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Neuropsychologia 48 (2010) 2385–2405

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Neuropsychologia

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hat, if anything, can monkeys tell us about human amnesiahen they can’t say anything at all?

lisabeth A. Murray ∗, Steven P. Wiseection on the Neurobiology of Learning & Memory, Laboratory of Neuropsychology, National Institute of Mental Health,ational Institutes of Health, Bethesda, MD 20892, United States

r t i c l e i n f o

rticle history:eceived 28 August 2009eceived in revised form0 December 2009ccepted 15 January 2010vailable online 25 January 2010

eywords:edial temporal lobe

a b s t r a c t

Despite a half century of development, the orthodox monkey model of human amnesia needs improve-ment, in part because of two problems inherent in animal models of advanced human cognition. First,animal models are perforce comparative, but the principles of comparative and evolutionary biology havenot featured prominently in developing the orthodox model. Second, no one understands the relation-ship between human consciousness and cognition in other animals, but the orthodox model implicitlyassumes a close correspondence. If we treat these two difficulties with the deference they deserve, mon-keys can tell us a lot about human amnesia and memory. Three future contributions seem most likely:(1) an improved monkey model, one refocused on the hippocampus rather than on the medial temporal

emory systemsippocampusrefrontal cortexnimal modelsonsciousness

lobe as a whole; (2) a better understanding of cortical areas unique to primates, especially the granularprefrontal cortex; and (3), taking the two together, insight into prefrontal-hippocampal interactions. Wepropose that interactions among the granular prefrontal areas create the kind of cross-domain, analog-ical and self-referential knowledge that underlies advanced cognition in modern humans. When theseproducts of frontal-lobe function interact with the hippocampus, and its ancestral function in navigation,what emerges is the human ability to embed ourselves in scenarios—real and imagined, self-generated

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. Introduction

Know then thyself, presume not God to scan;The proper study of Mankind is Man. . .He hangs between; in doubt to act, or rest,In doubt to deem himself a God, or BeastIn doubt his Mind or Body to prefer,Born but to die, and reas’ning but to err;Alike in ignorance, his reason such,Whether he thinks too little, or too much

—— Alexander Pope, Second Epistle of his Essay on Man, 1733

The editors of this issue posed a seemingly simple question:hat can research on monkeys tell us about human amnesia and

he organization of memory? If, as the poet claims, “the propertudy of mankind is man”, then the answer is clear: not much. Anti-ivisectionists, creationists, and proponents of “intelligent design”ould certainly agree. So, too, would many neuroscientists.

∗ Corresponding author at: Laboratory of Neuropsychology, National Institute ofental Health, Building 49, Room 1B80, MSC 4415, 49 Convent Drive, Bethesda, MD

0892-4415, United States. Tel.: +1 301 443 7401; fax: +1 301 402 0046.E-mail address: [email protected] (E.A. Murray).

028-3932/$ – see front matter. Published by Elsevier Ltd.oi:10.1016/j.neuropsychologia.2010.01.011

a coherent, conscious life experience.Published by Elsevier Ltd.

Yet memory research on monkeys stands on an unshakeablebiological foundation: monkeys and humans both descended froma common ancestor that lived 25–35 million years ago, much morerecently than for other laboratory animals. Monkeys have memo-ries, and the memory mechanisms of monkeys and humans havehad only this limited time to diverge.

With many research methods out of the question for apes,monkey research offers the best opportunity for developing ananimal model of human amnesia. So even if the “proper study”of humankind is humanity, to advance the poet into our gender-neutral modernity, the proper study of our simian relatives canmake an important contribution, one based on the many researchmethods precluded for apes and humans but permitted for mon-keys. For the study of monkey memory mechanisms, the main suchmethod involves the use of anatomically selective lesions or inac-tivations combined with tests of memory. Passingham (2009) hasexpounded recently on this point and we subscribe to many of hisviews. The Journal of Comparative and Physiological Psychology wasonce a significant academic journal in the field, and its title sum-
marizes the endeavor as well or better than current labels, such asexperimental neuropsychology or behavioral neuroscience.
Using the methods of comparative and physiological psychol-ogy, by whatever label, the quest for a monkey model of humanamnesia has continued for more than half a century. As is well

dx.doi.org/10.1016/j.neuropsychologia.2010.01.011

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nown, the orthodox model holds that the medial temporal lobeMTL), as a whole, contains the neural mechanisms of conscious

emory. To avoid calling it conscious memory in monkeys, proxyerms such as declarative memory, explicit knowledge, and othersave been pressed into service, but the use of surrogate terminol-gy matters little. As Clark, Manns, and Squire (2002, p. 524) putt:

the fundamental distinction is between the capacity for con-scious recollection of facts and events (declarative memory) andnondeclarative memory, which supports . . . forms of memorythat are expressed through performance rather than recollec-tion.

These definitions lead directly to a major problem for monkeyodels: monkeys express all of their memories through perfor-ance. Clark et al. (2002) meant to apply their definitions to

umans, but when applied to monkeys they lead to two rather sur-rising conclusions: monkeys lack both declarative memory andonscious recollection.

But, of course, it is not as simple as that. Memory research inonkeys, including the orthodox monkey model of human amne-

ia, depends on precisely the opposite assumptions. This line ofesearch has enjoyed a long, productive run, leading to impor-ant discoveries about the functions of the hippocampus, amygdala,ntorhinal cortex, perirhinal cortex, and parahippocampal cortex,long with the other structures that compose the MTL. On reflec-ion, however, this work has failed to achieve its initial goal ofxplaining the “dense amnesia” seen in certain human patients.affan (2002) has made this point convincingly, and we have pre-iously explained that viewing the MTL as a single entity subservingsingle memory function accords poorly with empirical results onemory tests, as well as with the principles of brain organization

nd comparative neuroanatomy (Murray & Wise, 2004).The history of this research underscores the obstacles encoun-

ered in developing animal models of advanced human cognition.he phrase “animal model”, itself, exposes these challenges androves the poet’s point: we “hang . . . in doubt” about whether toreat our species as entirely apart from other animals. In the poet’sords, we often think “too little, or too much” about this issue.hen we think too little, we ignore the differences between human

nd animal cognition and sometimes deny such differences alto-ether. When we think too much, even trivial distinctions appearo vitiate all animal models. Then we say, fallaciously, that humansnd other animals are not exactly the same, so they differ com-letely. As already mentioned, monkeys and humans have hadbout 30 million years to diverge, which seems like a mere 30 mil-ion years from one perspective but a long 30 million years fromnother. A productive middle ground acknowledges both the dif-erences between human and animal cognition and the similaritiesonveyed from our most recent common ancestor.

In what follows, we sketch a history of the monkey model ofuman amnesia from its roots in a celebrated clinical case (Sec-ion 2) to its current condition (Section 3). We then suggest somemprovements to the model (Section 4) and address a key questionn developing a monkey model of human amnesia: Can conscious-ess can be ignored (Section 5)? After presenting some examples ofhat monkey research can contribute without relying on assump-

ions regarding animal consciousness (Section 6), we imagine howuman consciousness could have arisen (Section 7). A quick notebout some convenient, but slightly erroneous, terminology used inhis article: By animals we mean nonhuman animals, and by mon-
eys we mean macaque monkeys, usually rhesus monkeys, unlesstherwise stated; we use the term ‘granular’ prefrontal cortex toefer to the homotypical areas of the frontal lobe, even though itas a homotypical cytoarchitecture rather than a granular one; inerms for memory, we use the term short-term memory to cover
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the related concepts of immediate memory and working memory;and we treat as equivalent declarative memory, explicit knowl-edge, conscious memory, recollection and recall. We define thehippocampal complex as the hippocampus proper (CA1–4 and den-tate gyrus), subicular complex and entorhinal cortex, along withone of their principal axonal pathways, the fimbria-fornix.

2. The unforgettable Henry Molaison

The most celebrated case of human amnesia was that of HenryMolaison, known universally as H. M. Henry rose to prominencebecause of a conjunction of three events. First, he received an exper-imental medical treatment involving a circumscribed ablation ofbrain tissue. Second, this operation produced a striking alterationin his memory. And, third, psychologists documented and charac-terized this dramatic change in his behavior (Corkin, 1984, 2002;Milner, 1972; Milner, Corkin, & Teuber, 1968; Scoville & Milner,1957). As a result, H. M. remains the textbook example of humanamnesia, and to say that his case dramatically influenced memoryresearch understates the case considerably.

The operation carried out in Henry, a bilateral ablation ofthe MTL, provided relief from epileptic seizures, which hadproved debilitating and intractable to pharmacological treatment.Although the operation ameliorated his seizures, it did more thanthat.

2.1. What was Henry’s problem?

Psychologists studied Henry for over five decades, but withina few years of his operation the major findings had emerged. Inessence, the surgery rendered Henry densely amnesic. Indeed, itwas Henry who taught psychologists what it meant to be denselyamnesic. As a result of his surgery, he had a devastating impairmentin creating certain kinds of memories from the time of his operationin 1953, at age 27, until his recent death at age 82.

At the same time, Henry’s memory for events prior to surgeryremained relatively intact. He did lose some memories stored priorto his operation, a phenomenon called retrograde amnesia. Thereremains an active debate regarding retrograde memory loss inamnesia (Moscovitch & Nadel, 1998; Nadel & Moscovitch, 1997),and Henry’s retrograde amnesia extended back more years and wasof greater severity than initially supposed. But the loss of old mem-ories did not propel Henry’s case to the prominence it attained,and we will not discuss retrograde amnesia further in this article.Despite some degree of retrograde amnesia, Henry’s spared remotememories allowed him to retain reasonably normal abilities in writ-ten and spoken language, social skills, and arithmetic, among othercognitive domains.

In addition to a relatively spared retrograde memory, Henryhad a reasonably functional short-term memory. That is, he couldremember and mentally manipulate a limited amount of informa-tion over intervals ranging from seconds to minutes, provided thatnothing distracted him. In formal testing, given material that hecould rehearse verbally (and consciously), H. M. could rememberitems without error for 40 s, the limit of one such test (Sidman,Stoddard, & Mohr, 1968). If he could encode the information ver-bally, Henry could remember it over longer periods, evidentlythrough constant rehearsal (Milner, 2005). For example, he couldremember a three-digit number for 15 min (Milner, 1959). To beclear, H. M. did have lower scores on certain tests aimed at assessing
short-term memory (Sidman et al., 1968), and so do other amnesics(Aggleton, Nicol, Huston, & Fairbairn, 1988; Squire, Zola-Morgan, &Chen, 1988). Such tests, however, suffer from many interpretationalproblems. For example, scores on these tests can be affected by therecall, from long-term memory, of both the items to be remembered

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nd the rules of the test, along with strategies for performing theeats of memory required. Unlike control subjects, amnesics cannotreate explicit long-term strategy, rule or item memories for useuring a given testing session or for subsequent sessions. Perhapsore importantly, scores on these tests often reflect some mixture

f implicit familiarity judgments and explicit recollection (see Sec-ions 3.2, 4.2 and 6.2). Accordingly, although control subjects getetter scores on tests that attempt to measure short-term mem-ry, these findings do not necessarily reflect a short-term-memoryeficit in amnesics. More likely, such results reflect the confound-

ng effects of familiarity judgments and the advantage that controlubjects have in recalling and deploying useful rules and strategiesrom long-term memory. Taking his daily life activities into account,t is clear that H. M. had a reasonably functional, if sometimes sub-ar, short-term memory. Had this not been so, he could not haveerformed the psychological tests that were, for decades, his mostotable occupation. What propelled H. M. to prominence—what weall his core deficit—involved his nearly complete inability to createong-term conscious memories.

Importantly, Henry’s problem did not lie in creating long-termemories per se. He could, for example, learn to draw within the

orders of a two-dimensional figure while viewing his hand andhe drawing in a mirror. This mirror-drawing task perturbs visualeedback, and the task takes a good deal of practice to master.ike healthy people, Henry learned this visuomotor skill in abouthree days (Milner, 1962). Unlike the healthy people, however,enry denied having seen the test materials and also disclaimedny knowledge of having learned the task. The ability to learn newotor skills lasted for the rest of his life, with one particularly

mpressive demonstration at age 69 (Shadmehr, Brandt, & Corkin,998). Henry not only learned new motor skills, but he also learnedew cognitive and perceptual skills such as mirror reading.

So if Henry had reasonably functional short-term memory andould create some long-term memories, how should we character-ze his problem? Despite his many intact mnemonic abilities, Henry
ould not create long-term memories that he could tell anyonebout, with very few exceptions (Corkin, 2002). Thus his amnesias best understood as a profound deficiency of conscious recollec-ion, specifically an inability to encode and later recall the facts andvents encountered in everyday life. Henry’s memory impairment
ig. 1. Depiction of the extent of the medial temporal lobe removal in patient H. M. A–Dlthough the neurosurgeon removed each structure bilaterally, the illustration shows the

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was global in its involvement of all domains of conscious knowl-edge, dense in its severity, and anterograde in that the most dramaticeffect of the surgery involved new memories as opposed to old(presurgical or premorbid) ones. Importantly, these characteristicsdo not apply to Henry, alone, but also to many other amnesics, somewith damage or disease involving some of the structures removedin his surgery (Baddeley & Warrington, 1970; Brooks & Baddeley,1976; Cohen & Squire, 1980).

Sadly, Henry’s inability to remember new people, names, placesand events longer than his short-term memory span made it impos-sible for him to live independently. He described his state as “likewaking from a dream . . . every day is alone in itself . . ..” (Milneret al., 1968, p. 217). As this quotation shows, conscious memoryis more than a simple record of facts and events; it permits us toembed ourselves in these facts and events—ordered in both spaceand time—thus providing the ‘feeling’ of a coherent, unified lifeexperience. We return to this topic in Section 7.

