Understanding Anterograde Amnesia Disconnections

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EPS Mid-Career Award 2006

Understanding anterograde amnesia: Disconnectionsand hidden lesions

John P. AggletonCardiff University, Cardiff, UK

Three emerging strands of evidence are helping to resolve the causes of the anterograde amnesiaassociated with damage to the diencephalon. First, new anatomical studies have refined our under-standing of the links between diencephalic and temporal brain regions associated with amnesia.

These studies direct attention to the limited numbers of routes linking the two regions. Second, neu-

ropsychological studies of patients with colloid cysts confirm the importance of at least one of theseroutes, the fornix, for episodic memory. By combining these anatomical and neuropsychological datastrong evidence emerges for the view that damage to hippocampalmammillary bodyanterior thal-amic interactions is sufficient to induce amnesia. A third development is the possibility that the retro-splenial cortex provides an integrating link in this functional system. Furthermore, recent evidenceindicates that the retrosplenial cortex may suffer covert pathology (i.e., it is functionally lesioned)following damage to the anterior thalamic nuclei or hippocampus. This shared indirect lesioneffect on the retrosplenial cortex not only broadens our concept of the neural basis of amnesia butmay also help to explain the many similarities between temporal lobe and diencephalic amnesia.

Keywords: Temporal lobe; Fornix; Memory; Subiculum; Entorhinal cortex; Hippocampus;Hypothalamus.

Correspondence should be addressed to John Aggleton, School of Psychology, Cardiff University, Park Place, Cardiff, Wales,CF10 3AT, UK. E-mail: [email protected]

This review expands on the content of the Experimental Psychology Society (EPS) Mid-Career Award talk of the same titlegiven to the EPS in 2006. The author wishes to thank the support of the Medical Research Council (MRC) and Wellcome

Trust, as well as the valuable assistance of G. Poirier, S. D. Vann, and L. Woods.

# 2008 The Experimental Psychology Society 1441http://www.psypress.com/qjep DOI:10.1080/17470210802215335

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This review presents evidence for an integratedmodel of the neuroanatomy of anterogradeamnesia, and it also suggests that the causes ofamnesia might extend beyond the effects of visiblepathology to include hidden or covert pathology.Findings from both clinical and animal studies are

combined to try and answer a question that firstemerged over 100 years ago (Gudden, 1896;Korsakoff, 1887) with the first formal descriptionsof organic amnesia and its possible pathology.The question is whether we can identify the keystructures that when damaged cause permanentamnesia and then infer why these structures are soimportant for memory. As there are multiple candi-date structures in more than one brain region thistask is unlikely to be straightforward.

The focus of this review is on organic antero-

grade amnesia, a failure to learn new informationfollowing brain injury. Current definitions of ante-rograde amnesia (e.g., Parkin, 1997) emphasizethe presence of severe and permanent deficits forthe recall of recent events (typically with poor recog-nition) that contrast with intact short-term memory,IQ, semantic memory, skill learning, simple classicalconditioning, perceptual learning, and priming.Consequently, the most striking effect is a loss ofepisodic memory. Given these dissociations it isnot surprising that the study of anterograde

amnesia has delivered important insights into thedistinctions between long-term and short-termmemory (Baddeley, 1990) and between explicitand implicit memory (Schacter, 1987). Morerecently, studies of amnesia have been at the fore-front of the debate into whether recognitionmemory is a unitary process or whether it comprisesmultiple, distinct processes (Squire, Wixted, &Clark, 2007; Yonelinas, 2002). From a different per-spective, uncovering the anatomical basis of antero-grade amnesia provides the first line of targets forresearch into the physiological and molecular basisof recognition memory and episodic memory.

Towards an integrated model of temporallobe and diencephalic amnesia

Pathology in two distinct brain regions, the medialtemporal lobe and the medial diencephalon, is most

consistently associated with anterograde amnesia. Itis almost universally agreed that the critical regionfor temporal lobe amnesia is the hippocampal for-mation (Spiers, Maguire, & Burgess, 2001), althoughthereremains much debateover the extent and natureof the contributions from pathology in the adjacent

parahippocampal region (Witter & Wouterlood,2002). Although diencephalic amnesia was firstinvestigated long before temporal lobe amnesia, itsneural basis remains far less certain. Within the dien-cephalon, which comprises the thalamus and hypo-thalamus, evidence exists to implicate a range ofstructures. These structures include the mammillarybodies and various thalamic nuclei, including theanterior thalamic nuclei, nucleus medialis dorsalis,nucleus parataenialis, nucleus lateralis dorsalis, andintralaminar nuclei (Aggleton & Sahgal, 1993;

Gold & Squire, 2006; Harding, Halliday, Caine, &Kril, 2000; Kopelman, 2002; R. G. Mair, 1994;W. G. P. Mair, Warrington, & Weiskrantz, 1979;Markowitsch, 1982; Mayes, Meudell, Mann, &Pickering, 1988; Vann & Aggleton, 2004; Victor,Adams, & Collins, 1971, 1989).

Classical neuropsychological studies have failedto provide definitive evidence concerning theneural basis of diencephalic amnesia. Such evi-dence would have to come from patients with awell-characterized amnesia that is associated with

pathology restricted to just one structure con-firmed by postmortem. Given the close proximityof the various thalamic nuclei and the presenceof numerous white matter tracts running throughthe diencephalon, any convincing evidence maybe a long time in coming. Fortunately, there arenumerous clues that can be drawn from the neu-ropsychology of amnesia, from the neuroanatomi-cal connections of the various candidate regions,and from animal models where the pathologycan be highly selective.

The most parsimonious overview of the neuralbasis of episodic memory would be that temporallobe amnesia and diencephalic amnesia reflectdysfunctions in the same shared mnemonicsystem. This situation could occur if temporallobe damage results in permanent dysfunctionsin diencephalic function and vice versathat is,there is an integrated, interdependent medial

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temporal lobe medial diencephalic system.There are, however, at least three other models.One possibility is that the disruptive effects ofmedial temporal and medial diencephalicdamage on memory are via quite independentactions. A second possibility is that damage in

both medial temporal and medial diencephalicregions causes permanent dysfunction in a thirdcommon region, which is principally responsiblefor amnesia and, hence, unites these two regionsindirectly. A weakness with this proposal is thatit presupposes the existence of a third region pri-marily responsible for amnesia, yet anterogradeamnesia is most consistently linked to themedial temporal lobe and the medial diencepha-lon. While there are some sites (e.g., medial pre-frontal cortex and retrosplenial cortex) that have

been implicated in anterograde amnesia and areconnected directly to both regions, evidence fortheir preeminent importance for memoryremains much weaker than that for either themedial temporal lobe or medial diencephalon. These factors do, however, suggest anotherpossibility that is essentially a hybrid of two ofthe three previous modelsnamely, that thereis a common third site of dysfunction (capableof adding to the impact of either medial temporalor medial diencephalic damage) but this effect is

additional to the shared integrated dysfunctionthat arises from either medial temporal lobe ordiencephalic damage. It is this final modelthat is most strongly supported by the presentreview.

Those accounts that closely link the medialtemporal lobe and medial diencephalic substratesfor amnesia are strengthened by both neuropsy-chological and neuroanatomical (next section)findings (Aggleton & Saunders, 1997). First, thecore features of diencephalic and medial temporallobe amnesia appear strikingly similar. It is, ofcourse, inevitable that at some level the two syn-dromes must be very similarthat is, a particularlysevere and persistent loss of new episodic learn-ingwhile other cognitive abilities (e.g.,priming, procedural learning, and short-termmemory) appear largely intact (Squire, 2004).For a while it was thought that temporal lobe

amnesia, but not diencephalic amnesia, is associ-ated with abnormally fast rates of forgetting(Huppert & Piercy, 1979). These original findingsprovoked much interest, but follow-up studieshave repeatedly failed to find this dissociation(Freed & Corkin, 1988; Freed, Corkin, &

Cohen, 1987; Kopelman, 2002; McKee &Squire, 1992).

A further possible difference concerns the rela-tive disruption of temporal contextual information(i.e., when an event occurred) in temporal lobe anddiencephalic amnesia.

There is evidence that patients with diencepha-lic amnesia are especially impaired at using or recal-ling temporal contextual information (Hunkin &Parkin, 1993; Hunkin, Parkin, & Longmore, 1994;Kopelman, Stanhope, & Kingsley, 1997; Parkin &

Hunkin, 1993; Parkin, Leng, & Hunkin, 1990;Shimamura, Janowsky, & Squire, 1990). The signifi-cance of this dissociation is, however, weakened bythe fact that nearly all of the studies on temporalcontext in diencephalic amnesia refer to patients with Korsakoffs disease (Hunkin & Parkin, 1993;Hunkin et al., 1994; Kopelman et al., 1997; Parkinet al., 1990; Shimamura et al., 1990). Because ofthe aetiology of Korsakoffs syndrome, this class ofdiencephalic amnesics ismost likelyto have additionalfrontalcortex impairments.This additional pathology

is pertinent as prefrontalcortex damageis itselfassoci-ated with difficulties in recalling temporal context(Kopelman, 2002; Kopelman et al., 1997; Mayes,Meudell, & Pickering, 1985; Shimamura et al.,1990). For this reason, arguably clearer evidence foran exaggerated deficit in the use of contextual infor-mation in diencephalic amnesia comes from thosesingle case studies (e.g., Hunkin et al., 1994; Parkin& Hunkin, 1993) where direct prefrontal damageseems less likely. Given that nuclei in the midline,anterior, anddorsomedialthalamusallhave reciprocalprefrontal cortex connections that will often be com-promised in cases of diencephalic amnesia, it mayprove that contextual deficits, via a disruption of pre-frontal interconnections, are a more frequent featureof this form of amnesia. Even so, as frontal lobedamage can disrupt temporal contextual processingwithout causing amnesia (Shimamura et al., 1990),it could be argued that this impairment does not

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constitute a core deficit. Consequently it appears thattemporal lobe and diencephalic amnesia share manyof the same features with remarkably little to separatethem. This conclusion brings us to the issue of themedial temporal lobe connections with the medialdiencephalon and how these connections might

help discriminate between the candidate regions fordiencephalic amnesia.

