consideration because perirhinal cortex does originate direct projections to the amygdala (Amaral, 1987; Van Hoesen