2.2. What was Henry’s ablation?

In 1953, no techniques could evaluate the extent of Henry’slesion. Until the advent of magnetic resonance imaging (MRI), theassessment of his lesion relied only on the neurosurgeon’s notes(Scoville & Milner, 1957). The surgeon, Scoville, intended to removethe amygdala and hippocampus in both cerebral hemispheres,along with the cortex lying immediately ventral to these structures,which would include the entorhinal cortex and the parahippocam-pal cortex (Fig. 1).

Decades later, an MRI scan assessed Henry’s lesion (Corkin,Amaral, Gonzalez, Johnson, & Hyman, 1997). It revealed a bilaterallysymmetric lesion, as intended, one that included the medial portionof the temporal pole cortex, most of the amygdala, most if not allthe entorhinal cortex, and slightly more than half of the hippocam-pus, along with the nearby subicular complex. Scoville had entirelyremoved the anterior (temporal) part of the hippocampus, and the
remaining, posterior (septal) portion had atrophied by the time ofthe scan (as had many other structures, such as the cerebellum).Although Corkin et al. (1997) reported that the perirhinal cortexand white matter of the temporal stem remained largely intact, thisremains an open question (Gaffan, 2002; Goulet, Dore, & Murray,
show sections at various anteroposterior levels, as indicated in the inset to the left.lesion extent in only one hemisphere. Reproduced from Scoville and Milner (1957).

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998). The integrity of a white matter bundle like the temporaltem is difficult to assess, and any damage to it would indirectlyompromise the function of perirhinal cortex because its afferentnd efferent projections pass through the temporal stem (Goulett al., 1998; Munoz, Mishkin, & Saunders, 2009). As we revise thisrticle, anyone with an internet connection can view the sectioningf Henry’s brain in real time. So a detailed post-mortem assessmentf his lesion remains for the future. Regardless of those final results,owever, no doubt remains that the neurosurgeon removed muchore than Henry’s hippocampus.The fact that the neurosurgeon’s lesion included much more

han the hippocampus, although recognized, did not dominate thearly interpretations of H. M.’s condition. Milner (1959), for exam-le, entitled an influential report on H. M. “The memory defect

n bilateral hippocampal lesions”. Early investigators focused onhe hippocampal complex because of several clinical observations.n their initial report, Scoville and Milner (1957) considered 10atients with MTL removals of varying extent, and the amountf hippocampal damage seemed to provide the best predictionf postsurgical amnesia. For example, one patient with bilateralemoval of the anterior MTL, sparing the hippocampus, showedittle memory impairment. A patient with a unilateral inferioremporal lobectomy, one that included the hippocampus andnderlying cortex, also had a fairly normal memory. Later, Penfieldnd Milner (1958) found severe memory impairment in only twof over 80 patients with unilateral temporal lobectomies. Theyuggested that these two patients had preexisting pathology ofhe contralateral hippocampus, and their idea later gained sup-ort from neuroanatomical analysis in similar patients (PenfieldMathieson, 1974). Despite the initial focus on the hippocampus,

ontribution of the MTL, as a whole, has dominated most recenteviews on amnesia. In Section 4, we reconsider Milner’s originaldea that damage to the hippocampal complex caused Henry’s coreeficit.

.3. What does Henry’s case tell us about human amnesia?

As we said earlier, Henry Molaison—who we call H. M. in theemainder of this article—taught psychologists what it meant toe densely amnesic, and his surgeon’s notes pointed to some ofhe brain structures involved in the disorder. But his amnesia is

isunderstood if construed as an impairment in memory per se.nstead, H. M. had a selective impairment in one among manyypes of long-term memory: conscious memory. Only when peopleave impairments in long-term conscious memory do we call theirisorder amnesia. H. M. and other amnesic patients have at theirisposal vast amounts of memory, including knowledge acquiredfter their amnesia began. When people have impairments in thesether kinds of memory, it goes by other names.

For example, technical knowledge—knowledge about tools andheir use—remains intact in amnesia. The loss of such knowledges called apraxia, not amnesia, and it depends on cortical areasutside the hippocampal complex and MTL. In humans, damageo the lateral temporal cortex selectively impairs tool recognitionnd naming. Functional neuroimaging studies of tool naming revealncreased regional blood-flow rates in visual motion areas and ven-ral premotor cortex (Chao, Haxby, & Martin, 1999; Chao & Martin,000; Martin & Chao, 2001). In the latter region, such activationsccur for naming tools relative to naming other objects, viewingictures of tools compared with viewing pictures of animals, faces,nd houses, and also when subjects generate words associated with
ool use (Martin & Chao, 2001). These and other findings supporthe idea that technical knowledge is represented in distributed net-orks of cortical regions that parallel the organization of other, less
pecialized sensory and motor systems, but not the hippocampalomplex or other parts of the MTL.

ologia 48 (2010) 2385–2405

To cite another example, social knowledge permits us to evalu-ate the mental states of other people, construed broadly to includeemotions, intentions, thoughts, beliefs, and desires. Such knowl-edge is thought to be processed and represented in a network ofregions composed of the amygdala, medial frontal cortex (includ-ing anterior cingulate cortex), and anterior insular cortex, alongwith the cortex of the temporal-parietal junction, posterior supe-rior temporal sulcus, and inferior frontal gyrus (Blakemore, 2008;Frith & Frith, 2007). For example, thinking about the mental stateof oneself or others engages portions of medial prefrontal cortex(Gilbert et al., 2006). Failure to encode, retrieve, or process socialknowledge is called autism or autism spectrum disorder, not amne-sia. Social knowledge, like technical knowledge, remains intact inpatients with global anterograde amnesia, including H. M. Notethat social knowledge in this sense differs from identity knowl-edge based on the ability to remember a new face or voice, whichamnesics lose.

Like individual identity knowledge, the ability to learn andremember new words and their meanings is lost in amnesia, butthe underlying syntactical knowledge remains intact. The loss ofknowledge about language is called aphasia, not amnesia. We couldgo on in this vein, delving into progressively more controversialareas. Hauser (2006), for example, has argued for an innate moralsense, one that subserves rapid moral judgments. Moral knowledgeremains intact in human amnesia and its loss could lead to disor-ders such as sociopathy and psychopathy. Psychopaths report thatwhat they have done is wrong and would be wrong for others, aswell, so their problem does not appear to lie at a conscious level.No one would call someone an amnesic because he or she lost theirmoral sensibilities.

The understanding that human amnesia involves a deficiency inconscious memory has important implications for monkey modelsof human amnesia. As noted in Section 1, nondeclarative (i.e., sub-conscious) memories are expressed through performance (Clark etal., 2002), and monkeys express all their memories through perfor-mance. Because monkeys cannot speak, primate researchers havehad to evaluate conscious memories with proxy tasks that invokethe concept of declarative memory or one of its equivalents. Next,we recount the history of this research.

3. History of the monkey model of human amnesia

3.1. Early efforts

Attempts to reproduce H. M.’s memory deficit in monkeys failedentirely at first. In the initial attempts, monkeys with bilaterallesions of the amygdala, hippocampus and underlying cortex couldlearn and remember the tested material without difficulty. Forexample, lesions of the MTL had little or no effect on the postopera-tive acquisition of object-discrimination problems, which measurethe ability of monkeys to learn and remember which of two objectsto choose in order to get food (Correll & Scoville, 1965a; Orbach,Milner, & Rasmussen, 1960). The lesions left retention of thosepostoperatively acquired memories intact, as well. In other testsof memory, monkeys with MTL lesions remembered single loca-tions for up to 60 s, the same as intact monkeys (Correll & Scoville,1967).

These early investigators did not know why their experimentsfailed. Early speculation focused on species differences or differ-ences between the lesions in monkeys and humans, but these
factors did not account for their results. Although the experimen-tal lesions in monkeys did not match those in H. M. exactly—noexperimental lesion could meet that standard—they included thehomologous structures: the amygdala, hippocampus, subiculum,and underlying cortex. We now know that weaknesses in the

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ehavioral tasks used, rather than lesion or species differences,aused the failure of these early attempts to model human amne-ia. Murray (1996) has summarized this early work in detail. Theesions these early investigators made certainly produced a serious

emory loss, as later research revealed. The memory tests used inhe 1950s and 1960s simply did not assess the types of memorieshat the monkeys lost, a problem that persisted for many years.

.2. Short-interval matching tasks

In the world of 1970s neuropsychology, a world in which, forecades, nothing anyone did produced a memory loss anything

ike H. M.’s, finally, at last, something did: the delayed matching-r nonmatching-to-sample task (Gaffan, 1974; Mishkin, 1978). Foronvenience, we refer to these tasks collectively as short-intervalatching tasks. In these tasks, a monkey sees one or more sample

bjects on a test tray or two-dimensional stimuli on a video screen.ater, the monkey has to choose an object or stimulus according tone of two rules. According to the matching rule, the monkey musthoose the sample object over a different object to obtain a foodeward. According to the nonmatching rule, it must choose anotherbject rather than the sample. Early attempts to use matching tasksad used a small set of stimuli, presented repeatedly from trial torial, and obtained ambiguous results (Correll & Scoville, 1965b). Ase discuss in Section 4.2, the number of items in the stimulus set

nd their frequency of appearance can affect the strategies used toolve the problem posed by short-interval matching tasks. The sub-equent and more successful versions of the task employed noveltimuli on each trial or a very large set of stimuli, which, in combi-ation with the requirement to remember either single or multipletimuli over increasingly longer delay intervals, yielded a memorympairment in monkeys with MTL (Mishkin, 1978) or fornix lesionsGaffan, 1974).

With this modified version of the matching task in hand, Mishkin1978) concluded that combined lesions of the amygdala andippocampus caused memory impairments like those of H. M. Mon-eys with such lesions could remember objects for 10 s or so, butould not do so very well over longer periods or when severalbjects had to be remembered simultaneously (Fig. 2). Additionaltudies from laboratories headed by Mishkin and Squire seemed,
t first, to verify Mishkin’s conclusion (Bachevalier, Parkinson, &ishkin, 1985; Murray & Mishkin, 1984; Saunders, Murray, &ishkin, 1984; Zola-Morgan & Squire, 1984, 1985; Zola-Morgan,
quire, & Mishkin, 1982). Lesions affecting the function of both theippocampus and amygdala, like the MTL removal in H. M., pro-

ig. 2. Performance of monkeys on short-interval matching tasks. When only one sample oemory involved the presentation of several samples to remember, called a “list”. Note tas 50% correct. Abbreviations: A + H, a group of monkeys with combined, selective lesio

ombined lesions of the amygdala (A) and hippocampus (H) plus underlying parahippocroup of monkeys with lesions of the hippocampal complex plus underlying parahippoonkeys had no brain lesions. A modified from Mishkin (1978); B modified from Meunie

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duced deficits across sensory modalities, produced larger deficitswhen the lesion was larger, and spared certain abilities, such as skilllearning. Lesions affecting either the hippocampus or the amygdala,alone, had little or no effect.

Two enormous problems, however, lay hidden in this appar-ent advance. One involved the attribution of the memory deficitto lesions of the amygdala and hippocampus, an issue we take uplater (Section 3.3). But an equally important problem involved thememory test used. Somehow, without anyone saying so explic-itly, short-interval matching tasks became the principal proxy testfor long-term, conscious memory in monkeys. In retrospect, itappears that the classification of the task in terms of “visual recog-nition”, “object recognition”, or “visual memory” took on greaterinfluence than warranted, given what the task actually measured.Although short delays and a “list” of sample objects produced adeficit in monkeys with certain lesions (Fig. 2A), the short-intervalmatching task seems an unlikely candidate for a monkey model ofhuman amnesia. As usually structured, the task measures mem-ory loss over the short term (seconds and minutes), but H. M.’score deficit involved an inability to create certain kinds of long-term memories (for recall days, weeks, months or years later). Hehad a reasonably functional short-term memory, as summarizedin Section 2.1, but failed spectacularly at creating conscious long-term memories. In what follows, we call results from short-intervalmatching tasks H. M.-irrelevant. This designation does not implythat H. M. or other amnesics perform such tests as well as con-trol subjects, but rather that such tests only indirectly address H.M.’s core deficit—his global deficit in creating conscious, long-termmemories. Short-interval matching tasks were among the mem-ory tests we discussed in Section 2.1, which measure a confoundedcombination of familiarity judgments, explicit recollections, andlong-term memories of items, rules and strategies, along with theirprincipal measure: short-term memory of the to-be-remembereditems. The applicability of short-interval matching tasks to humanamnesia has been challenged on other grounds, as well (Aggleton& Brown, 1999; Aggleton & Pearce, 2001). The distinction betweenH. M.’s core deficit in creating conscious long-term memories andother results plays a crucial role in the arguments we develop later.In Section 4.1, we argue that H. M.’s core deficit in anterogradememory resulted from damage to his hippocampal complex, and
that damage elsewhere in the MTL did not contribute to his coredeficit. In Section 6.2, we argue that familiarity judgments, whichstrongly affect performance on short-interval matching tasks, alsohave little to do with H. M.’s core deficit in conscious recollec-tion.
bject appeared, the delay varied from 10 to 120 s. Another way of taxing short-termhat longer list lengths imposed additional delays. The chance level of performancens of the amygdala (A) and hippocampus (H); A + H + Rh, a group of monkeys withampal cortex, which inadvertently disabled the subjacent rhinal cortex (Rh); H, acampal cortex; Rh, a group of monkeys with lesions of the rhinal cortex. Controlr et al. (1993) and Murray and Mishkin (1998).