Medial temporal lobemedial diencephalicinterconnections

In order to describe the relevant neuroanatomy it isfirst necessary to consider briefly the various candi-date sites for diencephalic amnesia (the mammillarybodies, anterior thalamic nuclei, nucleus medialisdorsalis, nucleus parataenialis, nucleus lateralis dor-

salis, and intralaminar thalamic nuclei). Two ofthese sites, the mammillary bodies and anteriorthalamic nuclei, stand out because of the conjunc-tion of both neuropsychological and neuroanatomi-cal findings. These structures are also notablebecause of their exceptionally close anatomicalrelationship; the principal efferent target of themammillary bodies is the anterior thalamic nuclei,these projections forming the mammillothalamictract (Vann, Saunders, & Aggleton, 2007).Furthermore, it is suspected that every cell in the

mammillary bodies projects to the anterior thalamicnuclei (Allen & Hopkins, 1988; Vann et al., 2007),though this is a one-way relationship with no returnprojections.

Pathology in the mammillary bodies andanterior thalamic nuclei has repeatedly beenlinked with diencephalic amnesia (Aggleton &Brown, 1999; Clarke et al., 1994; Dusoir, Kapur,Brynes, McKinstry, & Hoare, 1990; Gold &Squire, 2006; Harding et al., 2000; Hildebrandt,Mueller, Bussmann-Mork, Goebel, & Eilers,2001; Kopelman, 1995; Malamut, Graff-Radford, Chawluk, Grossman, & Gur, 1992; Tsivilis et al., 2008; Vann & Aggleton, 2004;Victor et al., 1971). It is important to note thatthese diencephalic amnesics show the same defin-ing features as those first described in theIntroduction (e.g., Clarke et al., 1994; Dusoiret al., 1990; Malamut et al., 1992; Squire,

Amaral, Zola-Morgan, Kritchevsky, & Press,1989). The mammillary bodies have long beenlinked with diencephalic amnesia (Gudden,1896) as these nuclei are always atrophied in theamnesic Korsakoffs syndrome. However, the pre-sence of concurrent pathology in other sites

(Harding et al., 2000; Victor et al., 1971, 1989)means that Korsakoff cases have failed to providedefinitive evidence. Examples of people withmammillary body damage as a result of tumoursor trauma (Dusoir et al., 1990; Hildebrandtet al., 2001; Tanaka, Miyazawa, Araoka, &Yamada, 1997) that do not appear to affect theother candidate diencephalic sites involved inKorsakoffs disease have proved to be very rare.Nevertheless, the few cases add support to the view that the mammillary bodies are necessary

for normal episodic memory (Vann & Aggleton,2004). At the same time, the memory deficitsassociated with mammillary body damage appearto be milder than those seen in amnesias wherethere is more widespread pathology (Kapur et al.,1998), suggesting the involvement of other areas.

The anterior thalamic nuclei have been stronglyimplicated in amnesia by a detailed, stereologicalanalysis of the pathology in Korsakoffs syndrome(Harding et al., 2000). In this study, neurodegen-eration in the anterior thalamic nuclei was the only

consistent pathology in alcoholic Korsakoff casesthat differentiated them from alcoholics with Wernickes encephalopathy (i.e., nonamnesiccases). Other evidence has come from neuropatho-logical analyses of rostral thalamic vascular accidentsthat result in amnesia. In some cases there is directdamage to the anterior thalamic nuclei (Clarkeet al., 1994; Ghika-Schmid & Bogousslavsky,2000; Pepin & Auray-Pepin, 1993), though thisdamage is never restricted to the anterior thalamicnuclei. More typically there is damage to themammillothalamic tract (Carlesimo et al., 2007;Malamut et al., 1992; Van der Werf, Jolles,Witter, & Uylings, 2003a; Van der Werf et al.,2003b; Van der Werf, Witter, Uylings, & Jolles,2000; Von Cramon, Hebel, & Schuri, 1985).Indeed, damage to the mammillothalamic tract, which carries projections from the mammillarybodies to the anterior thalamic nuclei, appears to


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be the best predictor of memory deficits after thal-amic strokes (Van der Werf et al., 2003a, 2003b;Van der Werf et al., 2000; Von Cramon et al.,1985). This finding may help to explain theamnesic case N.A. (Squire et al., 1989) who, fol-lowing a brain-penetrating injury with a miniature

fencing foil, sustained damage to the mammil-lothalamic tract along with the mammillarybodies, internal medullary lamina, and rostralmidline and intralaminar thalamic nuclei (centralmedial, reuniens, paracentral, central lateral, andrhomboid).

The mammillary bodies and the anterior thal-amic nuclei stand out from the rest of the medialdiencephalon for one other reason: Both receivedirect, dense inputs from the hippocampal for-mation (Aggleton, Desimone, & Mishkin, 1986;

Poletti & Creswell, 1977; Saunders, Mishkin, &Aggleton, 2005). These projections, which arisefrom the subicular complex and the entorhinalcortex, reach the diencephalon almost exclusively via the fornix (Aggleton et al., 1986; Aggleton,Vann, & Saunders, 2005b; Saunders et al.,2005). As shown in Figure 1, the only othermedial diencephalic structures to receive direct

innervations via the fornix are the thalamicnuclei reuniens, lateralis dorsalis, and paraventri-cularis, along with light projections to varioushypothalamic nuclei. Aside from nucleus lateralisdorsalis there is little current evidence to linkthese other nuclei with diencephalic amnesia,

although this could reflect the smallness of thesenuclei and the resultant difficulty of isolatingtheir contributions to memory.

Nucleus lateralis dorsalis is of interest forseveral reasons. First, this nucleus shares manyconnections with the anterior thalamic nuclei,and it has sometimes been categorized as part ofthe anterior thalamic group (Bentivoglio, Kultas-Ilinsky, & Ilinsky, 1993; Van Groen & Wyss,1992). Perhaps the major difference from theclassic anterior thalamic nuclei is that lateralis dor-

salis receives few, if any, inputs from the mammil-lary bodies (Vann et al., 2007). Interestingly, incontrast to the mammillary bodies and the anteriorthalamic nuclei, nucleus lateralis dorsalis receivesits direct hippocampal inputs via two parallelroutes in the primate brain (Aggleton et al.,1986; Saunders et al., 2005). Not only does thesubiculum project via the fornix but there is also

Figure 1. Diagrammatic representation of the location of the fornix and its divisions. The dashed arrows show fornical connections that aresolely efferent from the hippocampal formation, the narrow, solid arrows show fornical connections that are solely afferent to the hippocampal

formation, and the wide, solid arrows show reciprocal connections within the fornix. Abbreviations: AC, anterior commissure; ATN, anteriorthalamic nuclei; HYPOTH, hypothalamus; LC, locus coeruleus; LD, thalamic nucleus lateralis dorsalis; MB, mammillary bodies; RE, nucleusreuniens; SUM, supramammillary nucleus.




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a second route via the temporopulvinar bundle ofArnold. This second route runs caudally aroundthe pulvinar to reach lateralis dorsalis (Figure 2).

Functional evidence linking lateralis dorsaliswith the anterior thalamic nuclei and the mammil-lary bodies comes from electrophysiological

studies showing the presence of head directioncells in all three areas in rats (Blair, Cho, &Sharp, 1998; Mizumori & Williams, 1993;Taube, 1995, 1998). These head direction cellsfire when the head is pointed in a preferred direc-tion, set by distal visual stimuli, vestibular stimuli,or both. As a consequence, nucleus lateralis dorsa-lis contributes to spatial navigation, along with the

mammillary bodies and the anterior thalamicnuclei (Mizumori, Cooper, Leutgeb, & Pratt,2001; Taube, 1998; Vertes, Hoover, & Viana DiPrisco, 2004). Both lateralis dorsalis and theanterior thalamic nuclei are also functionallylinked by other electrophysiological studies,

which show a common pattern of training-induced activity during discriminative avoidancelearning (Gabriel, 1993). Lesion studies in rats(Aggleton & Brown, 1999; Aggleton, Hunt,Nagle, & Neave, 1996; Byatt & Dalrymple-Alford, 1996; Mizumori, Miya, & Ward, 1994;Sziklas & Petrides, 1998; Van Groen, Kadish, & Wyss, 2002; Vann & Aggleton, 2003, 2004;

Figure 2. Summary diagram showing the routes by which the hippocampus and parahippocampal region project to the thalamus. The thicknessof the lines reflects the density of the projection while the ovals group together the connections within a particular tract. The figure includes

previously published data concerning the efferents from the subiculum (Aggleton et al., 1986) and the parahippocampal region (Yeterian &Pandya, 1988). The perirhinal cortex consists of areas 35 and 36. Routes are not provided for the parahippocampal cortex as they have not yetbeen determined. Abbreviations: AD, anterior dorsal nucleus; AM, anterior medial nucleus; AV, anterior ventral nucleus; LD, nucleuslateralis dorsalis; MD, nucleus medialis dorsalis, including pars magnocellular (mc); PULV, pulvinar; TF, TH, parahippocampal cortex.


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Wilton, Baird, Muir, Honey, & Aggleton, 2001)have also shown that these same three structures(mammillary bodies, anterior thalamic nuclei,nucleus lateralis dorsalis) are required for thenormal learning of spatial tasks that are sensitiveto hippocampal lesions. Even though the severity

of the impairments often do not match thoseseen after hippocampal lesions, this pattern ofresults is clearly consistent with a functional linkwith the hippocampus.

At present, there is only limited neuropsycholo-gical evidence concerning nucleus lateralis dorsalis.In their review of postmortem cases of Korsakoffssyndrome, Victor et al. (1971) recorded lateralisdorsalis atrophy in 68% of their cases, placing itin the top three thalamic nuclei by frequency ofpathology. Similarly, Brion and Mikol (1978)

observed lateralis dorsalis abnormalities in 9 outof 11 Korsakoff cases, noting that it was themost frequent site of thalamic pathology in theirsample. In both studies, mammillary bodyatrophy was seen in all amnesic cases (Brion &Mikol, 1978; Victor et al., 1971). There is a lackof other clinical data on nucleus lateralis dorsalis,although a single case (Q.X.) described byEdelstyn, Hunter, and Ellis (2006) is informative.Q.X. suffers from marked deficits in verbalmemory as well as impaired recollection of the

Rey complex figure, with more subtle deficits inrecognition memory (Edelstyn, Ellis, Jenkinson,& Sawyer, 2002; Edelstyn et al., 2006). Recentmagnetic resonance imaging (MRI) scans indicate(Edelstyn et al., 2006) unilateral damage in themedial dorsal thalamic nucleus but bilateraldamage in lateralis dorsalis (called the dorsolat-eral thalamic nucleus in their paper). As thiswas the only site with suspected bilateral pathologythe authors argued that this nucleus might alsosupport memory.

Both the anterior thalamic nuclei and lateralisdorsalis have dense, reciprocal connections withthe retrosplenial cortex (areas 29, 30). This corticalregion, within the posterior cingulate area, pro-vides a potentially important, indirect route fromthe hippocampus to the anterior thalamic nucleiand lateralis dorsalis, as well as to the prefrontalcortex. The other key feature of these thalamic

nuclei (anterior and lateralis dorsalis) is that theyproject directly back upon the hippocampal for-mation (Amaral & Cowan, 1980; De Vito,1980). Once again, the retrosplenial cortex alsoprovides a potential route for indirect projectionsfrom the medial diencephalon to the medial tem-

poral lobe. For these neuropsychological and neu-roanatomical reasons the anterior thalamic nuclei(and lateralis dorsalis) stand out from all of theother candidate regions implicated in diencephalicamnesia as they are most likely to function recipro-cally with the hippocampus.

To test this view directly it is necessary to turn tostudies with animals. The first key finding is thatthe effects of selective anterior thalamic lesions andselective hippocampal lesions are alike in that theyboth disrupt tests of spatial learning and scene learn-

ing (Aggleton & Brown, 1999). Deficits have beenfound in both rats and monkeys on tasks thought tocapture aspects of episodic-like memorynamely,the ability to learn conjunctions between specificitems and their locations (Parker & Gaffan, 1997a,1997b; Wilton et al., 2001). Such learning tasks areof particular interest as they tax two (what? andwhere?) of the three key elements of episodic-likememory (Clayton & Dickinson, 1998). Direct evi-dencethat the anterior thalamic nucleiand the hippo-campus may be functionally interdependent comes

from disconnection studies with rats. In thesestudies crossed-unilateral lesions were made in thehippocampus and anterior thalamic nuclei,producingspatial memory deficits similar to those seen afterbilateral lesions in either structure (Henry, Petrides,St-Laurent, & Sziklas, 2004; Warburton, Morgan,Baird, Muir, & Aggleton, 2001).

An important test of this emerging medial tem-poralmedial diencephalic model is to examinethe effects of fornix damage on memory. Thefornix stands out because it is the primary routefrom the medial temporal lobe to the medial dien-cephalon (Figures 1 and 2). An integrated modelwould have to predict that fornix damage is suffi-cient to induce marked memory deficits, unlessthe functional interrelationships between the twoareas solely depend on the projections from thediencephalon to the hippocampal formation(which typically do not use the fornix). This




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latter scenario seems most unlikely given (a) thehigh density of the termination sites of the hippo-campal projections in the medial diencephalon,and (b) the reciprocal nature of many of theseconnections.

Do fornix lesions produce amnesia?

A seemingly definitive review that reported theoutcome of 193 patients who had received sur-geries in the region of the fornix concluded thatthere was no link between fornix damage andamnesia, reporting stereotaxic fornicotomies forepilepsy in which, to our knowledge, no persistentmemory loss has been reported so far (Garcia-Bengochea & Friedman, 1987, p. 363). Thisreported lack of any association between fornix

damage and amnesia was specifically noted bythe editor who added that the authors are to becongratulated for bringing this correlated neuro-pathological red herring to our notice so well.In spite of this plaudit, the quality of the evidenceused in their review was heavily criticized byGaffan and Gaffan (1991), and this criticism hasbeen followed by a spate of papers all describinghow fornix pathology is strongly linked to antero-grade amnesia (Aggleton et al., 2000; DEsposito,Verfaellie, Alexander, & Katz, 1995; Gaffan,

Gaffan, & Hodges, 1991; Hodges & Carpenter,1991; McMackin, Cockburn, Anslow, & Gaffan,1995; Poreh et al., 2006; Tsivilis et al., 2008;Vann et al., in press).

One valuable source of evidence has come fromthe study of patients with colloid cysts in the third ventricle (Figure 3). These benign tumours aresurgically removed to control hydrocephalus, butan occasional consequence of these tumours isthat the fornix is atrophied. In some cases, postsur-gical MRIs reveal that the tract is completelyinterrupted in one or both hemispheres. Carefulanalysis of these patients has shown that suchfornix interruption is associated with a clear ante-rograde amnesia (Aggleton et al., 2000; Gaffanet al., 1991; Gilboa et al., 2006; Hodges &Carpenter, 1991; McMackin et al., 1995; Porehet al., 2006) and, in some cases, with retrogradeamnesia as well (Gilboa et al., 2006). This

amnesia is evident in formal memory tests andmarkedly affects day-to-day life. Nevertheless, itis seemingly not as severe as that seen followingextensive bilateral medial temporal lobe ormedial diencephalic pathology.

Evidence from other aetiologies (e.g., varioustumours, trauma, vascular damage) also stronglysuggests that fornix loss can impair memory(DEsposito et al., 1995; Park, Hahn, Kim,Na, & Huh, 2000; Tucker et al., 1988; Vannet al., in press; Yasuno et al., 1999). Unfortunately,there is not a single reported amnesic case in which selective fornix loss has occurred withoutconcomitant damage elsewhere. Furthermore,many of the descriptions of fornix damage arehampered by the fact that they refer to singlecases. Even the few group studies of colloid cystcases have, until recently, only examined amaximum of 6 patients with bilateral loss of thefornix (McMackin et al., 1995) and a maximumof 12 colloid cyst cases, overall (Aggleton et al.,2000). Meanwhile, the presence of hydrocephalusin this condition, with its impact on other brainstructures (Tsivilis et al., 2008) makes it very

Figure 3. Magnetic resonance imaging (MRI) scan (midlinesagittal) of third ventricle colloid cyst. The colloid cyst (CC) liesimmediately adjacent to the fornix.


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difficult to rule out a contribution from otheraffected regions. As a consequence it may not bepossible to detect subtle cognitive deficits specifi-cally linked to fornix damage. Furthermore, noneof the neuropsychological studies has providedquantitative volume measurements of the fornix

or any other structures. This shortcoming meansthat it has never been possible to test whetherthe memory loss in this condition is actuallyassociated with the degree of fornix loss asopposed to the loss of any other structure.

In order to address these shortcomings werecently assessed an unusually large cohort ofcolloid cyst patients (n 38) who received stan-dardized psychometric (Tsivilis et al., 2008) andMRI volumetric (Denby et al., 2008, in press)measurement. All patients received surgery for

cyst removal at least 12 months prior to takingpart in the study. Memory testing including theWechsler Memory ScaleThird Edition (WMS-III), the Doors and People Test, and theWarrington Recognition Memory Test (WRMT), while the 3T MRI scanning protocols made itpossible to estimate the volumes of key structures(the mammillary bodies, fornix, hippocampus,entorhinal cortex, perirhinal cortex, parahippo-campal cortex, orbitomedial prefrontal cortex,orbitolateral prefrontal cortex, dorsomedial pre-

frontal cortex, dorsolateral prefrontal cortex, totaltemporal lobe, total hemisphere, and lateralventricles).

Memory deficits were widespread among the 38patients, even though only 3 had complete bilateralinterruption of the fornix. Careful analysis of thescans revealed that fornix atrophy (i.e., thinning without complete loss) was frequent, with over40% of both the left and right fornix volumes atleast one standard deviation below the meanfornix volume of a set of age-matched controls(Denby et al., in press). Of the other structuresmeasured, the most consistent changes werefound in the mammillary bodies, where over 50%of the left and right volumes were abnormallysmall (Denby et al., 2008).

To assess the possible impact of these pathol-ogies, correlations (n 38) were calculatedbetween the volumes of the 13 target brain

structures and the standard WMS-III memoryindices (Auditory Immediate, Visual Immediate,Immediate Memory, Auditory Delayed, VisualDelayed, Auditory Recognition Delayed, GeneralMemory, Working Memoryit is important tonote that the indices described as Immediate

refer to supraspan tasks that primarily tax long-term memory while the Auditory Recognitionindex tests recall as well as recognition). A veryclear pattern of results emerged: Mammillary bodyvolume was significantly correlated with all of theabove WMS-III Index scores, except for WorkingMemory (Tsivilis et al., 2008). In contrast, none ofthe other 12 structures correlated significantly witheven a single WMS-III index score.