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The deficiencies of short-interval matching tasks would benimportant if the orthodox monkey model of human amnesiaelied on other memory tests, too. Indeed, in an initial formula-ion of the orthodox model, Squire and his colleagues proposedbattery of “MTL-dependent” tasks to measure memory, includ-

ng: (1) object matching, (2) concurrent discrimination learning,3) retention of rapidly learned object discriminations, and (4) spa-ial delayed response (Zola-Morgan & Squire, 1985). We described

atching tasks above. The concurrent discrimination-learning taskequires monkeys to learn which of two objects, when selected,roduces a reward. In the concurrent procedure, the monkeys seeeveral pairs of objects before seeing any given pair again. In rapidbject-discrimination learning, the monkey chooses between theame two objects on a number of consecutive trials, and memoryor the correct (rewarded) item in the pair is tested by allow-ng the monkey to choose between the same two objects a dayr more later. The spatial delayed-response task is much like ahort-interval matching task, except that it requires the main-enance of spatial information—a cued location—over the shorterm, rather than nonspatial (object) information. Unfortunately,he battery of tests proposed by Zola-Morgan and Squire (1985)as failed the test of time. The concurrent discrimination-learningask depends largely on structures outside the MTL in mon-eys (Buffalo, Stefanacci, Squire, & Zola, 1998; Gaffan & Murray,992; Malamut, Saunders, & Mishkin, 1984; Phillips, Malamut,achevalier, & Mishkin, 1988), and, likewise, monkeys with MTL

esions can perform the spatial delayed-response and related taskss well as intact monkeys (Correll & Scoville, 1967; Murray &ishkin, 1986; Waxler & Rosvold, 1970). The “retention of rapidly

earned object discriminations” has some promise, but as devel-ped to date it combines acquisition and retention in a way thatoes little to clarify the nature of the impairment. In the end, of theour-task battery proposed by Zola-Morgan and Squire (1985), onlyhe short-interval matching tasks remain viable. And, as we haveiscussed here, that task does little to address H. M.’s core deficit.

.3. Localization and mislocation

Research on monkeys should, in principle, allow investigators toarrow the possible causes of H. M.’s amnesia in neuroanatomicalerms. Mishkin’s (1978) work seemed to have solved that problem,oo. He concluded that lesions of the hippocampus needed to beombined with lesions of the amygdala to replicate H. M.’s amne-ia. In support of his idea, recall that the surgeon’s notes indicatedhat H. M.’s amygdala had been removed bilaterally, along with hisippocampal complex, as summarized in Section 2.2.

Unfortunately, neither Mishkin’s original experiment nor anyollow-up studies of the early 1980s (Bachevalier et al., 1985;

ahut, Zola-Morgan, & Moss, 1982; Mishkin, 1978; Murray &ishkin, 1984; Saunders et al., 1984; Zola-Morgan et al., 1982;

ola-Morgan & Squire, 1984, 1985) included a control group to testhe possibility that damage to structures near the amygdala or theippocampus had caused the impairment that they observed. Asistory later revealed, Mishkin’s results had nothing to do with themygdala and only a little to do with the hippocampal complex (seeection 4.2). Fig. 2 shows that the deficit resulted almost entirelyrom inadvertent damage to the cortex underlying the hippocam-us and amygdala (Meunier, Bachevalier, Mishkin, & Murray, 1993;ee also Eacott, Gaffan, & Murray, 1994). These underlying corticalreas included the perirhinal cortex and entorhinal cortex, togetheralled the rhinal (Rh) cortex, which were either directly damaged
entorhinal cortex) or functionally compromised (perirhinal cor-ex) by the so-called “amygdala plus hippocampus” (A + H) lesion.lthough this surgical procedure left the perirhinal cortex largely
ntact, it inadvertently cut many of its efferent and afferent axons.he lesion that Mishkin called “amygdala plus hippocampus” was

ologia 48 (2010) 2385–2405

therefore much more extensive, which is why Fig. 2A designatesit as A + H + Rh. Mishkin’s “amygdala” lesion included the rostralentorhinal cortex and a portion of the connections to and from theperirhinal cortex. Likewise, his “hippocampal” lesion took out thecaudal entorhinal cortex and a different group of perirhinal cortexconnections. Thus, only the combined removal of the amygdala andhippocampus involved all of the entorhinal cortex, as well as thelion’s share of perirhinal connections. We now know that removalof the ‘rhinal’ cortex, alone, causes nearly all of the memory lossseen in Mishkin’s original experiment (Rh in Fig. 2B). In contrast,combined lesions of the amygdala and hippocampal complex haveno effect on the same task, provided that they are selective enoughto preserve the underlying cortex (A + H in Fig. 2B). [Parahippocam-pal cortex (areas TF and TH), which was also included in the originalamygdala plus hippocampal removal, likewise appears to makelittle or no contribution to the performance of short-interval match-ing tasks (Nemanic, Alvarado, & Bachevalier, 2004).]

Mishkin’s (1978) conclusions played a highly influential rolein developing the orthodox monkey model of human amnesia, ascheme that dates from the 1980s and early 1990s (Mishkin, 1982;Squire & Zola-Morgan, 1991). His results seemed to point beyondthe hippocampal complex to a larger group of structures in theMTL as the key substrates of conscious memory. Although basedon H. M.-irrelevant results that he initially attributed to the wrongbrain structures, Mishkin’s conclusions provided the foundation fortoday’s orthodoxy.

3.4. The legacies of history

The history of this line of research imparts many lessons aboutthe challenges faced by animal models of advanced human cogni-tion. A lot of things can go wrong — and they did. Once corrected,these mistakes would be mere historical curiosities, except thattwo of their legacies persist: (1) the concept of a reified MTL asa conscious-memory center and (2) the notion that short-intervalmatching tasks assess memory deficits like H. M.’s amnesia. Previ-ously (Murray & Wise, 2004), we focused on problems with the firstlegacy, the concept of an MTL that operates as a single functional“thing” to support another “thing” called a “memory system”. Wedeveloped Gaffan’s (2002) analysis by arguing that dense amnesiaresults from the peculiar geometry of the primate brain, in whichdifferent neural pathways funnel diverse information through atight spot, near the junction of the basal forebrain with the tempo-ral lobe, so that a lesion there has catastrophic effects on memory.Here we focus on the second legacy: the domination of the fieldby short-interval matching tasks. Only by invoking the concept ofa reified MTL do results from short-interval matching tasks enterthe orthodox monkey model of human amnesia. Performance onthese tasks depends on the perirhinal cortex, and if one excludesthat area from the model then the matching tasks can leave withit. The reverse is equally true: if one excludes short-term matchingtasks as H. M.–irrelevant, then the perirhinal cortex can leave themodel. Accordingly, we propose that an improved model might dis-pense with both the perirhinal cortex and short-interval matchingtasks, along with the concept of a reified MTL. Much the same can besaid for the parahippocampal cortex and the tasks dependent on it.This new, improved model of human amnesia would then look a lotlike Milner’s (1959) original one, which emphasized the hippocam-pal complex as the key to understanding H. M.’s amnesia, ratherthan the MTL as a whole. We emphasize that our previous analy-sis (Murray & Wise, 2004) does not differ all that much from the
present one. Both advance the idea that multiple afferent and effer-ent pathways of the hippocampal complex need to be damaged toproduce severe impairments in memory. They differ principally inwhether to include afferent and efferent pathways of the amygdala,perirhinal cortex or parahippocampal cortex in a monkey model

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f amnesia. If any of these structures compose a “memory center”alled the MTL, then the model must include their input and outputathways, too. Here we propose excluding them.

Recall that, originally, H. M.’s amnesia was attributed to theippocampal complex (see Section 2.2, Milner, 1959; Penfield &athieson, 1974). More recently, Clark et al. (2002, p. 524) like-ise concluded that “declarative memory depends on the integrity

f the hippocampus and related structures . . ..” So the question is:hat are the related structures? Not the MTL as a whole, manyarts of which are no more “related” to the hippocampus than aost of cortical areas outside the MTL, except by an accident ofvolutionary history that pushed the hippocampus into the tem-oral lobe of primates (as we explained in Murray & Wise, 2004).erhaps the “related structures” include only the subicular com-lex and entorhinal cortex, rather than the long list of components

ncluded in the orthodox monkey model of human amnesia.

.5. A way forward

To summarize the main points of this section, the orthodoxonkey model of human amnesia assigns the MTL, as an entity,

he role of encoding and later recollecting conscious memories.et the development of this model depended primarily on taskshat mainly measured memory on an inappropriate scale (short-nterval matching tasks) and on impairments caused by unintendedesions (of axons going to and from the perirhinal cortex). Seem-ngly unconcerned with the frailty of its historical foundation or itsependence on a swarm of weakly consistent evidence, proponentsf the model now consider it so well established that only evidenceerging on disproof could (or should) dislodge it (e.g., Mishkin,uzuki, Gadian, & Vargha-Khadem, 1997; Squire, Stark, & Clark,004; Suzuki, 2009; Suzuki & Baxter, 2009). Given its faulty foun-ation, however, it makes sense to reconsider the orthodox model

n its entirety, and along with it the literature regarding amnesian both monkeys and humans. Once we dispense with the conceptf a reified MTL, the model no longer needs to include either theerirhinal cortex or any tasks that depend on the perirhinal cor-ex, such as short-interval matching tasks. What remains? Morehan one might expect. And what remains could someday lead ton improved monkey model of human amnesia, one focused moren the hippocampal complex than on a reified MTL, and one sup-orted by tasks that measure long-term memory more rigorouslyhan do short-interval matching tasks.

. Toward an improved monkey model of human amnesia

.1. Does hippocampal damage cause amnesia in humans?

A considerable body of evidence points to the hippocampalomplex as the source of H. M.-like amnesia. As discussed ear-ier (Section 3.3), H. M. failed to store new facts and events thate could recall and express, hence the term declarative memory.t this point we need to distinguish between two main types ofeclarative memory: event memory, a term which is often used

nterchangeably with episodic memory, and fact memory, alsonown as semantic memory. We also need to distinguish betweenecollection and familiarity. Section 6.2 develops this distinction inore detail, but for now we can consider recollection as equiv-

lent to declarative memory and familiarity as something else.ome evidence indicates that hippocampal lesions interfere withpecific recollections and memories for events, but spares familiar-
ty judgments (e.g., Aggleton & Shaw, 1996), and there have beenlaims that hippocampal damage also spares memories for facts, i.e.,emantic memories (Vargha-Khadem et al., 1997; Vargha-Khadem,adian, & Mishkin, 2001). We need to consider these two claimseparately.
ologia 48 (2010) 2385–2405 2391

4.1.1. The hippocampal complex subserves episodic memoryOne line of evidence concerning episodic vs. semantic memory

comes from a study of children with early hippocampal dam-age. Initially, they were reported to have profound impairmentsin episodic memory, with nearly complete sparing of semanticmemory (Vargha-Khadem et al., 1997, 2001). MRI-based vol-ume estimates in these select subjects indicated that they had asmaller hippocampus than controls: the only structure so affected.Subsequent studies of these and other patients with damagerestricted to the hippocampus have shown, contrary to the ini-tial reports of Vargha-Khadem et al., that these lesions do impairthe acquisition of semantic memories (Gardiner, Brandt, Baddeley,Vargha-Khadem, & Mishkin, 2008; Holdstock, Mayes, Isaac, Gong,& Roberts, 2002; Manns, Hopkins, & Squire, 2003). Holdstock etal. (2002) emphasized that the hippocampus plays an especiallyimportant role in the rapid acquisition of semantic (factual) infor-mation, just as it does for the rapid acquisition of episodic (event)memory (see also Kapur, 1994). Patients with hippocampal dam-age can acquire semantic knowledge only slowly, through repeatedexposure to factual material (Gardiner et al., 2008; Holdstock et al.,2002). Thus, the functional distinction between the hippocampalcortex and most other cortical areas could relate to rapid versusslow learning (McClelland, McNaughton, & O’Reilly, 1995) ratherthan to episodic versus semantic memory per se. Of course, episodicmemories require rapid learning because they often capture sin-gular events. Even with these ideas in mind, we need to accountfor H. M.’s nearly complete incapacity to acquire semantic knowl-edge (Gabrieli, Cohen, & Corkin, 1988), compared to other amnesicpatients, many who can acquire such information slowly. This dis-crepancy could have resulted from the fact that, in contrast to manyother amnesic patients, H. M. had a complete surgical removal ofthe anterior (temporal) hippocampus or more extensive damage tothe remainder of the hippocampal complex (i.e., the fimbria-fornix,subicular complex and entorhinal cortex).

Another study examined a series of 38 patients who had under-gone colloid cyst removals. Colloid cysts typically form in the thirdventricle, and their removal often results in damage to the fornix,which passes through the ventricle and to which the cyst maybecome attached. Indeed, the fornix may be compromised beforethe surgery. All the subjects in this study received structural MRIscans to measure the fornix, mammillary bodies and related struc-tures. Strikingly, the volume of the mammillary bodies, whichindirectly reflects the integrity of the fornix, significantly corre-lated with the scores for 13 of 14 tests of episodic memory (Tsiviliset al., 2008). No other structures showed such a consistent relation-ship between size and memory scores. Because the fornix servesas the main afferent and efferent fiber bundle of the hippocampalcomplex, including the subicular complex, this finding, like that ofVargha-Khadem et al. (2001), points to a key role for these struc-tures in episodic memory.

4.1.2. The hippocampal complex subserves recollectionRegarding the issue of recollection vs. familiarity judgments,

one issue involves whether they represent a single process ortwo distinct processes, both underlying recognition memory. Somehave argued that preserved familiarity, in the face of recollec-tion losses, might result from a single process, one with a lowerthreshold for familiarity judgments than for explicit recollection(Squire, Wixted, & Clark, 2007). Recent results indicate otherwise.Vann et al. (2009) studied the patients mentioned above, who hadundergone surgical removal of a colloid cyst. Using three different
experimental methods, they found that patients with small mam-millary bodies had impairments in recollection memory relativeto patients with large mammillary bodies; familiarity judgmentsdid not differ between groups. Although several cases had earlierbeen reported to show this same pattern—impaired recollection

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ith spared familiarity—there had also been reports to the contrary,ith differing etiologies of amnesia complicating the interpreta-

ion within and across studies. The study by Vann et al. (2009)epresents a significant advance because of three methodologicaltrengths: the large number of patients with a single etiology ofemory impairment; the use of a structural measure to identify

ubgroups (small vs. large mammillary bodies); and the use of sev-ral, complementary methods to assess familiarity and recollection.s such, it presents the strongest evidence to date in favor of the

dea that the hippocampal complex subserves recollection ratherhan familiarity.