For tests of recognition memory a very differentpattern was seen (Tsivilis et al., 2008). Here,

mammillary body volume and fornix volume cor-related with just one out of six recognition tests(Word Recognition, WRMT). Closer inspectionof the data from the Doors and People Test(which assesses both recall and recognition) wasespecially illuminating. Both left fornix volumeand left mammillary body volume correlated sig-nificantly with the overall recall scores, but not with the recognition scores. Indeed, fornixvolume and mammillary body volumes both corre-lated significantly with the Recall/Recognition

difference for this test (i.e., the smaller the struc-ture the greater the difference between these twoforms of memory).

While it is not clear whether the mammillarybody atrophy in the colloid cyst cases solelyreflected the loss of afferent hippocampal fibres(Loftus, Knight, & Amaral, 2000) or whether itwas partially caused by direct damage to the struc-ture, this study (Tsivilis et al., 2008) providesunusually strong evidence that hippocampal effer-ents within the fornix are vital for memory, withparticular support for the contributions of themammillary bodies. At the same time, both mam-millary body volume and fornix volume were farmore weakly correlated with recognition than with recall. This dissociation could be clearlyseen when the colloid cyst patients who had beenable to take all psychometric tests (n 34) weredivided into those in the bottom third with




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respect to mammillary body volume (n 11) andthose in the top thirdthat is, the caseswith largest mammillary body volumes (n 11). There was a highly significant group differencefor composite scores of recall performance(Figure 4). This group difference was found both

for tests of supraspan (immediate) recall andfor tests of delayed recall (Figure 4)that is,mammillary body atrophy was associated withpoor recall. In contrast, combining the scoresfrom the various recognition memory tests failedto reveal a difference between the two groups,resulting in a significant interaction betweengroup and type of memory task (recall versusrecognition).

This patternimpaired recall and relativelyspared recognition following fornix-mammillary

body atrophyis predicted by a particular modelof hippocampalmedial diencephalic interactions(Aggleton & Brown, 1999). In that model it isargued that the extended hippocampal systemcomprising the hippocampus, fornix, mammillary

bodies, and anterior thalamic nuclei is vital forthe encoding and, hence, subsequent recall of epi-sodic information. This same model also assumesthat recognition memory depends on two inde-pendent processes. One depends on the recollec-tion of the event (recollection); the other

depends on a signal of stimulus familiarity(knowing). Selective disruption of the extendedhippocampal system (e.g., fornix damage) should,therefore disrupt recollective recognition as itrelies on episodic memory. In contrast, famili-arity-based recognition is spared because parahip-pocampal areas (e.g., perirhinal cortex) can stillsupport this function. For this reason, the relativesparing of recognition in the colloid cyst caseswould have been predicted.

Following publicationof theAggletonand Brown

(1999) model other neuropsychological studies haveprovided support for the central features of themodel. Amnesics with selective hippocampaldamage can show a relative sparing of recognition(Aggleton & Brown, 2006; Aggleton et al., 2005a;Baddeley, Vargha-Khadem, & Mishkin, 2001;Bastin et al., 2004; Holdstock et al., 2002; Mayes,Holdstock, Isaac, Hunkin, & Roberts, 2002;Skinner & Fernandes, 2007; Yonelinas, 2002), withadditional evidence that this sparing reflects the pre-served use of familiarity (Aggleton et al., 2005a;

Bastin et al., 2004; Holdstock et al., 2002;Quamme, Yonelinas, Widaman, Kroll, & Sauve,2004; Turriziana, Fadda, Caltragirone, &Carlesimo, 2004; Yonelinas, 2002). Likewise, fornixdamage can disproportionately impair recall(Aggleton et al., 2000; Gilboa et al., 2006;McMackin et al., 1995; Vann et al., in press), withevidence that familiarity-based recognition is spared(Aggleton et al., 2000; Gilboa et al., 2006).Similarly, mammillary body damage appears tospare recognition (Dusoir et al., 1990; Hildebrandtet al., 2001), and, while comparisons between famili-arity-based and recollective-based recognition haveyet to be reported in such cases, our data from the38 colloid cyst patients would support such a distinc-tion. In accord with this view, there is evidence thatmammillothalamic tract damage also targets therecollective aspect of recognition with relativesparing of familiarity (Carlesimo et al., 2007).

Figure 4. Comparison between the 11 colloid cyst cases with thesmallest mammillary bodies (small MB) and the 11 cases with thelargest mammillary bodies (large MB). The bar graphs show themean scaled scores (Y axis, population norm 10.0) for the tests

of recall and recognition from the Wechsler Memory ScaleThirdEdition (WMS-III) and the Doors and People Test. Results aredivided into immediate recall (I; 7 tests), delayed recall (D; 7tests), and recognition (6 tests)see Tsivilis et al., 2008. Theterm immediate does not refer to tests of short-term memory.While those patients with the smallest mammillary bodies aresignificantly worse on both recall measures, this difference was not

found for recognition (Warrington Recognition Memory Test,WRMT; Doors & People; Face Recognition tests from WMS-III).


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It is, however, the case that not all patients witheither fornix or hippocampal damage show a relativesparing of recognition (Cipolotti et al., 2006;Kopelman et al., 2007; Manns, Hopkins, Reed,Kitchener, & Squire, 2003; J. M. Reed & Squire,1997). Furthermore, there remains much debate

over the validity of two-process models of recog-nition (Squire et al., 2007). It has been argued thatan alternative approach is to fit the data into aunitary model of recognition (Donaldson, 1996;Squire et al., 2007). In particular, it is suggestedthat a single continuum based around signal strengthcan account for current findings, such that strongmemories are perceived as recollective while weakmemories are only perceived as familiar (Squireet al., 2007). Because such models benefit from par-simony it could be argued that they should provide

the default explanation. A further, related issue con-cerns the validity of psychological tests purported todiscriminate familiarity-based recognition fromrecollective-based recognition (Squire et al., 2007; Wais, Mickes, & Squire, 2008). This issue stemsfrom the fact that any attempt to derive separatemeasures of these two putative aspects of recognitionmemory depends on making assumptions that arethemselves difficult to prove independently.

One solution might be to look for patientgroups who show comparable levels of recall yet

differ markedly on recognition. At the same timeit would be necessary to match for task difficulty(recall vs. recognition) and to avoid ceiling orfloor effects. Matching for task difficulty is,however, problematic because methods of testingrecall and recognition are fundamentally different(e.g., two stimulus forced-choice recognition with a chance rate of 50%). One solution is tocalibrate scores against population norms (e.g.,Z scores) and then compare. With these con-straints in mind it is informative to consider per-formance of the colloid cyst patients (Tsiviliset al., 2008) on the Doors and People Test.Not only does this test compare recall and recog-nition, but the recognition tests are sufficientlydemanding to remove ceiling effects.

Comparisons between the subgroups withlarge mammillary bodies (n 11) and withsmall mammillary bodies (n 11) showed that

the latter group suffered a significant recalldeficit based on the mean scaled scores, butthere was no difference for recognition (Tsiviliset al., 2008). Furthermore, the mean recallscores (for the large mammillary subgroup) andthe mean recognition scores (for both the large

and the small mammillary body subgroups) didnot differ from age-matched population normsfor the Doors and People Testthat is, theresults were not compromised by scaling effects. This pattern of results (spared recognition butimpaired recall) is difficult to reconcile with aunitary model as it would be supposed that a dis-proportionate loss of strong memories wouldimpact on recognition as well as recall. A similarconclusion comes from a single case study ofa man with bilateral fornix damage following

tumour removal (Vann et al., in press). Despitehaving persistent problems in learning new episo-dic information he was able to show normal per-formance levels on the Warrington RecognitionMemory Test even when a delay of 24 hr wasimposed between sample presentation and test(normally the test phase immediately followsthe sample phase). This manipulation makesthe task appreciably harder, and so one wouldpredict that a person more reliant on weakmemories (as predicted by the unitary model)

would make more errors, yet this pattern wasnot found (Vann et al., in press).Not surprisingly the Doors and People Test has

previously been used with amnesics (e.g., Aggletonet al., 2000; Manns & Squire, 1999). In one ofthese studies (Manns & Squire, 1999) hippocam-pal damage following anoxia was associated withcomparable recall and recognition deficits, apattern of results qualitatively different to thatdescribed here after fornix damage associatedwith colloid cysts (Aggleton et al., 2000; Tsiviliset al., 2008). While this difference is not yet fullyunderstood, it may reflect the complexity of fullydescribing the pathological changes followinganoxia (see section Assumptions about lesionstudies).

A consideration of the anatomy of the fornixprovides other clues and predictions concerningthis mnemonic system. While the primate fornix




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contains a great many fibres originating in the hip-pocampal field CA3 (Saunders & Aggleton,2007), the direct projections to the mammillarybodies and anterior thalamic nuclei arise almostentirely from the subicular region (Figure 5;Aggleton et al., 1986; Rosene & Van Hoesen,

1977; Saunders et al., 2005). If, as suggested,these particular efferents are vital for episodicmemory, then bilateral pathology of the subicularcortices that spares the CA fields of the hippo-campus should be sufficient to induce an antero-grade amnesia. At present this predictionremains untested.

The fornix also contains a great number offibres running to sites other than the diencephalonthat could potentially support memory and soexplain why fornix damage might induce

amnesia. Most notable among these projectionsare those to the prefrontal cortex and theseptum/basal forebrain. The dense, reciprocalconnections between the hippocampal formationand the septal/basal forebrain complex are ofespecial interest as the septum/diagonal band provides the principal source of cholinergic innervations to the hippocampus (Alonso, U, &Amaral, 1996). It has been assumed that these

hippocampal afferents support mnemonic(Hasselmo, Wyble, & Wallenstein, 1996) andattentional (Baxter & Chiba, 1999) processes.One particular aspect of these hippocampal affer-ents that has received a great deal of attention isthat both cholinergic and GABAergic (where

GABA denotes gamma-aminobutyric acid)inputs from the septum appear to generate andcontrol hippocampal theta rhythm (Vertes &Kocsis, 1997). Linked to this discovery is thegrowing consensus that theta is important foreffective hippocampal encoding (Hasselmo,2005; Hasselmo & Eichenbaum, 2005; Vertes,2005).

This functional description of the efferentsfrom the basal forebrain to the hippocampus mayinitially seem to contradict the emphasis placed

on the importance of medial temporal projectionsto the medial diencephalon throughout thisreview. In fact, these two viewpoints are notmutually exclusive. One possibility is that thefunctions of the septal/basal forebrain connectionsvia the fornix are to optimize the activity of thehippocampus/entorhinal cortex prior to or aftertheir interactions with the medial diencephalon.In other words, by having essentially different

Figure 5. Source of fornix fibres from within the medial temporal lobe in the rhesus monkey (Macaca mulatta). The percentages refer to the proportion of retrogradely labelled cells following the implantation of horseradish peroxidase gel in different sites within the fornix.Abbreviation; MTT, mammillothalamic tract. (Data from Saunders & Aggleton, 2007.)


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roles these two sets of hippocampal connections donot replace each other, and both are likely to beneeded for effective hippocampal functioning.

A rather different proposal (Gaffan, 2002) isthat dense medial temporal lobe amnesia arisesfrom widespread disruptions of temporal cortical

function, and that a key element of this syndromeis the loss of inputs from the basal forebrain andmidbrain (Easton, Ridley, Baker, & Gaffan,2002; Gaffan, 2002; Turchi, Saunders, &Mishkin, 2005). It is also argued that whilefornix damage contributes to the full syndrome,it only produces a mild version as the loss of thistract is not sufficient to completely disrupt corticalplasticity (Gaffan, 2002). The same proposal alsoacknowledges the potential, additional contri-bution from efferents via the fornix to the medial

diencephalon (Easton et al., 2002). The notionthat fornix damage will not induce an amnesia assevere as that seen after extensive bilateral medialtemporal damage (Gaffan, 2002) is, indeed, con-sistent with case descriptions (e.g., McMackinet al., 1995). Nevertheless, the loss of this tract issufficient to induce the core features of theamnesic syndrome, except that recognitionmemory can be spared. This sparing presumablyreflects a relative lack of impact of fornix loss onthe parahippocampal cortices (Brown &

Aggleton, 2001). Furthermore, the notion thatthe underlying deficit in amnesia is a loss of corti-cal plasticity (Gaffan, 2002) does accord withmuch of the present proposal as the impact offornix loss is not just upon the medial diencepha-lon but is also indirectly upon regions such as theretrosplenial and medial prefrontal cortices(Aggleton & Brown, 2006; Garden et al., 2008;Garden et al., 2006; Vann, Brown, Erichsen, &Aggleton, 2000a, 2000b; see section Covert path-ology, amnesia, and the retrosplenial cortex).Points of difference would appear to be thegreater emphasis that is placed on the importanceof hippocampal dysfunction in the present modeland the anatomical routes by which this can occur.

A consideration of the anatomy of the extendedhippocampal system shows that the anterior thal-amic nuclei project back upon the hippocampus(not via the fornix), and so it is quite plausible

that many of the critical hippocampaldiencepha-lic interactions are reciprocal. This view fits withthe concept of a closely integrated system. Littleis known, however, about the ways in which themedial diencephalon might act back upon the hip-pocampal formation, and it is necessary to rely on

experiments with animals where it is possible toproduce selective manipulations among the manydiencephalic nuclei. Studies with rats have shownthat anterior thalamic lesions induce abnormalitiesin hippocampal activity as measured by immedi-ate-early gene activity (Jenkins, Dias, Amin, &Aggleton, 2002a; Jenkins, Dias, Amin, Brown,& Aggleton, 2002b; see section Anterior thalamiclesions and covert pathology). More diffuse thal-amic lesions reduce the release of hippocampalacetyl choline (Savage, Chang, & Gold, 2003).

There is also convincing lesion evidence to con-clude that navigation mechanisms that rely onhead direction cells are dependent on the projec-tions from the mammillary bodies (lateral mam-millary nucleus) to the anterior thalamic nuclei(anterior dorsal thalamic nucleus) and, thence, tothe hippocampus (Bassett & Taube, 2005; Blairet al., 1998; Taube & Muller, 1998). Theseexamples establish the principle that the medialtemporal medial diencephalic interdependencymay best be seen as reciprocal (Vann &

Aggleton, 2004). As a consequence, the discon-nection studies with rats (Henry et al., 2004;Warburton et al., 2001), which have shown thatthe hippocampus and anterior thalamic nuclei areinterdependent for at least some aspects ofspatial learning, cannot determine in which direc-tion the effects are most critical.

Finally, as alluded to earlier (in the sectionTowards an integrated model of temporal lobeand diencephalic amnesia), there is a further,more complex way in which these regions mightbe functionally linked. There could be a thirdregion that is anatomically connected with boththe hippocampus and the anterior thalamicnuclei, and which functionally links these struc-tures. One candidate region of considerablecurrent interest is the retrosplenial cortex (see thesection Covert pathology, amnesia, and theretrosplenial cortex). Rather than argue that




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the retrosplenial cortex is the sole common sourceof temporal and diencephalic anterograde amnesia,a much more plausible case can be made that dys-functions in this cortical area contribute to bothdiencephalic and temporal lobe amnesias and,hence, increase their similarity. In order to con-

sider the evidence for this novel notion it is necess-ary to first consider the ways in which lesionevidence is usually presented and interpreted.

Assumptions about lesion studies

The functional effects of brain damage never occurin isolation. At the same time, interpreting theoutcome of selective brain injury remains one ofthe most powerful tools in the quest to understandthe relationship between brain structure and func-

tion. It should, however, be remembered thatlesion studies do not examine the functions ofthe structure removedrather they study theextent to which the brain can compensate in theabsence of that structure. Even so, the traditionalfocus has been on describing overt structuraldamagefor example, defining lesions by theextent of cytoarchitectonic damage as seen inNissl stained sections. The implicit assumptionbehind this approach is that other intact structurescan perform normally apart from any disconnec-

tion of information caused by the lesion (be itafferent or efferent).At this point, a critical distinction must be

made. All researchers would accept that anylesion will cause a minimum of two other brainregions to behave abnormallyfor example, by aloss of afferent information and the loss of anefferent target. The question to be consideredhere is whether the distal effects of conventionallesions can be much more than just deafferenta-tion. It should first be recognized that somelesions will cause overt pathology in sites outsidethe primary lesion target. There are numerousexamples of anterograde or retrograde degener-ation (e.g., prefrontal cortex lesions causing celldeath and associated gliosis in the thalamicnucleus medialis dorsalis), but these effects arestill overt. The issue here is whether covert orcryptic pathology can occur. The defining

feature of such instances would be intact cytoarch-itecturethat is, no overt cellular changes orgliosiscombined with a persistent abnormalityin the way in which that structure processes allafferent or efferent information so that it is func-tionally rendered as lesioned.

There is, in fact, a long history to the notionthat damage to one part of the brain can have itseffects at a distance (Finger, Koehler, & Jagella,2004). Probably the most influential notion isthat of diaschisis. This term is most closelylinked with the work of Constantin vonMonakow (Finger et al., 2004; von Monakow,1911) although his ideas were predated by othersfrom the 19th century. The diaschisis theory sup-posed that in addition to the temporary effects oftrauma (oedema, changes in blood flow), the

mere disconnection of an area could induceimpairment of function in that area. The term dia-schisis was usually applied to transient disruptionsfollowing acute injury, which von Monakow(1911) saw as an abolition of local excitability.Different rates of recovery could, however, befound in different regions (Finger et al., 2004),and while the emphasis was on recovery vonMonakow also supposed that some remote dia-schisis effects could be very long lasting (diaschisisprotractiva). The concept of diaschisis was very

important both in attempting to understand howrecovery from brain insult may occur and in broad-ening our interpretations of lesions. The problem with this concept was how best to define andmeasure such hidden pathology. As a consequence,there still remains a debate over the existence ofcovert pathology and its relevance for amnesia.

Covert pathology, amnesia, and theretrosplenial cortex

The debate over whether covert pathology con-tributes to amnesia has up to now focused on tem-poral lobe amnesia (for opposing views seeBachevalier & Meunier, 1996; Squire & Zola,1996). The term covert pathology is used to referto an area that appears normal by standard histo-logical means and yet is functionally lesioned. Itis assumed that these changes are permanent and


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that they do not just reflect a disconnection ofspecific information (even though they arecaused by a disconnection). The task would be toconfirm that a region is rendered functionallyunresponsive following distal damage, even whenit is stimulated by surviving pathways.

In the case of temporal lobe amnesia much ofthe debate has centred on the extent of functionalbrain damage following hypoxia or occlusion ofthe posterior cerebral artery. The latter procedureproduces ischaemic damage in the hippocampus.It has been observed in monkeys that the effectsof ischaemic hippocampal damage on tests of rec-ognition memory are more disruptive than con-ventional lesions even though the apparent extentof cellular loss is comparable (Bachevalier &Meunier, 1996; but see Squire & Zola, 1996).