Importantly, a single-case study of a patient receiving surgeryor relief of intractable epilepsy has reported the opposite pat-ern of impairment. Surgeons removed left anterior temporal lobetructures from that patient, including much of the perirhinalortex, entorhinal cortex and most of the amygdala. The hippocam-us remained intact. After surgery, the investigators tested theatient on four separate neuropsychological measures, all of whichevealed impaired familiarity judgments but preserved recollec-ion (Bowles et al., 2007). The pattern of impaired familiarity inhe face of intact recollection is critical in distinguishing betweenne- and two-process models of recognition memory. Althougheveral patients have now been reported to display impaired recallut preserved familiarity, these findings might result from a singlerocess, one with a lower threshold for familiarity than for rec-llection judgments (Squire et al., 2007). Although only a singlease, the patient with impaired familiarity but preserved recollec-ion (Bowles et al., 2007) seems to rule out the one-process accountnd argues strongly that two distinct processes contribute to recog-ition memory: recollection, which depends on the hippocampalomplex, and familiarity, which does not. We return to this topic inection 6.2, when we consider the results of hippocampal lesionsn rodents that support this idea.

.1.3. Lesions of the hippocampal complex cause amnesiaOther patients, selected and studied because of their amne-

ia, have undergone intensive neuropsychological testing. and, inome cases, neuropathological analysis, as well (Rempel-Clower,ola, Squire, & Amaral, 1996; Zola-Morgan, Squire, & Amaral, 1986).europathological analysis often misses sites of brain damage, but

aking these reports at face value, we review the findings with anye to providing a complete picture of the neural substrates ofmnesia. As in H. M., the memory impairment in these patientsccurred in the absence of deficits in other cognitive domains. Inhe four patients with detailed neuropathological reports, moder-te anterograde amnesia occurred with bilateral cell loss limitedrimarily to CA1 in patients R. B. and G. D., whereas a severe antero-rade memory impairment occurred with bilateral cell loss in CA1,A2, CA3, the dentate gyrus, the subiculum, and the entorhinal cor-ex (patient W. H.). W. H. also displayed marked atrophy of the

ammillary bodies, but neither R. B. nor G. D. had such shrinkage.his finding agrees with neuroanatomical findings showing thatfferent fibers from the subicular complex make up the bulk of theornix and with results from patients with the removals of colloidysts near the fornix, outlined above. Taken together, these findingsoint to a role for the hippocampal complex in conscious memory,ather than for the MTL as a whole.

Another amnesic patient with a detailed neuropathologicaleport, patient E. P., suffered from viral encephalitis (Stefanacci,uffalo, Schmolck, & Squire, 2000). E. P.’s extensive brain damage

ncluded the hippocampal complex, perirhinal cortex, parahip-
ocampal cortex, and fusiform gyri, along with atrophy in temporal,arietal and insular cortex. Despite this massive extension ofathology beyond H. M.’s lesion (Fig. 1) and beyond W. H.’s anoxicamage (CA1, CA2, CA3, the dentate gyrus, the subiculum, and thentorhinal cortex), E. P.’s amnesia was about the same as theirs. All
ologia 48 (2010) 2385–2405

three patients had similar scores on the delay component of therevised Wechsler Memory Scale, which tests the memory for infor-mation presented 25–35 min earlier (Rempel-Clower et al., 1996;Stefanacci et al., 2000). The finding that the extension of E. P.’s lesionbeyond the hippocampal complex caused no more impairmentthan the two patients with damage confined to the hippocampalcomplex again points to the hippocampal complex, rather than theMTL, as the key to understanding conscious memory in humans.

4.1.4. Activity in the hippocampal complex correlates withself-referential event memory

Functional imaging studies have also pointed to a role for thehippocampal complex in functions fundamental to conscious mem-ory. This work has revealed a network of structures that changeblood-flow rates in relation to autobiographical memory retrieval(Conway, Pleydell-Pearce, Whitecross, & Sharpe, 2003; Maguire,2001; Svoboda, McKinnon, & Levine, 2006), including episodicmemory. Maguire and her colleagues have identified neural cor-relates of two separable components of episodic memory: sceneconstruction and connection to self (Hassabis, Kumaran, & Maguire,2007; Hassabis & Maguire, 2009). Their functional neuroimagingstudies required subjects to recall recent episodic memories, toretrieve fictitious experiences constructed one week earlier, andto construct new fictitious experiences while being scanned. Anal-ogous object-based tasks served as controls. When contrasting thethree conditions involving personal experiences (imagined or real)relative to the three conditions involving objects, a network of brainregions showed task-related effects, including the hippocampus,parahippocampal gyrus, retrosplenial cortex, precuneus, posteriorparietal cortex, and ventromedial prefrontal cortex. When con-trasting real and fictitious events, three brain regions had higherblood flow for real memories: the precuneus, posterior cingulatecortex, and anterior medial prefrontal cortex (area 10). Becauseactivation in area 10 and posterior cingulate cortex occurred onlyduring episodic memory recall, Maguire and her colleagues iden-tified these two regions as contributing to functions beyond sceneconstruction and involving the subjects embedding themselves inthe events. The posterior cingulate cortex and area 10 have alsobeen implicated in self-reflection (Johnson et al., 2002), theoryof mind (Amodio & Frith, 2006; Kumaran & Maguire, 2005), andthinking about future events (Addis, Moscovitch, & McAndrews,2007; Hassabis et al., 2007). Thus, these two regions may contributeto episodic memory by supporting processing related to the self(Conway & Pleydell-Pearce, 2000) and mental time travel (Tulving,2002; Wheeler, Stuss, & Tulving, 1997), a topic taken up again inSection 7.2. Studies emphasizing episodic memory as a constructiveprocess bring to the fore an aspect of episodic memory not alwaysappreciated. Episodic memory allows us not only to create a contin-uous record of life experience, with the self embedded, but also torecombine stored information in novel ways that permit us to eval-uate the suitability of different potential courses of action (Hassabis& Maguire, 2009). The involvement of area 10 catches our attentionfor two reasons: this area, often called the frontal pole cortex, isthe largest area in the prefrontal cortex of humans (Öngür, Ferry,& Price, 2003), and it expanded so much during human evolution(Semendeferi, Armstrong, Schleicher, Zilles, & Van Hoesen, 2001)that it dominates the geometry of the anterior brain and braincase.The initial study of neuronal activity in monkeys concluded that thelikely homologue of the frontal pole cortex plays a role in monitor-ing or evaluating self-generated decisions (Tsujimoto, Genovesio, &Wise, 2010). This conclusion has some relevance to the ideas about
self-reference and cross-domain knowledge presented in Section 7.
4.1.5. The hippocampal complex subserves trace conditioningAnother line of research linking the hippocampus with con-

scious memory comes from studies of Pavlovian eye-blink

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onditioning. Hippocampal lesions cause a deficit in one kindf Pavlovian learning called trace conditioning (McEchron,ouwmeester, Tseng, Weiss, & Disterhoft, 1998; McEchron &isterhoft, 1999; Solomon, Vander Schaaf, Thompson, & Weisz,986). In Pavlovian conditioning, an initially neutral stimulus,alled the conditioned stimulus, precedes an unconditioned stim-lus, which triggers a reflex response. With repeated exposure,he conditioned stimulus comes to elicit a similar response. In thetandard conditioning paradigm, the conditioned stimulus remainsresent until the unconditioned stimulus occurs after a fixed delay.ence the name for this paradigm: delay conditioning. When theonditioned stimulus occurs only briefly, then goes away before thenconditioned stimulus occurs, learning still takes place. The condi-ioned stimulus is thought to leave a “trace” behind, hence the namef this paradigm: trace conditioning. Hippocampal damage causesdeficit in trace conditioning but not delay conditioning. According

o Clark et al. (2002), conscious awareness, not stimulus memoryer se, affects trace conditioning. In their experiments on eyeblinkonditioning, manipulations that increased awareness (e.g., explicitnstructions) increased the speed of trace conditioning and thosehat decreased awareness (e.g., distraction) slowed it. In addition,hen they manipulated expectancy for the unconditioned stimu-

us, an air puff, the probability of a conditioned response correlatedith expectancy in trace conditioning but not in delay condition-

ng. These results point to the importance of conscious awarenessn the functions of the hippocampal complex, even for the learningf low-order, conditioned reflexes.

.2. Does hippocampal damage cause H. M.-relevant memoryeficits in monkeys?

Section 4.1 points to the hippocampal complex, rather than theTL as a whole, as the neural substrate for the kind of long-termemories lost in human amnesics like H. M. If so, then a monkeyodel of human amnesia should focus on the hippocampal com-

lex, rather than the conglomeration of structures known as theTL. Furthermore, the task used in such a model should yield a

attern of impaired and preserved memory functions similar tohose seen in H. M. and similar patients. As we explained in Section, short-interval matching tasks do not fit the bill very well.

Given that H. M. and other amnesics have a reasonablyunctional short-term memory, it should not be surprising thatomplete bilateral removal of the hippocampal complex caneave performance on short-interval matching tasks unaffected in

onkeys—under certain circumstances (Correll & Scoville, 1965b;urray & Mishkin, 1984, 1998). Most straightforwardly, mon-

eys can solve the problem posed by short-interval matchingasks through focused, attentive maintenance of object representa-ions in short-term (‘working’or ‘maintenance’) memory, and laterpplying either the matching or nonmatching rule. One can think ofhis algorithm as a strategy: one among many solutions to a givenroblem. However, as we explained in Section 3.2, short-intervalatching tasks often measure more than short-term memory,

nd perhaps for this reason damage to the hippocampal complexalone) or transection of the fornix can affect performance on cer-ain versions of the task. We think that differences in the monkeys’trategies could account for inconsistent results both within andetween laboratories. Depending on the number of stimuli usednd other factors, monkeys can solve the problem posed by match-ng tasks by using various strategies in addition to, or insteadf, short-term maintenance memory. One such strategy involves
hoosing an object based on its familiarity, i.e., on the basis ofhether the item has been encountered previously. This strategy
mounts to a discrimination of novel from familiar items. Alterna-ively, monkeys might choose an object based on how recently itas been viewed, as opposed to its familiarity or novelty.

ologia 48 (2010) 2385–2405 2393

In matching tasks that employ a small set of stimuli, it seemslikely that monkeys keep a representation of the sample in short-term memory, a process that does not depend on the integrityof the hippocampal complex. The application of a short-term-memory strategy could explain the lack of effect of hippocampallesions on matching tasks with small stimulus sets (see Section3.2, e.g., Correll & Scoville, 1965b, who used two stimuli). In con-trast, tasks employing large stimulus sets may lead to reliance onrecency or familiarity strategies instead of, or in addition to, a short-term-memory strategy. Here we divide larger stimulus sets intothose that use novel (trial-unique) stimuli (or a set sufficientlylarge, more than 1000 items or so, to resemble novel stimuli)and those that use an intermediate number of stimuli (∼300–400stimuli). Repeated presentation of stimuli—as occurs with interme-diate set sizes—would hamper familiarity judgements, because allstimuli become familiar, and thereby promote a recency strategy.This strategic bias might explain why hippocampal-lesion studiesinvolving intermediate-sized stimulus sets have tended to showdeficits on matching tasks (Beason-Held, Rosene, Killiany, & Moss,1999; Zola et al., 2000; see also Gaffan, 1974), whereas those withlarger stimulus sets (Murray & Mishkin, 1998; Nemanic et al., 2004)and small stimulus sets (Correll & Scoville, 1965b) have not. Thisinterpretation implies that the hippocampal complex subservesrecency judgments, an account supported by the finding that fornixtransection causes a deficit in recency memory, but leaves noveltyand familiarity judgments intact (Charles, Gaffan, & Buckley, 2004).Note that, to the extent that recency judgements depend on theorder of event sequences, they can be related directly to the con-cept of episodic (event) memory. On the other hand, the use of afamiliarity strategy—as likely occurs with large set sizes and trial-unique stimuli—could render performance immune from damageto the hippocampal complex (see Sections 4.1 and 6.2). Beyondthe size of stimulus sets, other factors could also affect the strat-egy used by monkeys, such as having the monkeys learn the taskpostoperatively (Beason-Held et al., 1999; Zola et al., 2000) ratherthan preoperatively (Murray & Mishkin, 1998) and how often thememory interval changes during a block of trials (Gaffan, 1974; seeBaxter & Murray, 2001 for additional discussion). Because of theircomplexity and dependence on several strategies, short-intervalmatching tasks seem to us to be a poor choice for improving themonkey model of human amnesia. So we need a different task, onefor which hippocampal dysfunction causes a pattern of spared andimpaired memory functions like those seen in human amnesia.