Brain imaging studies have added weight to theidea that the functional lesion in anoxia mightextend beyond the evident physical lesion (Grubbet al., 2000; Markowitsch, Weber-Luxemburger,Ewald, Kessler, & Heiss, 1997). Arguably themost striking result is that by Mumby and co-workers who first compared conventional hippo-campal lesions with hippocampal lesions inducedby vascular occlusion in rats (Mumby et al.,1996). While the former method had little orno effect on recognition (Mumby, 2001), the

ischaemic preparation produced robust deficits(Mumby et al., 1996; Wood, Mumby, Pinel, &Phillips, 1993). While the latter method led togreater recognition deficits, it did not producemore hippocampal damage. The quite remarkablething about this study was the discovery that conventional hippocampal lesions made prior tovascular occlusion resulted in a smaller recognitiondeficit than that seen after occlusion only (Mumbyet al., 1996). This finding was interpreted asshowing that hippocampal activity in response tothe vascular insult normally provokes hiddenchronic dysfunctions in extrahippocampal areas,but these effects are protected by first removingthe hippocampus. A problem for this type ofinterpretation remains the difficulty of specifythose sites suffering covert pathology, closely lin-ked to the problem of finding a suitable markerfor this putative effect.

One possible site for covert pathology in bothtemporal amnesia and diencephalic amnesia isthe retrosplenial cortex. It has long been appre-ciated that the retrosplenial cortex has dense,reciprocal connections with both the anteriorthalamic nuclei and hippocampal formation.

Neuropsychological studies of amnesia have alsoshown that damage to this area can cause ante-rograde amnesia (Maguire, 2001b; Rudge &Warrington, 1991; Valenstein et al., 1987; Yasuda, Watanabe, Tanaka, Tadashi, & Akiguchi, 1997)and topographical amnesia (Maguire, 2001b;Yasuda et al., 1997). Furthermore, functional neuroi-maging studies repeatedly find raised retrosplenialactivity during a range of memory (Cabeza &Nyberg, 2000; Maddock, Garrett, & Buonocore,2001; Maguire, 2001a, 2001b) and spatial navigation

(Epstein, Parker, & Feiler, 2007; Iaria, Chen,Guariglia, Ptito, & Petrides, 2007) tasks. It follows,therefore, that a hypothetical loss of retrosplenialfunction should contribute to the memory deficitscaused by damage to a remote area (unless thefunctional effects are completely redundant).

Lesion studies with rats also reveal the import-ance of the retrosplenial cortex for learning andmemory, with the majority of studies confirmingthe importance of this region for spatial memory(Aggleton & Vann, 2004; Cooper & Mizumori,

2001; Sutherland & Hoesing, 1993; Whishaw,Maaswinkel, Gonzalez, & Kolb, 2001) includinglearning the locations of specific objects (Vann &Aggleton, 2002). These deficits are similar tothose seen after both hippocampal and anteriorthalamic lesions, consistent with the close anatom-ical relationships between these three regions. It isalso noteworthy that the retrosplenial cortex islinked to spatial navigation in both rats andhumans, which has itself been closely linked toepisodic memory (Bird & Burgess, 2008).

Evidence to suppose that the retrosplenialcortex might suffer covert pathology largelycomes from animal studies. One of the first discov-eries was that the retrosplenial cortex is abnormallysensitive to drugs that act upon glutamate recep-tors. Following systemic NMDA blockade, pyra-midal and multipolar cells in layers III and IVof the retrosplenial cortex swell at low drug




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doses, with cell death (overt pathology) at higherdoses (Olney, Labruyere, & Price, 1989; Olney,Sesma, & Wozniak, 1993). These findings suggestthat distal lesions that change glutamatergicactivity in the retrosplenial cortex might bringabout subtle pathological changes in this cortex.

It is also known that the retrosplenial cortex issensitive to local NMDA blockade in the anteriorthalamus (Tomitaka, Tomitaka, Tolliver, &Sharp, 2000). Given that the dense inputs fromthe anterior thalamus to the retrosplenial cortexare primarily glutamatergic (Gonzalo-Ruiz, Sanz,Morte, & Lieberman, 1997), it might be predictedthat the loss of these inputs could severely affectretrosplenial function.

Anterior thalamic lesions and covertpathology

Because covert pathology is, by definition,hidden it is necessary to look for a marker of neur-onal function that could become abnormal, eventhough the neurons under investigation appearnormal. The class of markers we have concentratedon in our research are known as immediate-earlygenes. It has long been known that neurons caninfluence other neurons via ion gated channels atthe synapse to increase or decrease the likelihood

of a postsynaptic action potential. It is also nowclear that trans-synaptic activation can also stimu-late slower, longer term changes in the postsyn-aptic neuron that involve the induction ofprogrammes of gene expression. Genes that areresponsive to trans-synaptic activation fall intotwo general classes: Immediate-early genes areactivated rapidly (within minutes of neuronalstimulation) while late-response genes areinduced (or repressed) more slowly and are depen-dent on new protein synthesis (Sheng &Greenberg, 1990). As immediate-early genes areactivated without the need of a protein messengerthey are seen as de novo. Their relatively earlyactivation, combined with the fact that someimmediate-early genes (e.g., c-fos) are inducibletranscription factors that can orchestrate the tran-scription of other downstream genes places themas potential candidate markers of covert pathology.

This is because their role at the head of a cascade ofchanges means that abnormal immediate-earlygene activity is likely to signal a broad array ofother changes.

A further reason for measuring immediate-earlygene activity is that some immediate-early genes

(e.g., Arc, zif268, c-fos) have a role in synaptic pro-cesses thought to be central to plasticity and learn-ing (Bozon, Davis, & Laroche, 2002; Countryman,Kaban, & Colombo, 2005; Davis, Bozon, &Laroche, 2003; Guzowski, Setlow, Wagner, &McGaugh, 2001; He, Yamada, & Nabeshima,2002; Tischmeyer & Grimm, 1999; Vann et al.,2000a, 2000b). While immediate-early genes arenot direct markers of neuronal activity, as thesegenes can have very different baseline levels ofactivity in different brain sites, and there are

occasions when their activity does not parallel neur-onal activity (Herdegen, 1996), these genes may beappropriate assays of retrosplenial cortex function.It is, for example, known that c-Fos activity isincreased in the retrosplenial cortex following theperformance of spatial memory tasks that are sensi-tive to retrosplenial lesions (Vann & Aggleton,2002). In addition, the retrosplenial cortex showsrelatively high baseline levels of both c-Fos andZif268, and so any hypometabolism is unlikely tobe hidden by floor effects.

The first studies, therefore, looked at theimmediate-early gene status of the rat retrosple-nial cortex following anterior thalamic lesions.Over a series of studies we repeatedly foundthat that anterior thalamic lesions result in dra-matic losses of retrosplenial immediate-earlygenes activity without overt pathology (Jenkins,Vann, Amin, & Aggleton, 2004; Figures 6, 7).Both bilateral and unilateral excitotoxic(NMDA) lesions of the rat anterior thalamicnuclei cause spectacular decreases in c-Fosactivity in the retrosplenial cortex (Jenkinset al., 2002a, 2002b, 2004). Our studies haveshown that: (a) Anterior thalamic nuclei lesionscause massive reductions in c-Fos levels (80% ormore) that are most dramatic in the superficiallayers of the granular retrosplenial cortex (Rga,Rgb; Figures 6, 7); (b) anterior thalamic nucleilesions cause even greater c-Fos depletions in


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rats 10 months postsurgery, and that thesedepletions also become evident in the dysgranular

retrosplenial cortex and the deeper laminae of thegranular regions; (c) anterior thalamic nucleilesions do not affect just one immediate-earlygene as matching patterns of Zif268 depletionsare also found (Jenkins et al., 2004); (d) the Foschanges are not specific to the lesion technique(both neurotoxic and radio-frequency lesionshave the same effect) or strain of rat; (e) thislesion-induced hypoactivity is not universal for

all retrosplenial disconnections as lesions of theentorhinal cortex, a region that is reciprocally

connected to the retrosplenial cortex (Burwell &Amaral, 1998), have little or no effect onFos levels (Albasser, Poirier, Warburton, &Aggleton, 2007); (f) anterior thalamic lesions donot alter the appearance of the retrosplenialcortex, as determined by standard histologicaltechniques (see also Van Groen, Vogt, & Wyss,1993) or counts of Nissl stained cells (Jenkinset al., 2004)that is, the changes are covert.

Figure 6. Photomicrographs of coronal sections showing c-Fos-positive cells (dark) in the rat retrosplenial cortex (granular B). The left section(A) is from a normal brain; the right section is from a brain in which there is a lesion in the anterior thalamic nuclei (ATN). The loss of c-Fosin the superficial layers following the lesion is immediately apparent, while there is no change in deeper layers. Scale bar 200 ml.

Figure 7. Bar graphs showing c-Fos positive cell counts in retrosplenial cortex (Rga, Rgb, Rdg), as well as primary auditory cortex (AUD)insula cortex (AIP), motor cortex (MOP), and primary visual cortex (VISP) following excitotoxic lesions in the anterior thalamic nuclei (left:data from Jenkins et al., 2002b) and hippocampal formation (data from Albasser et al., 2007). Counts in each region are compared with those

from a control brain (left) or control hemisphere (right), and so a score of 100 reflects an identical count in the lesioned and intact hemispheres.By distinguishing the retrosplenial counts for the superficial layers (IIII) and for all layers it can be seen that anterior thalamic lesions have amuch greater impact on superficial c-Fos levels.