Of course, damage to the hippocampus causes many deficits inmemory, and we cannot review the vast literature on this topichere. Note that our question is not, Does hippocampal damagecause memory deficits in monkeys?, but rather, Does hippocam-pal damage cause H. M.-relevant memory deficits in monkeys?As a further complication, many of the deficits in spatial mem-ory that have been attributed to the hippocampus in monkeys(Angeli, Murray, & Mishkin, 1993; Mahut & Moss, 1986; Parkinson,Murray, & Mishkin, 1988) resulted instead from inadvertent dam-age to the underlying parahippocampal cortex (Malkova & Mishkin,2003; Murray & Mishkin, 1998). Lesions confined to the hippocam-pal complex, alone, cause impairments in navigating within alarge-scale environment (Hampton, Hampstead, & Murray, 2004a;Lavenex, Amaral, & Lavenex, 2006), remembering a location withina scene (Murray, Baxter, & Gaffan, 1998), remembering two or morelocations simultaneously (Beason-Held et al., 1999), and remem-bering the locations of objects in an array (Bachevalier & Nemanic,2008). One synthesis of these data holds that spatial tasks requiring
an extrinsic (allocentric) frame of reference depend on the integrityof the hippocampal complex (Banta Lavenex & Lavenex, 2009),which helps bring the monkey data into line with results fromother species, including rodents, reptiles and teleost fishes. Takentogether, these results and ideas suggest that the ancestral role of

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he hippocampal complex, one that evolved early in vertebrate his-ory, involves navigation in an extrinsic reference frame (Rodriguezt al., 2002). But deficits in spatial memory and navigation do not, onheir face, resemble H. M.’s global anterograde amnesia very closely.ater, in Section 7, we consider a more general conceptualizationf navigation, with special attention to self-referential navigation.

.3. A way forward

A promising line of monkey research involves the object-in-lace scene task devised by Gaffan (1994). This task requiresonkeys to identify and touch the one of two foreground “objects”

n a complex scene composed of several geometric forms of vary-ng size, shape and color. Selection of the correct foreground object

ithin a scene leads to delivery of food reward, and monkeys areequired to learn several such scenes concurrently. It has beenroposed that the object-in-place scenes task taxes episodic mem-ry in monkeys (Gaffan, 1994), a topic we take up in more detailn Section 5.4. For now, we note that damage to separate partsf the extended hippocampal system, including the fornix, ante-ior thalamus, and mammillary bodies, yields a deficit on this taskGaffan, 1994; Parker & Gaffan, 1997a, 1997b). Because the deficitshat follow the different lesions have the same magnitude, andecause addition of a fornix transection to monkeys that have sus-ained a mammillary body lesion yields no greater impairment, itppears that these structures work together as a functional unit.lthough the object-in-place scenes task provides clear evidence

or the learning of object discriminations embedded in complexcenes, and clear evidence of being dependent on the hippocam-al complex, it needs some development to serve as part of aompelling monkey model of human amnesia. Monkeys learn thendividual discriminations over several trials, a learning rate thatontrasts with the one-exposure event-capture that characterizesonscious, episodic memory in humans. Nevertheless, the recollec-ion of remote memories seems to be mediated via corticocorticalnteractions involving the prefrontal cortex (Browning & Gaffan,008a, 2008b), while new learning depends on the fornix (Buckley,ilson, & Gaffan, 2008).A variant of Gaffan’s object-in-place scenes task has been used

n human neuropsychology, specifically, in patients who had sus-ained fornix transection as a consequence of surgical removalf colloid cysts (Aggleton et al., 2000). Although these patientshowed impairments, they were mild ones. The fornix-damagedroup performed significantly worse than the two control groupsnly on the first of four trials with a set of 20 object-in-placecenes. Thus, it seems likely that fornix damage must combine withther disruptions to produce a severe amnesia. And, indeed, Gaffan,arker, and Easton (2001) found more severe effects on memory inonkeys, relative to those seen after fornix transection, when they

ombined fornix transection with section of the anterior temporaltem and amygdala lesions. They examined the effect of such com-ined lesions on several memory tasks, including the short-intervalatching task and the concurrent object-discrimination task, alongith the object-in-place scenes task. Gaffan et al. (2001) found

evere impairments on all three tasks. For both object-in-placecenes and concurrent object-discrimination learning, combinedesions caused larger deficits than either fornix transection, alone,r damage to the temporal stem and amygdala, alone. For theatching task, section of the temporal stem and amygdala pro-

uced the full impairment; addition of fornix transection had nodditional effect. The latter finding is consistent with the idea
hat perirhinal cortex, rather than the hippocampus, is essentialor performance on matching tasks with large stimulus sets. One
onkey with the full combined lesion retained a large number ofreoperative learned concurrent-discrimination problems, whichesembles H. M.’s preserved remote memories. Accordingly, Gaffan

ologia 48 (2010) 2385–2405

et al. (2001) concluded that the pattern of impairments resembledthat seen in humans with dense amnesia. Some of these findingsmight seem inconsistent with the ideas propounded here. Theyseem more in line with the idea that many structures, includingthe hippocampus, need to be compromised in order to producea severe, H. M.-like impairment. To the contrary, we think thatthese findings point to the multiple routes by which the hippocam-pal complex can communicate with other brain regions, such asthe prefrontal cortex. Thus, to produce a severe amnesia, fiber-cutting lesions need to include more than the fornix. Interruptionof the temporal stem and fornix could, together, eliminate most ifnot all of the routes through which the prefrontal cortex and hip-pocampal complex communicate. Accordingly, the object-in-placescenes task holds considerable promise for future development ofthe monkey model of human amnesia, especially when combinedwith a more refined analysis of the routes of information flow toand from the hippocampal complex.

Along with the object-in-place scenes task, a task involving thearbitrary mapping of symbolic information to actions holds somepromise. This task, sometimes called conditional motor learningor simply the arbitrary mapping task, involves nothing more thanlearning and later retrieving simple stimulus–response (S–R) asso-ciations. A nonspatial visual cue instructs one action while other,similar cues instruct different actions. By “nonspatial” cue, we meanobject-like stimuli with many features that distinguish one cuefrom another. In the typical training and testing procedure, a singlestimulus appears on a video screen and the monkey must chooseamong several responses, only one of which will produce a reward.A computer randomly selects one stimulus from a set on each trial,so several trials might intervene between repetitions of a givenstimulus, with different stimuli and responses, some correct andsome incorrect. This feature of the task requires the monkeys to laydown long-term memories of the cue-action mappings. For exam-ple, monkeys sometimes take several testing sessions, extendingover days, to learn a new set of cue-action mappings, especiallyduring early phases of training. When that happens, they invari-ably begin each day near the level of performance reached at theend of the previous day. The arbitrary mapping task thus differsimportantly from the short-interval matching task, which mon-keys could solve by maintaining a representation of the samplestimulus in short-term memory and later applying the matchingor nonmatching rule. It differs from the object-in-place scenes taskin that monkeys can (although they do not always) learn the map-pings from the experience of a single, successfully performed trial(Brasted, Bussey, Murray, & Wise, 2005), like the one-exposureevent-capture that characterizes conscious, episodic memory inhumans.

We and others have studied the neural substrates of arbitrarymapping. Damage to the hippocampal complex yields a pattern ofdeficits and preserved memory functions in the arbitrary mappingtask that matches H. M.’s amnesia fairly closely. Like H. M., mon-keys with lesions of the hippocampus and subjacent cortex have adramatic deficit in new learning that depends on long-term mem-ory, as explained above (Murray & Wise, 1996). As shown in Fig. 3A(unfilled circles), bilateral ablation of the hippocampus and sub-jacent cortical areas causes substantial deficits in the learning ofnew arbitrary mappings (Murray & Wise, 1996; Wise & Murray,1999, 2000). Also like H. M., the lesioned monkeys can recall mem-ories that they had established prior to their surgery. They also hadpreserved knowledge of at least three specific response strategies,learned prior to surgery, which depended on an intact short-term
memory (Wise & Murray, 1999). The results we observed for thissimple S–R task thus matched H. M.’s pattern of amnesia and pre-served mnemonic capacities much more closely than results fromshort-interval matching tasks and many other tasks used to probehippocampal function.

E.A. Murray, S.P. Wise / Neuropsych

Fig. 3. The effects of removing the hippocampal complex and transecting the fornixon the arbitrary mapping task. (A) Learning curves for two kinds of arbitrary map-ping tasks. One study (triangles) involved a comparison of learning rates in a controlgroup of monkeys (filled triangles) with a group of monkeys that had undergonefornix-transection (unfilled triangles). In this experiment, both the cues and theresponses differed along nonspatial dimensions. The other study (circles) used sim-ilar cues but spatial responses. It involved a comparison between preoperative(filled circles) and postoperative (unfilled circles) performance of a single group ofmonkeys, which had undergone bilateral removals of the hippocampus, as well asunderlying parahippocampal cortex. Abbreviations: H+, lesions of the hippocampusplus subjacent parahippocampal cortex; Fx, fornix. (B) Average number of errorstoB

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functions are unaffected. Indeed, there is evidence for a disruption

o criterion (+S.E.M.) for novel mapping problems, which used different numbersf cues and response targets, denoted as the cue:target ratio. A reproduced fromrasted et al. (2005); B reproduced from Brasted et al. (2003).

Not only does the overall pattern of impaired and preservedemory functions seem to match those of H. M. and similar

mnesics, but the deficit appears to be “global” in the sense that itoes not depend on anything having to do with spatial factors suchs stimulus location or the response being spatially differentiatedBrasted, Bussey, Murray, & Wise, 2003). Brasted et al. (2003) usedtemporally differentiated response set in which monkeys had toither repeatedly tap a touch screen or maintain contact with itor about 4 s or 8 s. As shown in Fig. 3A, we obtained nearly identi-al results for spatially and temporally (nonspatially) differentiatedesponses. We found little difference between the effects of fornixransections (Fig. 3A, unfilled triangles) and aspiration lesions ofhe hippocampus plus subjacent cortical areas (Fig. 3A, unfilled cir-les). The results also did not depend on whether we comparedreoperative vs. postoperative performance, as opposed to post-perative performance in lesioned vs. control monkeys (Fig. 3A).ig. 3B shows an effect of task difficulty. In the easiest versionf the mapping task, such as when monkeys need only to mapwo cues onto two responses, fornix transection causes a small
nd only marginally significant deficit. When the task becomesore difficult, such as when monkeys need to map six or more
timuli onto three responses, large and highly significant deficitsmerge.

ologia 48 (2010) 2385–2405 2395

Although the arbitrary mapping task has its advantages, theimpairment in new learning in monkeys with hippocampal-complex lesions does not reach the severity of amnesia in H. M.or similar patients. Lesioned monkeys eventually learn new map-pings, and they improved with experience in doing so. This factlimits the applicability of the task to a monkey model of humanamnesia, probably because there are other, slower ways to learnnew mappings, which depend on structures outside the hippocam-pal complex. We also know that extensive (but incomplete) damageto the hippocampus proper does not cause any deficit on this task(Brasted et al., 2005), much like the patients described above withdamage to parts of the hippocampal complex (Section 4.1). Recallthat damage restricted to CA1 produced mild anterograde amne-sia, whereas more extensive damage to the hippocampal complexproduced severe symptoms (Rempel-Clower et al., 1996). The fastmapping of visual stimuli onto other visual stimuli (also known asvisual–visual paired associate learning) could provide yet furtherimprovements in the behavioral tests used for a monkey modelof human amnesia. Note that we avoid the circular reasoning thatoften characterizes discussions of the present kind. We do not clas-sify the arbitrary mapping task as a test of conscious memory, bywhatever label. Instead, we make two points: (1) the arbitrary map-ping task could serve as a potentially useful component of a batteryof tests probing hippocampal function, and (2) it enables us to studymany attributes of interest (rapid, sometimes one-trial learning,preserved remote memories, etc.). In Sections 6.1 and 6.2, we takeup these two ideas again and call them the ablation-correlationapproach and the attribute approach, respectively.

Even if it is agreed that an improved monkey model of humanamnesia should focus more on the hippocampal complex thanon the MTL as a whole, and on tasks that produce a patternof impairments more like those of H. M. and other amnesicsthan short-interval matching tasks can manage, a major problemremains: monkeys still cannot tell us what they remember. Thetraditional approach to this problem is to dismiss it as intractable(or inconsequential) and to use proxy tasks and proxy terms forconscious memory, instead. The next section addresses whetherthe issue of consciousness can be avoided in an attempt to developimproved animal models of human amnesia.

5. Can the issue of consciousness be avoided?

5.1. Declarative memory

There have been several attempts to deal with the problem ofanimal consciousness. Squire and his colleagues have long held thatany memory test in animals disrupted by damage to one or more ofthe structures composing the MTL can be considered a declarative(i.e., conscious) memory (Zola-Morgan, Squire, & Ramus, 1994). Thisapproach ensures that any kind of memory dependent on the hip-pocampal complex, entorhinal, perirhinal and/or parahippocampalcortex automatically receives the same conscious-memory sta-tus typically applied to memory loss in human amnesics, exceptfor the use of the proxy term declarative memory instead ofconscious memory. As noted by others, however, this approachamounts to little more than circular reasoning (Morris, 1984; Nadel,1992).

Another flaw in the orthodox model concerns a different aspectof logic. Just because a deficit in conscious memory is the most con-spicuous result of bilateral MTL removal does not imply that other

of implicit (as opposed to explicit) spatial memory (Chun & Phelps,1999) and implicit spatial perception (Lee, Buckley et al., 2005;Lee, Bussey et al., 2005) after hippocampal damage in humans,as well as evidence for disrupted object and face perception (as

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pposed to memory) after brain damage that includes perirhinalortex (Barense et al., 2005; Lee, Bussey et al., 2005). Accordingly,he conclusion that a kind of memory is conscious memory because

TL lesions cause deficits in it fails on two counts: circular logic andffirming the consequent. [Symbolically: p implies q; q is true (thusffirming the consequent); therefore (fallaciously) p is true. In prac-ice it goes like this: If the MTL functions specifically in declarative

emory, then we should see deficits in declarative-memory tasks.e see deficits in declarative-memory tasks (thus affirming the

onsequent), therefore (fallaciously) the MTL functions specificallyn declarative memory.] Formal logic aside, note that issues regard-ng the perirhinal cortex and its functions go away once we excludehe perirhinal cortex and short-interval matching tasks from the

onkey model of human amnesia.In recognition of these problems, there have been other

ttempts to invoke the concept of conscious memory, as dis-inct from other types of memory, without using the wordonsciousness. Inherent in all of these schemes is the implicationhat some kind of memory in animals corresponds to conscious

emory in humans, regardless of the proxy term used for it.ike the declarative–procedural dichotomy or the declarative–ondeclarative dichotomy, the use of terms that indirectly connotehe attribute of conscious knowledge serves to reinforce the ideahat MTL damage leads to the disruption of conscious memory innimals without having to say so explicitly. Next, we take up threef these attempts.