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The anterior thalamic nuclei have direct con-nections with the retrosplenial cortex, and so itis important to consider why the observed retro-splenial immediate-early gene hypoactivitymight reflect a more fundamental disturbance ofcortical function than just the loss of one source

of afferent information. Evidence against themere disconnection view comes from thefinding that layers II and upper III of retrosplenialcortex show by far the most extreme loss of Fos-positive cells (80% plus) while the deeper layerscan appear unaffected. This distribution doesnot reflect those laminae with thalamic inputs,as these projections terminate in a variety oflayers (I, II, IV; Van Groen & Wyss, 2003).More importantly, the anterior thalamic lesionsleave intact a wide array of other excitatory

inputs (Gonzalo-Ruiz et al., 1997) to the super-ficial retrosplenial cortex (e.g., from the subicu-lum, postsubiculum, lateral dorsal thalamicnucleus, and entorhinal cortex; Figure 8). Evenso, c-Fos activity is still massively suppressedafter anterior thalamic lesions under a widearray of behavioural conditions (Jenkins et al.,2004). More compelling evidence has comefrom the recent finding that cutting the mammil-lothalamic tract is sufficient to cause strikingdecreases of retrosplenial cortex immediate-early

gene levels (Albasser & Vann, 2007). This

surgery only indirectly disconnects the retrosple-nial cortexthat is, all direct inputs remainintact (Figure 8)yet the immediate-early geneloss is similar to that seen after anterior thalamiclesions. Thus, it seems increasingly unlikely thatthe immediate-early gene loss just reflects a

decrease of neuronal activity as so many inputsare left intact.

Other evidence that retrosplenial cortex func-tion depends on the integrity of the anterior thala-mus comes from a crossed lesion study in rats(Sutherland & Hoesing, 1993). Unilateral lesionsof the anterior thalamic nuclei combined with uni-lateral retrosplenial cortex lesions in the contralat-eral hemisphere lead to spatial memory deficits inthe Morris water maze. The covert pathology viewwould have to predict such a result, but more tra-

ditional explanations can also account for theseresults. Likewise, recording studies show thatanterior thalamic lesions markedly disrupt retro-splenial function (Gabriel, 1993; Gabriel et al.,1983). Not only has it been found that the cellsin the rabbit retrosplenial cortex show training-induced activity that parallels acquisition of anavoidance task, but this plasticity does not developfollowing anterior thalamic lesions (Gabriel, 1993;Gabriel et al., 1983).

Even more striking evidence that anterior thal-

amic inputs might be needed for the maintenance

Figure 8. Schematic diagram showing sources of inputs to the retrosplenial cortex. The multiple afferents should ensure that when one source isremoved the cortex is only partially deafferented. Abbreviations: AD, anterior dorsalis; AM anterior medialis; AV, anterior ventralis.


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of retrosplenial plasticity comes from a recentelectrophysiological study of retrosplenial cortexslices (Garden et al., 2008; Garden et al., 2006).Unilateral anterior thalamic lesions were made inrats that were sacrificed five weeks after surgery.Comparisons were then made between the retro-

splenial slices from the two hemispheres. Whileit was possible to induce long-term depression(LTD) in slices from the intact hemisphere, thiswas not the case for the slices from the hemisphere with a thalamic lesionthat is, having a distallesion in the thalamus disrupted retrosplenial plas-ticity (Figure 9). This loss of LTD was found inthe superficial cell layers in the retrosplenialcortex and so corresponds to the cortical laminashowing the most pronounced immediate-earlygene loss after anterior thalamic lesions. This

loss of plasticity is especially informative as it ishard to ascribe it to an absence of afferent stimu-lation as stimulation was applied locally by theexperimenter (Garden et al., 2008; Garden et al.,2006). Indeed, no changes in fast glutamatergicsynaptic transmission were found in retrosplenialcortex slices following anterior thalamic lesions,nor any cell loss. For this reason, the LTDdeficit cannot be due to the loss of actual afferentinformation, as matching patterns of stimulationwere applied in both sets of slices. Therefore, by

most standard measures this cortex appearednormal following anterior thalamic lesions.Nevertheless, there were intrinsic plasticityabnormalities within the cortex caused by the thal-amic lesion several weeks earlier.

A very different approach was then used to tryand identify the nature of these intrinsic changes.All previous assessments of immediate-early geneactivity provided only a very narrow picture of ret-rosplenial gene activity following anterior thalamiclesions as only two genes were studied in a singleexperiment. Microarray technology was next usedin order to give a more global picture of geneactivity change following anterior thalamiclesions (Poirier et al., in press). Rats with unilat-eral, anterior thalamic lesions were exposed to anovel environment for 20 min, and granular retro-splenial tissue was sampled from both hemispheresafter 30 min, 2 hr, or 8 hr.

Complementary analytical approaches revealedpervasive gene expression differences between theretrosplenial cortex ipsilateral to the thalamiclesion (lesion) and contralateral to the lesion(intact). The expression of many genes wasreduced after thalamic lesions, and pathways that

exhibited lower relative levels of specific mRNAsincluded both energy metabolism and plasticity-related pathways (signal transduction and tran-script/protein regulation). These changes infunctional gene expression may be driven bylesion-associated changes in the expression ofmultiple transcription factor genes, including brd8,c-fos, fra-2, klf5, nfat5, neuroD1, nfix, nr4a1,RXRg, smad3, smarcc2, and zfp91 (Poirier et al., inpress). These microarray findings confirm that theretrosplenial changes are not just confined to a few

immediate-early genes but also provide insightsinto how reductions in metabolic activity and aloss of plasticity might follow remote thalamiclesions.

Hippocampal lesions and retrosplenialactivity

Another major input to the retrosplenial cortexoriginates from the hippocampal formation(Wyss & Van Groen, 1992), raising the question

of whether the loss of these inputs might alsomarkedly disrupt retrosplenial function. Prior evi-dence comes from crossed disconnection lesionstudies showing that the hippocampus and retro-splenial cortex make interdependent contributionsto spatial memory (Sutherland & Hoesing, 1993).In order to examine this relationship we used thesame methodology as that described abovethatis, measuring the impact of hippocampal lesionson retrosplenial cortex immediate-early genelevels (Albasser et al., 2007).

Lesions of the rat hippocampus, whether madeby radiofrequency or by the injection of neurotox-ins, had very similar and consistent effects uponthe retrosplenial cortex. Clear reductions in theexpression of both c-Fos and Zif268 wereobserved, so that counts of immediate-earlygene positive cells were typically reduced by onehalf (Figure 10; Albasser et al., 2007). Unlike




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Figure 9. Anterior thalamic lesions result in a layer-specific loss of long-term depression (LTD) in retrosplenial cortex. (a) Induction ofhomosynaptic LTD in normal retrosplenial cortex. (b) Following an anterior thalamic lesion there is a complete loss of LTD inrestrosplenial slices ipsilateral to the lesion.


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the effects of anterior thalamic lesions, this

immediate-early gene hypoactivity was evidentin both the superficial and the deep layers of thegranular cortex. Thus, a clear loss of the c-Fossignal was seen in layer V in addition to layersII and upper III (Figure 10; Albasser et al.,2007). Once again, there was no consistent evi-dence for a loss of neuronal numbers or changesin cellular morphology in the retrosplenialcortexthat is, these changes were not detectableby standard methods.

While more evidence is required, the pattern ofresults points to a hypersensitivity in the retrosple-nial cortex following the loss of certain inputs (fromthe anterior thalamic nuclei and from the hippo-campus). Not surprisingly, there may be someimportant clinical corollaries of these distal lesioneffects upon the retrosplenial cortex. Of especialnote is the repeated finding of posterior cingulatehypoactivity in Alzheimers disease (Minoshima,

Foster, & Kuhl, 1994; Minoshima et al., 1997).

This hypoactivity is of particular interest as it isoften the first metabolic change observed in posi-tron emission tomography (PET) scans of thedisease (Minoshima et al., 1994, 1997). Posteriorcingulate hypoactivity, and in particular retrosple-nial hypoactivity, is also found in subjects withmild cognitive impairment (Nestor, Fryer, Ikeda,& Hodges, 2003a; Nestor, Fryer, Smielewski, &Hodges, 2003b), which is often a prodromal stageof Alzheimers disease. Both anterior thalamic andhippocampal pathology occur relatively early inthe progression of Alzheimers disease (Braak &Braak, 1991a, 1991b). A testable hypothesis isthat pathology in the hippocampus, the anteriorthalamic nuclei, or both could induce the posteriorcingulate hypoactivity. The significance of thisnotion is not only that it provides a potential mech-anism for cingulate hypoactivity but it also high-lights how dysfunctions (some overt, some covert)

Figure 10. Photomicrographs of neuronal density (NeuN) and c-Fos levels in granular retrosplenial cortex (Rgb) in rats with either a shamsurgery (control, A, B) or a bilateral ibotenate hippocampal lesion (C, D). The brightfield photomicrographs of horizontal sections show thecomparable levels of neurons (A, C), which contrast with the striking loss of c-Fos-positive cells following hippocampal lesions (D versus B).Scale bar, 100mm.




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could occur in multiple sites early on in the pro-gression of this disease.

A consideration of anterograde amnesia reveals asimilar situation. In cases of Korsakoffs diseasethere is always a loss of cells in the mammillarybodyanterior thalamic pathway (Harding et al.,

2000; Victor et al., 1971). It is also the case thatKorsakoffs disease is consistently associated withposterior cingulate hypoactivity (Fazio et al., 1992; Joyce et al., 1994; Paller et al., 1997; L. J. Reedet al., 2003). Amnesia brought about by anoxia ismore often associated with temporal lobe pathologyand is once again associated with cingulate hypoac-tivity (Fazio et al., 1992). The implication is thatretrosplenial dysfunction is a common feature ofboth temporal lobe and diencephalic amnesias. Aloss of retrosplenial cortex function would not only

exacerbate the effects of the temporal and dience-phalic lesions but could also help to explain whytemporal lobe and diencephalic amnesias share anoverwhelming proportion of common features.

CONCLUSIONS

By combining anatomical and neuropsychologicalfindings a strong case can be made for a directlylinked core of structures in the medial temporal

lobe and medial diencephalon that support episo-dic memory. At the centre of this system is thefornix with its direct and indirect connectionsfrom the hippocampus to the anterior thalamicnuclei. This view of an integrated, interlinkedsystem does not mean that the component partsshare the same functions; rather, they have differ-ent functions that act upon a common class ofinformation. One key locus of interaction is thehippocampus, though the retrosplenial cortexmay also prove to be crucial. Another key area islikely to be the medial prefrontal cortex(Aggleton & Brown, 2006), though this has notbeen discussed in the present review. This viewof diencephalic amnesia with its focus on theanterior thalamic nuclei and their connections will not, however, provide a full account of thecondition for several reasons. Most critically, thepathology in patients with diencephalic amnesia

is never confined to just one thalamic nucleus, sothere are other potential sources of disruption tocognition. Furthermore, there is much evidencethat other medial thalamic nuclei are also import-ant for cognitionfor example, medialis dorsalis(Mitchell & Gaffan, 2008). A likely reflection of

this fact is the evidence that the severity andbreadth of the memory loss seen in diencephalicamnesia is often greater than that seen in patients with more restricted pathology in the fornix ormammillary bodies (Aggleton & Shaw, 1996;Kapur et al., 1998; McMackin et al., 1995). Oneexample concerns the severity of the recognitionmemory loss, which, as pointed out previously,appears to be relatively spared in comparison with recall when there is more selective damageto the extended hippocampal system. The impli-

cation is that damage to other medial diencephalicregions can disrupt familiarity-based recognition. This notion accords with the additive effects ofrostral medial and caudal medial thalamic lesionson the size of recognition memory deficits inmonkeys (Aggleton, 1986).

The source of these additional deficits from within the diencephalon has yet to be confirmed,though candidate structures include various intrala-minar nuclei as well as medialis dorsalis (Mitchell &Dalrymple-Alford, 2005; Van der Werf et al.,

2003a, 2003b). It has to be remembered, however,that these sites do not have direct hippocampal con-nections, and so their actions on cognition are pre-sumably qualitatively different to those of theanterior thalamic nuclei (Mitchell & Dalrymple-Alford, 2005). The one exception to this caveat isnucleus reuniens. This midline thalamic nucleus isof great potential interest as it has reciprocal hippo-campal connections, some of which pass throughthe fornix (Aggleton et al., 1986; Saunders &Aggleton, 2007). In addition, nucleus reuniensalso appears to receive inputs from the mammillarybodies and projects to the retrosplenial cortex (VanGroen & Wyss, 2003; Vann et al., 2007). In these ways, nucleus reuniens mirrors the properties ofthe anterior thalamic nuclei. While next tonothing is known about the impact of damage tonucleus reuniens, electrophysiological studies haverevealed that in the rat this nucleus has a potentially


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important role in controlling excitation in the CA1hippocampal field (Vertes et al., 2004). The parallelanatomical properties with the anterior thalamicnuclei are highly suggestive of a important functionon cognition, which remains to be determined.

More speculative remains the notion that both

temporal lobe and diencephalic amnesia arecharacterized by hidden pathology in a common,distal sitenamely, in the retrosplenial cortex.As explained, this condition (covert pathology) would have considerable clinical significance forour understanding of various dementias as wellas for amnesia. This notion also raises the possi-bility that the retrosplenial cortex is notuniquethat is, a number of brain regions mightshow a hypersensitivity to deafferentation. Theseissues serve as a reminder of the complexity of

interpreting lesion data and the value of mappingdistal activity changes to build a more completepicture of the amnesic brain.

Original manuscript received 7 November 2007Accepted revision received 16 May 2008

First published online 31 July 2008

REFERENCES

Aggleton, J. P. (1986). Memory impairments caused byexperimental thalamic lesions in monkeys. Revue

Neurologique, 142, 418424.Aggleton, J. P., & Brown, M. W. (1999). Episodic

memory, amnesia and the hippocampal-anteriorthalamic axis. Behavioral Brain Science, 22, 425 444.

Aggleton, J. P., & Brown, M. W. (2006). Interleavingbrain systems for episodic and recognition memory.Trends in Cognitive Science, 10, 455463.

Aggleton, J. P., Desimone, R., & Mishkin, M. (1986). The origin, course, and termination of the hippo-campo-thalamic projections in the macaque. Journalof Comparative Neurology, 243, 409422.

Aggleton, J. P., Hunt, P. R., Nagle, S., & Neave, N.(1996). The effects of selective lesions within theanterior thalamic nuclei on spatial memory in therat. Behavioural Brain Research, 81, 189198.

Aggleton, J. P., McMackin, D., Carpenter, K., Hornak, J.,Kapur, N., Halpin, S., et al. (2000). Differential effectsof colloid cysts in the third ventricle that spare orcompromise the fornix. Brain, 123, 800815.

Aggleton, J. P., & Sahgal, A. (1993). The contributionof the anterior thalamic nuclei to anterogradeamnesia. Neuropsychologia, 31, 1001 1019.

Aggleton, J. P.,& Saunders, R. C. (1997).Therelationshipsbetween temporal lobe and diencephalic structuresimplicated in anterograde amnesia. Memory, 5, 4971.

Aggleton, J. P., & Shaw, C. (1996). Amnesia and recog-nition memory: A reanalysis of psychometric data.

Neuropsychologia, 34, 51 62.Aggleton, J. P., & Vann, S. D. (2004). Testing the import-

ance of the retrosplenial navigation system: Lesion sizebut not strain matters: A reply to Harker and

Whishaw. Neuroscience and Biobehavioural Reviews,28, 525531.

Aggleton, J. P., Vann, S. D., Denby, C., Dix, S.,Mayes, A. R., Roberts, N., et al. (2005a). Sparingof the familiarity component of recognitionmemory in a patient with hippocampal pathology.

Neuropsychologia, 43, 1810 1823.

Aggleton, J. P., Vann, S. D., & Saunders, R. C. (2005b).Projections from the hippocampal region to themammillary bodies in macaque monkeys. European

Journal of Neuroscience, 22, 2519 2530.Albasser, M. M., Poirier, G. L., Warburton, E. C., &

Aggleton, J. P. (2007). Hippocampal lesions halveimmediate-early gene protein counts in retrosplenialcortex activity: Distal dysfunctions in a spatialmemory system. European Journal of Neuroscience,

26, 1254 1266.Albasser, M. M., & Vann, S. D. (2007). Mammillary

body projections to the anterior thalamic nuclei are

necessary for normal immediate-early gene expressionin retrosplenial cortex. Neural Plasticity, B1.08.

Allen, G. V., & Hopkins, D. A. (1988). Mamillarybody in the rat: A cytoarchitectonic, golgi and ultra-sound study. Journal of Comparative Neurology, 275,3964.

Alonso, J. R., U, H. S., & Amaral, D. G. (1996).Cholinergic innervation of the primate hippocampalformation: II. Effects of fimbria/fornix transection.

Journal of Comparative Neurology, 375, 527551.Amaral, D. G.,& Cowan,W. M. (1980). Subcortical affer-

ents to the hippocampal formation in the monkey.

Journal of Comparative Neurology, 189, 573 591.Bachevalier, J., & Meunier, M. (1996). Cerebral ische-

mia: Are the memory deficits associated with hippo-campal cell loss? Hippocampus, 6, 553560.

Baddeley, A. (1990). Human memory: Theory and prac-tice. Hove, UK: Lawrence Erlbaum Associates.

Baddeley, A., Vargha-Khadem, F., & Mishkin, M.(2001). Preserved recognition in a case of




24/32

developmental amnesia: Implications for the acqui-sition of semantic memory? Journal of Cognitive

Neuroscience, 13, 357369.Bassett, J. P., & Taube, J. S. (2005). Head direction

signal generation: Ascending and descending infor-mation streams. In S. I. Wiener & J. S. Taube(Eds.),

Head direction and cells and the neural mechan-isms of spatial orientation (pp. 83109). Cambridge,MA: MIT Press.

Bastin, C., Vander Linden, M., Charnallet, A., Denby, C.,Montaldi, M., Roberts, N. et al. (2004). Dissociationbetween recall and recognition memory performancein an amnesic patient with hippocampal damagefollowing carbon monoxide poisoning. Neurocase,10, 330344.

Baxter, M. G., & Chiba, A. A. (1999). Cognitive func-tions of the basal forebrain. Current Opinion in

Neurobiology, 9, 178183.Bentivoglio, M., Kultas-Ilinsky, K., & Ilinsky, I. (1993).

Limbic thalamus: Structure, intrinsic organization,and connections. In B. A. Vogt & M. Gabriel(Eds.), Neurobiology of the cingulate cortex and limbicthalamus(pp. 71122). Boston: Birkhauser.

Bird, C. M., & Burgess, N. (2008). The hippocampusand memory: Insights from spatial processing.

Nature Reviews Neuroscience, 9, 182194.Blair, H. T., Cho, J., & Sharp, P. E. (1998). Role of the

lateral mamillary nucleus in the rat head directioncircuit: A combined single unit recording andlesion study. Neuron, 21, 1387 1397.

Bozon, B., Davis, S., & Laroche, S. (2002). Regulated

transcription of the immediate-early gene Zif268:Mechanisms and gene dosage-dependent functionin synaptic plasticity and memory formation.Hippocampus, 12, 570577.

Braak, H., & Braak, E. (1991a). Alzheimers diseaseaffects limbic nuclei of the thalamus. Acta

Neuropathologica, 81, 261268.Braak, H., & Braak, E. (1991b). Neuropathological

stageing of Alzheimer-related changes. ActaNeuropathologica, 82, 239259.

Brion, S., & Mikol, J. (1978). Atteinte du noyaulateral dorsal du thalamus et syndrome de Korsakoff

alcoolique [Pathology in the thalamic nucleus latera-lis dorsalis in the alcoholic Korsakoff s synd

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