.2. Goal-directed behavior

Another proxy term for conscious memory is goal-directedehavior, as defined by Balleine and Dickinson (1998). According tohese authorities, goal-directed behavior can be identified by two

ain characteristics: (1) sensitivity to the value of the goal and2) knowledge of the relationship between actions and the goalr outcome of those actions. In practice, these two characteristicsre measured using reinforcer devaluation (to assess the behav-oral effects of manipulating the value of the goal) and contingencyegradation (to assess the behavioral effects of disrupting the rela-ionship between action and goal/outcome). According to Balleine2005), the memory guiding goal-directed behavior is the sames declarative memory, which is, as we have seen, the unstatedquivalent of conscious memory. Equating conscious memory withgoal-directed behavior” depends on the dubious assumption thathere is only one kind of goal-directed behavior. If there are twor more kinds, with one conscious and the others subconscious,hen reinforcer devaluation or contingency degradation proce-ures do not help us very much. Indeed, a considerable amountf goal-directed behavior in humans is mediated subconsciously.uring sleepwalking, for example, people behave in a goal-directedanner although they are not in a conscious state. Many goal-

irected reaching movements proceed entirely without consciousontrol, a well-characterized phenomenon called autopilot controlMilner, Karnath, & Desmurget, 2003; Pisella et al., 2000; Prablanc,esmurget, & Grea, 2003), and this phenomenon extends to loco-otion and other movements, as well. Koch & Crick (2001, p. 893)

efer to the control of human behavior by “the zombie within”. Ashey point out:

brain systems perform complex yet routine tasks without directconscious input. . .. Such systems can deal with certain com-monly encountered situations automatically, which is why we
call them ‘zombie’ agents. One can become conscious of theactions of one’s own zombie, but usually only in retrospect. Thebest evidence comes from studying dissociation of ‘vision forperception’ and ‘vision for action’ in both healthy humans andpatients.
ologia 48 (2010) 2385–2405

Wegner (2002) has likewise pointed out that much of humanbehavior runs automatically, without conscious control. In retro-spect, our consciousness generates reasons for our actions, alongwith the illusion that they were consciously controlled.

5.3. Voluntary behavior

Passingham (1993) attempted to deal with the issue of animalconsciousness by focusing on decision-making. In his view, whenan animal has a choice between two or more alternative actions, thedecision to choose one of them can be characterized as voluntary;otherwise it is simply “motivated” behavior. Motivated behaviordepends on associating stimuli with rewards, the availability offood, and so forth. This approach has several advantages, not theleast of which is the ease of application to both human and mon-key research. But this operational definition of voluntary actioncannot substitute for the deeper and more difficult concept of con-sciousness. The problem, as explained above, is that many humanbehaviors that qualify as voluntary in Passingham’s sense of theword, are mediated subconsciously.

5.4. Episodic-like memory

Other stand-ins for conscious, human memory include the flex-ible association of items learned as paired associates (Eichenbaum& Bunsey, 1995), among others, but we would like to focus on stud-ies that attempt to model episodic memory, because we touchedupon this line of research in Section 4.1 and it comes up again inSection 7. Gaffan (1994) has argued for the learning of complexscenes (object-in-place scenes) as an assay of episodic memory inmonkeys. In his view, the fornix operates as part of a hippocampus-fornix-mammillary body-anterior thalamic circuit that contributesto the representation of complex scenes, including the spatialarrangement of objects in scenes, and this type of memory preventsconfusion between memories of similar events. Taken on its ownterms, this approach has promise. However, if one seeks to equatesuch episodic memories, if they are that, with conscious memories,the problem that arises is the same as with goal-directed or vol-untary behavior. Furthermore, these tasks and ideas deal only withthe aspect of episodic memory involving scenes, not, as explainedin Section 4.1, with embedding oneself in an event.

We emphasize that we do not question the importance ofepisodic memory in understanding human amnesia. No one doubtsthat H. M.’s surgery cost him the ability to encode and retrieve eventmemories, in terms of what happened, where it happened, andwhen. The problem involves studying episodic memory in animalmodels. A series of experiments examined food-caching behaviorin scrub jays to test whether they expressed knowledge of whatfoods they had cached, where they had cached it, and when (Clayton& Dickinson, 1998, 1999). On the basis of these experiments, itappears that scrub jays know what, where, and when they cacheda particular type of food, which has been taken as evidence thatscrub jays have episodic memory. It has been especially surpris-ing that despite several efforts to address this issue in rats andmonkeys, little evidence for what-where-when memory has turnedup. In some cases, the when component of a putative what-where-when memory can be explained away as circadian (time-of-day)or recency (passage-of-time) effects, rather than a true ordering ofan event in time (see Eacott & Easton, 2010, this issue; Hampton &Schwartz, 2004 for reviews). One attempt to deal with this prob-lem has involved the use of a variant of spontaneous tests of object
recognition in rodents. Eacott and her colleagues have argued thatwhich rather than when is the important factor in episodic memorybecause it provides the context, beyond location per se, in which anevent occurred. Eacott and her colleagues (Eacott & Norman, 2004;Easton, Zinkivskay, & Eacott, 2009) showed that rats can reliably

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emember that a particular object (what) was located in a particu-ar arm of the maze (where) in a specific context (which), and thathis ability depends on the fornix. The same fornix-lesioned ratserformed tests of object recognition normally. Together, the find-

ngs have been taken as evidence that rats with fornix lesions havempaired recall (based on results from the what-where-which test),ut intact familiarity judgments (based on results from object-ecognition tests) (Eacott & Easton, 2010, this issue). Anotherttempt involved rapid acquisition of food location (Day, Langston,Morris, 2003). Cued recall of recently acquired food-place pairs,

ut not remotely learned food-place pairs, depended on activity inhe hippocampus. Although Day et al. (2003) linked their findingso episodic memory in humans, we note that they refrained fromlaiming their rats possessed the same ability. Does the existencef what-where-when memory in scrub jays or what-where-whichemory in rats mean that they have conscious memories? As has

een noted convincingly by others, what-where-when memory iseither necessary nor sufficient evidence of the ability to con-ciously recollect an event (Suddendorf & Corballis, 2007a, 2007b).umans can have what-where-when knowledge without recollect-

ng an event, and conversely, can recall an event without fullnowledge about what, where and when something happened. Theame objections apply to what-where-which memory. The findingsn scrub jays and rodents have spawned unnecessary controversy,ainly revolving around whether the what-where-when memory

bserved in birds really “corresponds” to the human experience ofonscious episodic memories. The proxy term “episodic-like mem-ry” has been used in an attempt to avoid this problem (Clayton,ussey, Emery, & Dickinson, 2003), but evading the problem doesothing to resolve it.

.5. A way forward

To summarize the main points of this section, we can neithergnore the problem of animal consciousness nor resolve it. What,n that seemingly forbidding context, can monkeys tell us aboutonscious memories? The next section explores how an improvedonkey model of human amnesia can provide useful insights with-

ut depending upon assumptions about monkey consciousness.

. What monkeys can tell us about human amnesia

If an improved monkey model of human amnesia cannot copeith the concept of consciousness (Section 5) and dispenses with

he concept of a reified MTL, results from short-interval matchingasks, and tasks that depend on perirhinal cortex (Sections 3 and), how can it help us understand human amnesia? At least threepproaches have been used to surmount the fact that monkeysannot tell us what they remember. We call them the ablation-orrelation approach, the attribute-correlation approach, and theeport-based approach. The ablation-correlation approach focusesn the brain structures that contribute to conscious memory inumans; the attribute-correlation approach deals with the char-cteristics of conscious memory; and the report-based approachelies on actions that reveal the contents of memory. Although allhree approaches can adopt a weak form that depends on circulareasoning about animal consciousness, they all can be developedn ways that accord with the principles of comparative and evolu-ionary biology. Sections 6.1, 6.2 and 6.3 address, respectively, how
hese three approaches to studying memory in animals can pro-ide insight into human amnesia and memory without dependingn assumptions about animal consciousness. Sections 6.4 and 6.5laborate an important aspect of the ablation-correlation approach,he contribution of the prefrontal cortex and its interaction with theippocampal complex.
ologia 48 (2010) 2385–2405 2397

6.1. Ablation-correlation approach

The ablation-correlation approach aims at understanding thefunction of homologues, in monkeys, of structures that subserveconscious memory in humans. Even if, as some experts believe,consciousness emerged in humans (Section 7), we can neverthe-less understand the neural underpinnings of conscious knowledge,and how it is stored, by studying the homologous structures inmonkeys. We do not need to make any assumptions about mon-key consciousness to pursue this line of research or to applyits results to human memory. Of the large body of work onhippocampal function, we focus on a couple of key, illustrativecontributions.

6.1.1. MTL reification theoryOne tenet of the orthodox monkey model of human amnesia

is that the many structures composing the MTL make more-or-less the same contribution. An alternative view holds that differentparts of the MTL perform different functions, such as the idea thatthe hippocampal complex mediates episodic memory. Likewise, asreviewed above (Section 4.1), several lines of evidence indicate thatonly one portion of the MTL in humans, the hippocampal complex,plays an important role in recollection (Aggleton & Brown, 2005;Diana, Yonelinas, & Ranganath, 2007; Eichenbaum, Yonelinas, &Ranganath, 2007). Evidence suggests that a different circuit, onethat includes the perirhinal cortex and medial dorsal nucleus ofthe thalamus (Aggleton & Brown, 1999), but not the hippocampalcomplex (or its principal subcortical targets), mediates familiarityjudgments.

The question of whether the various components of the MTLfunction cooperatively or in a specialized manner can be testedin monkeys without making assumptions about monkey con-sciousness, simply by examining the functional organization ofhomologous structures in the two species. The finding that thevarious structures composing the MTL in monkeys have severaldissociable functions (Murray, Bussey, & Saksida, 2007; Murray &Wise, 2004), in addition to the familiarity-recollection dichotomyjust mentioned, supports the division-of-labor side of the argu-ment. These findings illustrate how a monkey model of humanamnesia can help resolve controversies from the human literature.It would be a strange circumstance, indeed, if the perirhinal cortex,entorhinal cortex, parahippocampal cortex, hippocampus properperformed different functions in monkeys, but lost all of these spe-cializations in humans. On grounds of parsimony, we can rejectsuch a notion.

6.1.2. The multiple memory-trace theoryTo cite another example, monkey research can test another

tenet of the orthodox monkey model of human amnesia: that theMTL is essential for only a limited period of time, during whichnewly acquired memories are consolidated elsewhere in the brain,an idea that has been disputed in the multiple memory-tracetheory (Moscovitch & Nadel, 1998; Nadel & Moscovitch, 1997).Yanike, Wirth, and Suzuki (2004), for example, studied the neu-rophysiology of the hippocampus in an arbitrary mapping task likethat described in Section 4.3. They found that the hippocampusrepresents established, highly familiar stimulus–response map-pings, along with novel ones. As elaborated in Section 4.3, previouslesion studies had shown that lesions of the hippocampal com-plex (including the fornix) cause a large deficit in learning suchmappings, with preserved ability to perform according to pre-
operatively learned ones (Brasted et al., 2003; Wise & Murray,1999). The most parsimonious account of the findings from lesionstudies is that brain regions outside the hippocampal complexstore the familiar mappings, and there is evidence that theseoutside locations include parts of the prefrontal cortex and pre-

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otor cortex (Bussey, Wise, & Murray, 2001). Lesion studies,owever, cannot address whether familiar mappings are rep-esented in the hippocampal complex, along with novel ones.he neurophysiological findings of Yanike et al. (2004) resolvehis question: the hippocampal complex represents both novelnd familiar mappings. These findings from monkeys, there-ore, support the multiple-trace theory and further illustrate howe can test ideas about human amnesia and memory withoutaking assumptions about monkey consciousness. (Note that

he phrase familiar mappings, in the sense used for this task,ears no relation to the concept of familiarity, as discussedbove.)

In summary, learning as much as we can about the function ofhe hippocampal complex will provide insight into human amnesiaithout making any assumptions about the existence of consciousemories in monkeys. Recall that in addition to losing the ability

o encode new conscious memories, human patients with damageo the hippocampus have deficits on spatial learning. So by study-ng the other things that the hippocampus does, and how it does

hat it does, indirect knowledge can be gained about hippocampalunction in conscious memory. As Gaffan (1998, 2002) has arguedorcefully, what the hippocampus does depends on the inputs iteceives. If it gets inputs in humans that reflect our conscious men-al operations, then it will do with those inputs what it does with itsther ones, whatever that might be. We develop this idea furthern Section 7.2.

.2. Attribute-correlation approach

A second approach in developing and improving animal models
f human amnesia focuses on the characteristics of conscious mem-ry. This approach builds on the ablation-correlation approach and,ike it, requires no assumption that the memories in monkeys (orther animals) are conscious ones, only that that have a particularroperty in common.
ig. 4. ROC curves that distinguish familiarity and recollection in a recognition task. Fromippocampal lesions. (A) Left, ROC curve for amnesic patients (black) and for control suOC curves. Right, estimates for recollection and familiarity components of the ROC curippocampal (H) lesions and for controls. A modified from Yonelinas et al. (2002); B mod

ologia 48 (2010) 2385–2405

6.2.1. One- vs. two-process models of recognition memoryAs discussed above in Section 4.1, clinical evidence points to

two components of human recognition memory — familiarity andrecollection. Evidence for the distinction between familiarity andrecollection comes from several sources, including neuropsycho-logical studies, investigations with event-related potentials, andfunctional neuroimaging studies. One relevant method involves aparticular attribute of conscious memory in humans, the shape ofROC curves. ROC stands for receiver operating characteristic and itmeasures the trade-off between selectivity and sensitivity duringattempts to decode a given signal. In this case, the signal involvessuccessful performance of a memory task. With maximal sensi-tivity, a target signal will always be detected (a “hit”), but othersignals will be mistaken for the target signal (a “false alarm”). Withminimal sensitivity, false alarms can be prevented, but so too willdetection of the target signal. In the context of signal detection,ROC plots involve hits as a function of false alarms (Fig. 4). In testsof recognition memory in amnesic patients, the ROC curve hasa mirror symmetry with respect to the major diagonal (the graydashed line in Fig. 4A). Yonelinas et al. (2002) have interpretedthis result as reflecting a spared capacity for familiarity judgments.The ROC curve in control subjects shows a marked asymmetry(Fig. 4A), which they have interpreted as reflecting a combinationof the recollection and familiarity components of recognition (forreview see Eichenbaum et al., 2007). A study by Fortin, Wright, andEichenbaum (2004) showed that intact rats given a test of odormemory, with response criteria biased by using different levels ofreward magnitude, displayed similarly shaped, asymmetrical ROCcurves. Rats with hippocampal lesions displayed symmetrical ROCcurves and whereas their ROC measures of familiarity matched that
of control animals, their recollection measure was reduced, sug-gesting that familiarity mediates odor recognition in the rats withhippocampal lesions (Fig. 4B). Taken together with the findingsfrom humans, these data support the idea that the hippocampalcomplex subserves the recollection component of item recognition
amnesic patients with presumed hippocampal damage and from rats with selectivebjects (gray). The dashed gray line provides a reference for the symmetry of theve. Error bars represent ± S.E.M. (B) In the format of A, but for rats with selectiveified from Fortin et al. (2004).

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see also, Section 4.1). We need not assume that such behaviorsepend on rat consciousness, as implied by calling these memoriesdeclarative”

We could cite examples of other attributes of conscious mem-ry amenable to similar testing, such as one-trial acquisition, rapidxtinction, temporal order information of certain kinds, memoryor context, relational knowledge, and so forth, but the examplef ROC curves proves the point: we do not require assump-ions about animal consciousness to test the attributes of humanonscious memory in animals. From this perspective, we caniew the attribute-correlation approach two ways. Perhaps certainemories have a given attribute because they are conscious. Alter-

atively, conscious memories could have the attributes they have,uch as a particular shape of the ROC curve, because the hippocam-al complex mediates such memories and confers that attributealong with others) on all of its memories, conscious and subcon-cious.

.3. Report-based approach

Obviously, animals cannot provide a verbal report abouthe contents of their memory. Nevertheless, a relatively recentpproach to studying memory in animals requires them to “report”n percepts and memories. Stoerig and Cowey (1997) pioneeredhis approach in a blindsight task, and Hampton later developedwo methods for training monkeys to report a lack of memory. Inhe direct one (Hampton, 2001), he operantly conditioned mon-eys to report the lack of a memory. Monkeys first touched a picturehat served as the sample in the short-interval matching task. Next,

onkeys could choose one of two pictures, which remained theame across trials: one (picture A) led to delivery of a nonpreferredeward and the other (picture B) led to the short-interval matchingest. Successful performance of the test yielded a preferred reward.y touching picture A the monkey could opt out of the memory testnd thus “report” either that it had forgotten the sample or that aample stimulus had not appeared on that trial. For long delay inter-als, when the likelihood of forgetting increased, the monkey moreften touched picture A, which Hampton interpreted as a reportbout the loss of the item in short-term memory. In a second, lessirect reporting procedure, Hampton, Zivin, and Murray (2004b)equired monkeys to select among four opaque tubes, one of whichontained a food reward. Sometimes the monkeys could see thexperimenter bait the tube in advance of its selection, sometimesot. During testing, the monkeys could look down the tube to see

f it had food, if they chose to do so. As expected, monkeys lookedown the tubes more often when they had not seen the experi-enter bait the tube, which suggests that the monkeys knew what

hey did not know.Versions of report-based tasks have been used in pigeons, rats,

nd monkeys in an attempt to use actions to probe the con-ents of memory (Hampton & Schwartz, 2004; Roberts et al.,009; Sutton & Shettleworth, 2008). These tests provide a toolo examine behavior that has an important attribute of humanonscious memory, the ability to make reports about the contentf one’s own memory, without requiring assumptions about ani-al consciousness. Of course, we cannot rule out the possibility

hat these “reports” are simply conditioned responses, with thenimal’s behavior following a complex pattern of reward probabil-ties and outcome valuations, especially in relation to cost factorsuch as prolonged attentiveness. Nevertheless, like the attribute-orrelation approach, report-based procedures seek to understand
he neural basis of behaviors that resemble aspects of conscious
emory in humans. If report-based approaches can be extended torobe long-term memory and examine its neural substrates, thenhey could yield substantial insight into human amnesia withoutepending on any assumptions about animal consciousness.

ologia 48 (2010) 2385–2405 2399

6.4. The granular prefrontal cortex

The ablation-correlation approach relies on the study of homo-logues, in monkeys, of the structures underlying conscious memoryin humans. This approach can extend beyond the hippocampalcomplex to other brain regions implicated in the encoding orretrieval of conscious memories, such as episodic memories. Neu-roimaging reports too numerous to mention (e.g., Spaniol et al.,2009) show that the granular prefrontal cortex plays an impor-tant role in episodic memory. But another reason also supportsthe inclusion of prefrontal cortex in a monkey model of humanamnesia: Monkeys, like humans and other primates, have a gran-ular prefrontal cortex, but rodents and other mammals lack theseareas. All mammals have agranular frontal areas, which often goby the name prefrontal, but the granular prefrontal cortex is aprimate innovation (Preuss, 1995; Wise, 2008). Accordingly, mon-key models of amnesia have the considerable advantage that theycan include the granular prefrontal cortex. This contention seemsstrange in the context of current memory research in monkeys,which has focused so intently on the MTL. But all mammals havehomologues of the structures composing the MTL: the amygdala,hippocampus, subicular complex, entorhinal cortex, perirhinal cor-tex, and (with somewhat less confidence) parahippocampal cortex.Only primates have homologues of the granular prefrontal cortex.

Using the methods precluded for humans and apes, the study ofmonkeys offers additional tools for understanding the functions ofthe granular prefrontal cortex, as well as studying how prefrontalcortex interacts with the hippocampal complex. Of course, thatunderstanding remains for the future, and we cannot review thevast literature on prefrontal cortex here. But we favor the idea thatthe granular prefrontal cortex stores knowledge about behavior,including ordered sequences of actions and likely outcomes, alongwith their contexts (Duncan, 2001; Shallice, 2001; Wise, 2008;Wood, Romero, Makale, & Grafman, 2003).

6.5. Prefrontal–hippocampal interactions

A monkey model of human amnesia also permits an analysis ofprefrontal–hippocampal interactions. These two sets of structureshave both direct (Barbas & Blatt, 1995; Cavada, Company, Tejedor,Cruz-Rizzolo, & Reinoso-Suarez, 2000; Goldman-Rakic, Selemon,& Schwartz, 1984; Insausti & Munoz, 2001) and indirect connec-tions via entorhinal, perirhinal, retrosplenial, and parahippocampalcortex (Insausti, Amaral, & Cowan, 1987; Munoz & Insausti, 2005;Suzuki & Amaral, 1994). Yet little, if anything, is known about thefunctions of these interactions. The orthodox model emphasizes therole of the entorhinal cortex as the sensory gateway from neocortex(e.g., perirhinal and parahippocampal cortex) to the hippocampusand back. If the focus of an improved model shifts from the MTLconcept to the hippocampal complex, then entorhinal cortex takeson increased importance as an indirect route connecting the hip-pocampus to the prefrontal cortex, along with the direct projectionsbetween the hippocampus and prefrontal cortex. On this view, theentorhinal cortex subserves a “relay function” in a broad frame-work that places perirhinal, parahippocampal, prefrontal, and otherneocortical areas on an even footing.

One anatomical clue about prefrontal–hippocampal interac-tions concerns the distinction between the temporal parts of thehippocampal complex (called anterior in primates and ventral inrodents) and the septal parts (called posterior in primates anddorsal in rodents). The anterior region has the bulk of direct inter-
connections with the prefrontal cortex (for example, see Cavada etal., 2000), and there is ample evidence for differential roles of theanterior and the posterior parts of the hippocampal complex. Theposterior region subserves accurate spatial navigation and the ante-rior region seems to be important in other functions (Bannerman

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t al., 2003; Kjelstrup et al., 2002). Among their differences, thewo regions differ in the size of their place fields, the parts of aodent’s environment for which a neuron in the hippocampal com-lex increases its discharge rate. The posterior hippocampus hasmaller place fields (<1 m) and the anterior hippocampus has largernes (∼10 m) (Kjelstrup et al., 2008). The large place fields in thenterior hippocampus may aid in generalizing spatial contexts, andherefore mediating navigation in a more general sense than usu-lly understood, whereas the posterior hippocampus may mediateavigation in the more usual sense.

So far, we have discussed how an improved monkey model ofuman amnesia might focus on the hippocampal complex and its

nteraction with the prefrontal cortex. In the next section, we putorward the idea that conscious memory in humans depends onhese two structures and their interactions.

. What history can tell us about human amnesia

.1. What have we got that they ain’t got?

What makes the Hottentot so hot?What puts the “ape” in apricot?What have they got that I ain’t got?

——The Cowardly Lion, from The Wizard of Oz (1939)

The Cowardly Lion posed some probing questions. The Hot-entots have something hot alright: human consciousness. Butnstead of pointing to that, The Lion agreed to a different answer:Courage!” That was wrong; The Cowardly Lion had plenty of brav-ry. In terms of prowess, he was more of a lion than a “mowesssic]”. Yet he was not a lion at all: just another constructionf human fiction. The creation of The Cowardly Lion epitomizeshe human ability to imagine animals acting like people, whichequires analogical and metaphorical thinking across two cogni-ive domains: social knowledge and biological (natural history)nowledge (Mithen, 1996). We return to this theme shortly.

We discussed above how an improved monkey model of humanmnesia might focus on the hippocampal complex and its interac-ion with the prefrontal cortex. Could conscious memory dependn these interactions? We think that it might. In order to placehis idea in a concrete conceptual framework, we relate a storybout the evolution of human consciousness, drawn primarilyrom two sources (Klein & Edgar, 2002; Mithen, 1996). For read-rs uncomfortable with untestable evolutionary stories, or simplyninterested in them, we suggest skipping to Section 7.2. The

deas presented there and elsewhere in this article do not dependn our evolutionary story. As one of our sources says: “the cruxere is logic and parsimony, not evidence” (Klein & Edgar, 2002,. 273). We present these speculations in order to make our

dea about prefrontal–hippocampal interactions more concrete,ith no claim of originality or adequate scholarship. But it seems

hat every neuroscientist over the age of 55 eventually gets therge to write an article on consciousness, and ours follows. In it,e refrain from parsing the distinctive meanings of declarativeemory, explicit knowledge, sentience, consciousness (in gen-

ral), access consciousness, phenomenal consciousness, awareness,nd so forth. Searle’s famous Chinese Room was, until this point,nmentioned, and we will not mention it again. If these issuesould be decided by dueling definitions or thought experiments,hat would have happened a long time ago. But when we address
he question, What can monkeys tell us about human amnesia?,t would be dishonest to assume that they view the world with aonsciousness that very much resembles ours. The fact is that weo not know, and we doubt very much that anyone else knowsither, whether monkeys or other animals have a human-like con-
ologia 48 (2010) 2385–2405

sciousness. In the remainder of this article, however, we assume thatnonhuman animals lack any cognitive capacity that closely resem-bles the conscious awareness of modern humans. The assumptionimplies that our kind of consciousness arose some time duringhuman evolution, after the divergence of our ancestors from thelineages that gave rise to other apes.

As we mentioned in Section 1, monkeys diverged from thehuman lineage about 30 million years ago. In those 30 millionyears, humans developed language, extensive tool use, and aculture capable of transmitting innovations to succeeding gener-ations. Monkeys display both cultures (or ‘traditions’) and tool use(Visalberghi et al., 2009), but with meager capacities compared toours, and the same goes for language (Hauser, Chomsky, & Fitch,2002). We do not deny that glimpses of these abilities exist inother animals, and we do not need to deny such glimpses in orderto recognize the huge gulf between human and animal cognition.As the poet quoted in the introduction made clear: we humansseem of two minds when it comes to other animals; we either denyany similarity or deny any difference. In collections of papers likethe current special issue or academic anthologies, one can read anarticle by one author agonizing about whether chimpanzees, forexample, have anything remotely resembling human conscious-ness, alongside an article from a different author assuming withoutreservation that rats have a consciousness just like ours. We believethat the differences between human and animal cognition amountto a cognitive discontinuity between them and us (Penn, Holyoak,& Povinelli, 2008), without denying any of the cognitive similaritiesdocumented by primatologists, for example, intent on disprovingevery claim of unique human capacities.

So if something important happened to animal consciousnessafter the divergence of humans from our closest primate relatives,how did this come about? The line of thought we outline here comesfrom anthropologists and archeologists who study the artifacts ofhuman prehistory (Klein & Edgar, 2002; Mithen, 1996). Somewherearound 6 million years ago, give or take a few million years, anancestral species split into the lineage that evolved into the chim-panzees and bonobos of modern times and a lineage from whichthe first anatomically modern humans descended. Later, theseanatomically modern humans became “behaviorally modern” aswell. Although their interpretations remain somewhat controver-sial, these archaeologists base their conclusion on the observationthat tool kits, art, and other artifacts left behind by these peoplechanged dramatically about 50,000 years ago, although their brain(and postcranial) anatomy remained fairly constant. At 25 yearsper generation, these were our grandparents2000, or something likethat. As Klein and Edgar (2002, p. 271) put it:

the relationship between anatomical and behavioral changeshifted abruptly about 50,000 years ago. Before this time,anatomy and behavior appear to have evolved more or lessin tandem, very slowly, but after this time anatomy remainedrelatively stable while behavioral (cultural) change acceleratedrapidly. What could explain this better than a neural change thatpromoted the extraordinary modern human ability to innovate?

Often called the creative explosion, these innovations came longafter the increases in brain size that occurred in our ancestors ∼2.5million years ago and again about 600,000 years ago. As summa-rized by Klein and Edgar (2002, p. 235), the innovations of thesepeople included “solidly built houses, tailored clothing, more effi-cient fire places, and new hunting technology that not only allowed. . . [them] to displace their predecessors but also to colonize the
harshest, more continental parts of Eurasia where no one hadlived before.” The production of cave art exemplifies their manydepartures from the behavior of previous people. It appears thatthese people first evolved in east Africa and later took over theworld, displacing people who had done much the same thing ear-

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ier in human history. According to this view of human prehistory,ithin the past 50,000 years or so our ancestors evolved from a

enign if clever mammal into one capable of creating The Cowardlyion.

Not only did the tool kit and other artifacts become much moreiverse 50,000 years ago, but certain kinds of artifacts appearedhat people had never (or only very rarely) made before. Among thetems that caught the attention of the archaeologist Stephen Mithen1996), behaviorally modern humans fashioned parts of animalsnto tools and other things. This observation, among others, led himo propose that a major change in human cognition occurred at theime these new people emerged. The cognitive characteristics ofhese humans allowed them to represent and model their physicalnd social worlds, and their place in it. Specifically, Mithen pro-osed that before about 50,000 years ago our ancestors had severalpecialized cognitive modules, one for social knowledge, anotheror knowledge of animals and other aspects of the ecosystem andnvironment, and yet another for technical knowledge. Accord-ng to his view, before about 50,000 years ago language was notery important outside the social domain within which it evolvedsee also Burling, 2005; MacNeilage, 2008). After a few fortuitous

utations, the barriers between these domains of knowledge brokeown, resulting in a creative explosion of cross-domain analogies,he ability to apply language to technical and biological knowl-dge, improved and innovative tool manufacture and use, and morefficient (as well as safer) hunting.

Mithen has used a cathedral metaphor to explain his idea. Imag-ne a cathedral with a number of chapels walled off from eachther. These represent the domains of knowledge before the cre-tive explosion. Knowledge in one domain could not contribute tony other or to anything that might be construed as general knowl-dge. The creative explosion followed the penetration of thosealls by conceptual passage ways allowing humans, for example,

o conceive of using animal material as tools. Before the creativexplosion, according to Mithen, tool making and knowledge aboutnimals had been “walled off” from each other. Afterward, interac-ion between the two domains of knowledge allowed the linkage ofhese knowledge sets. In a sense, these metaphorical passage waysnabled our ancestors to “see” a tool inside an animal bone, much asheir specialized technical knowledge had previously allowed themnd their ancestors to “see” a tool within a rock. The interaction ofnowledge domains underlies higher-order analogical reasoning,he ability to attribute events to unseen causes, and a well devel-ped ability to attribute mental states to others, all now identifieds likely areas of discontinuity between human and nonhumannimals (Penn et al., 2008).

As Penn et al. put it (2008, p. 123):

The crux of the matter, then, is to identify the specific changes tothe hominid architecture that enabled . . . [behaviorally modernhumans] to reason about higher order relations in a structurallysystematic and inferentially productive fashion, and ultimatelyresulted in the evolution of our unique linguistic, mentalistic,logical, and causal reasoning abilities.

.2. Prefrontal products and the hippocampal complex

We suggest that conscious memory evolved in our humanncestors after changes in their (our) granular prefrontal cortexade it possible for different domains of knowledge to interactith each other and with a representation of self. The fruits of these

nteractions, when exchanged with the hippocampal complex,ould mediate human consciousness. We note that the appearancef the granular prefrontal cortex predates the creative explosiony tens of millions of years; it appeared before the divergence ofonkeys from the human-ape lineage (Preuss, 1995, 2007a, 2007b;

ologia 48 (2010) 2385–2405 2401

Wise, 2008). Thus, the evolution of a granular prefrontal cortexdid not lead directly to the creative explosion, but a change inits organization might have done so. We have previously noted,in Section 4.1, that the frontal pole cortex expanded in humans tobecome the largest part of the granular prefrontal cortex. Taken asa group, the granular prefrontal areas bring into physical proxim-ity neural representations from virtually every sensory, emotional,and cognitive domain. Accordingly, the neural interconnectionsamong these domains are more direct and presumably strongerthan cross-domain interconnections among more posterior parts ofneocortex. Such close proximity could promote mappings or associ-ations among different domains of knowledge. In terms of Mithen’scathedral metaphor, the proximity of distinct cognitive domains inthe prefrontal cortex, along with some organizational or connec-tional change, could have promoted the perforation of walls thatseparate each chapel from the others.

Take, for example, our introspective views about the conse-quences of our own actions in pocket billiards. We believe that thecue ball hit the 8-ball because of our intention to send it there withour cue stick. So when we see circles bounce off each other on avideo display, we attribute intention to them, as well. Accordingto the idea espoused here, the attribution of intent to circles comesfrom a mapping between representations of intention in one part ofprefrontal cortex and the representation of inanimate objects suchas circles, also in prefrontal cortex. Except for prefrontal cortex,these representations are remote from each other and weakly inter-connected. In prefrontal cortex, they are closer and more directlyconnected.

According to Mithen, the key cognitive domains specific tohumans include knowledge about other people (social knowl-edge, including moral and language knowledge), knowledge abouttools and objects (technical knowledge), and knowledge aboutplants and animals (natural-history knowledge). Technical knowl-edge means more than just the ability to use and modify sticks;for example, it entails the ability to imagine the tool withinan otherwise much-less-useful rock. Cross-domain analogies andmetaphors depend on associative mappings between representa-tions of these different domains of knowledge. When we connectsocial knowledge to natural-history knowledge, it creates intu-itions about human nature; when we connect technical knowledgeto social knowledge, it creates animism, the belief that objectssuch as tools and rocks have feelings and intentions; when weconnect natural-history knowledge to social knowledge, we gener-ate anthropomorphism, antivivisectionism, many of Gary Larson’scartoons, and The Cowardly Lion. Cross-domain interactions couldenable analogical and metaphorical relations that not only providethe contents of consciousness, but when combined with self-reference also establish consciousness per se.

Gaffan (2002) has argued that the monkey and human prefrontalcortex function in a domain-general manner, without functionalspecializations of any kind. His subsequent neuropsychologicalstudies and those of others (Baxter, Gaffan, Kyriazis, & Mitchell,2009; Buckley et al., 2009; Dias, Robbins, & Roberts, 1996), alongwith decades of neuroanatomical and neurophysiological research,shows that his idea was overstated in the form expressed at thattime. Viewed more generally, however, the granular prefrontalcortex might well function in the development of cross-domainknowledge of the sort required for domain-general informationprocessing, and this idea accords well with existing theories ofprefrontal cortex function (Duncan, 2001; Miller & Cohen, 2001;Shallice, 2001). Duncan, especially, has pointed to the granular pre-
frontal cortex as the substrate for fluid intelligence, the same termthat Mithen uses for uniquely human consciousness. This idea alsoresembles the conception of consciousness as a global workspace(Baars, Ramsoy, & Laureys, 2003) subserved, at least in part, by thegranular prefrontal cortex.

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If the granular prefrontal cortex changed in a way that perfo-ated the walls in Mithen’s cognitive cathedral, it would generateovel cognitive representations. This creative information couldhen interact with the hippocampal complex in the way that pre-rontal interactions always do, whatever that way is. This ideancorporates elements of the global workspace, but still recognizeshe specializations within the granular prefrontal cortex. Accord-ng to this idea, human consciousness arises from an interactionetween the hippocampal complex and knowledge representa-ions in the prefrontal cortex, but becomes stored in both areas, anderhaps in other areas, as well. A model of this kind could explainhy neither prefrontal lobotomy (Al-Hai, 2005) nor hippocampec-

omy obliterates consciousness.These ideas could also account for deficits in the acquisition of

emantic knowledge in amnesia. If prefrontal–hippocampal inter-ctions subserve conscious memory in humans, they must bessential not only for the acquisition of episodic memories, aslready discussed, but also for the acquisition of facts available toonscious awareness. H. M. could not create either kind of mem-ry. We propose that item information, such as that processednd stored by the inferior temporal and perirhinal cortex (Davies,alliday, Xuereb, Kril, & Hodges, 2009; Levy, Bayley, & Squire,004; Schmolck, Kensinger, Corkin, & Squire, 2002), is conveyed tohe granular prefrontal cortex, which, in turn, interacts with theippocampal complex through direct (prefrontal–hippocampal)athways as well as indirect ones (via entorhinal cortex). This ideaontrasts with the current orthodoxy, which views the perirhi-al and parahippocampal cortex as playing the key role, if nothe sole role, in funneling information into the hippocampus (e.g.,

ishkin et al., 1997). Thus, in considering a monkey model ofuman amnesia, we favor an approach that focuses as much onrefrontal-hippocampal interactions as on inputs to hippocampuselayed by entorhinal cortex. We do this in part because we doot ascribe special status to neocortical areas included in a “thing”alled the MTL (Murray & Wise, 2004). Prefrontal–hippocampalnteractions could complement inputs to the hippocampus relayedia perirhinal, parahippocampal and entorhinal cortex to underliehe acquisition of explicit semantic knowledge.

Finally, the ideas put forward here also lead directly to the pro-osed autonoetic functions of the prefrontal cortex (Wheeler etl., 1997), perhaps in association with the hippocampal complex.he phenomenological experience of remembering is thought toely on a self-knowing (i.e., autonoetic) consciousness (Tulving,001, 2002), a concept related to prospection (Buckner & Carroll,007). Suddendorf and Corballis (2007a) have proposed that thebility to place oneself in the past or future, termed mental timeravel (MTT), enables reconstruction of the particulars of pastvents. Recall what H. M. said about his daily life experience: “its like waking from a dream . . . every day is alone in itself . . ..”Section 2.1). Hurford (2007, p. 79) put this idea in the contextf episodic memory when he hypothesized “that an instance ofuman uniqueness is the inability of non-humans explicitly toecall episodes before the last period of sleep, related to a quali-ative difference. . . [in] MTT, which perhaps only humans can do.”urford (2007) also noted the connection between episodic mem-ry and a sense of self: episodic memory appears later in humanevelopment than does semantic memory, with neonatal amnesiaiving way to life-long conscious memories at about the same ages episodic memory first appears. Recall also the distinction drawny Maguire and her colleagues between two aspects of episodicemory: scene memory and embedding oneself in events (Section

.1). The latter involves the connection between episodic memorynd a sense of self. As Hurford (2007, p. 68) put it: “My episodicemories are memories of what I experienced—I was there.” Self-

eferential analysis, combined within an ability to navigate throughemembered and imaginary places and times, could be a key link

ologia 48 (2010) 2385–2405

between the novel knowledge generated by prefrontal cortex andthe ancestral function of the hippocampal complex in navigation.Together, cross-domain mappings in the granular prefrontal cor-tex, self-reference, and prefrontal-hippocampal interactions couldhave lead to a creative explosion.

8. Conclusion and summary

Neuropsychological research on animals remains an essentialtool for gaining a deep understanding of memory mechanisms andtheir failures. Notwithstanding its well known limitations, impair-ments in behavior caused by selective lesions or inactivationscan tell us something with a durable logic and a straightforwardinterpretation that other methods lack. We know that many neuro-scientists believe that functional neuroimaging, neurophysiologicalresearch, or others methods can provide the same insight. Everyneuroscientist has an opinion, of course, but these attitudes reflect adeep misunderstanding of the relevant research methods and theirinterpretational limitations. As important as they are, measuresof local blood-flow rates, neuronal spike density, and electricalpotentials of dubious provenance cannot substitute for the inter-pretational logic of experimental neuropsychology, perhaps betterunderstood by its traditional name: comparative and physiologicalpsychology.

Despite the promise offered by a monkey model of humanamnesia, its goals have yet to be attained. Nevertheless, the set-backs and false starts related in Section 3 point to problems inpractice, not deficiencies in principle. As the poet in our openingquotation says, humans are born to err in “reas’ning”, and the self-corrective aspect of science works reasonably well over the longterm. With improved experimental designs and interpretations,proper attention to control procedures, adherence to the principlesof comparative and evolutionary biology, and a forthright approachto the issue of animal consciousness, research on monkeys canachieve its goal of developing an improved and more useful modelof human amnesia.

In conclusion, we consider the baseball adage that you can’treplace somebody with nobody. That doesn’t mean a whole lot inthe world of memory research, and, in baseball, it doesn’t mean awhole lot more. But it does remind us to state an alternative to theorthodox model of human amnesia in equally attractive, parsimo-nious, and easy-to-remember terms. Section 4.1 cites precedentsfor some parts of our idea, which, despite many uncertainties, goeslike this: The hippocampal complex, through interactions with thecross-domain knowledge generated by the granular prefrontal cor-tex, creates conscious memories. It does so, in part, by extendingits ancestral function in spatial navigation to other forms of navi-gation, which guide an individual’s representation of self throughspace and time, ordered sequences of events, and the memories ofobjects, people, plants, and animals, not to mention cowardly lions.

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what, if anything, can monkeys tell us about human amnesia when they can’t say anything at all?

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