A

mMtDpsdlpaaramo©

K

1

ac

Hf

H

0d

Neuropsychologia 45 (2007) 1232–1246

Recall and recognition memory in amnesia: Patients with hippocampal,medial temporal, temporal lobe or frontal pathology

Michael D. Kopelman a,∗, Peter Bright a,1, Joseph Buckman a, Alex Fradera a,Haruo Yoshimasu a,2, Clare Jacobson a, Alan C.F. Colchester b

a King’s College London, Institute of Psychiatry, London, United Kingdomb Kent Institute of Medicine and Health Sciences, University of Kent,

Canterbury, Kent, United Kingdom

Received 28 July 2005; received in revised form 10 October 2006; accepted 22 October 2006Available online 30 November 2006

bstract

The relationship between recall and recognition memory impairments was examined in memory-disordered patients with either hippocampal,edial temporal, more widespread temporal lobe or frontal pathology. The Hirst [Hirst, W., Johnson, M. K., Phelps, E. A., & Volpe, B. T. (1988).ore on recognition and recall in amnesics. Journal of Experimental Psychology: Learning, Memory, & Cognition, 14, 758–762] technique for

itrating exposure times was used to match recognition memory performance as closely as possible before comparing recall memory scores.ata were available from two different control groups given differing exposure times. Each of the patient groups showed poorer recall memoryerformance than recognition scores, proportionate to the difference seen in healthy participants. When patients’ scores were converted to Z-cores, there was no significant difference between mean Z-recall and Z-recognition scores. When plotted on a scatterplot, the majority of theata-points indicating disproportionately low recall memory scores came from healthy controls or patients with pathology extending into theateral temporal lobes, rather than from patients with pathology confined to the medial temporal lobes. Patients with atrophy extending into thearahippocampal gyrus (H+) performed worse than patients with atrophy confined to the hippocampi (H−); but, when H− patients were givenshorter exposure time (5 s) and compared with H+ at a longer exposure (10 s), their performance was virtually identical and did not indicate

ny disproportionate recall memory impairment in the H− group. Parahippocampal volumes on MRI correlated significantly with both recall andecognition memory. The possibility that findings were confounded by inter-stimulus artefacts was examined and rejected. These findings argue

gainst the view that hippocampal amnesia or memory disorders in general are typically characterised by a disproportionate impairment in recallemory. Disproportionate recall memory impairment has been observed in a number of published cases, and the reason for the varying pattern

btained across hippocampal patients requires further examination.2006 Elsevier Ltd. All rights reserved.

; Rec

rT

eywords: Amnesia; Memory disorders; Hippocampus; Medial temporal lobes

. Introduction

It is widely accepted that recognition memory reflectscombination of a familiarity judgement and a degree of

onscious recollection, whereas recall memory depends upon

∗ Corresponding author at: 3rd Floor, Block 8, South Wing, St. Thomas’sospital, London SE1 7EH, United Kingdom. Tel.: +44 207 188 5396;

ax: +44 207 633 0061.E-mail address: michael.kopelman@kcl.ac.uk (M.D. Kopelman).

1 Now at Anglia Ruskin University, Cambridge, United Kingdom.2 Now at Dept. of Neuropsychiatry, Showa University, Northern Yokohamaospital, Japan.

&cmiawtdtpa

028-3932/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.oi:10.1016/j.neuropsychologia.2006.10.005

ognition; Recall

ecollective processes (Giovanello & Verfaellie, 2001; Jacoby,oth, & Yonelinas, 1993; Mayes, Holdstock, Isaac, Hunkin,

Roberts, 2002). However, there is considerable controversyoncerning the effects of amnesia upon recall and recognitionemory, respectively. One view is that hippocampal amnesia,

ncluding cases of developmental amnesia, is specifically char-cterised by a disproportionate impairment in recall memory,hereas recognition memory is preserved. A second view is

hat amnesic or memory-disordered patients in general manifest

isproportionate recall memory impairment. A third view ishat amnesia, including that which follows focal hippocampalathology, produces a proportionate impairment in both recallnd recognition memory. This controversy relates to views of

psych

hicmrnia‘

gSplim‘jishpfal

edeehtrwiwtspVpMeYAimopwFfitneB

s(mSpttahprspdsER

dpts11DPjetstmpVeipdi

rhlR&2tsTtn(n

M.D. Kopelman et al. / Neuro

ippocampal function—whether the hippocampi are involvedn encoding/retrieval processes in general, or whether theyontribute specifically to the contextual/associative/relationalemory processes which characterise recollection. This, in turn,

elates to whether recollection (recall) and familiarity (recog-ition) should be viewed as ‘redundant’ processes (recollectionncorporates whatever happens in familiarity plus further oper-tions), ‘independent’ (different but overlapping operations) orexclusive’ processes (different and non-overlapping).

On the basis of a meta-analysis of single case and smallroup studies of memory-disordered patients, Aggleton andhaw (1996) (see also Aggleton & Brown, 1999) argued thatatients with pathology within the hippocampi, fornices, mamil-ary bodies, mamillo-thalamic tract or anterior thalami showedmpairments on verbal and visual recall but not recognition

emory. In such patients with damage to what they called theextended hippocampal circuit’, memory based on familiarityudgements (recognition) was intact, whereas recall memory,nvolving recollection of contextual features, such as time andpatial location, was impaired. They argued that combinedippocampal and parahippocampal (including entorhinal anderirhinal) lesions were required to produce an impairment inamiliarity-based or recognition memory. However, there was‘floor’ effect in the recall scores of the subjects with larger

esions in their meta-analysis, making interpretation difficult.There are other cases, which provide support for this hypoth-

sis. Vargha-Khadem, Gadian, Watkins, and Connelly (1997)escribed three patients with a developmental amnesia forveryday events, resulting from brain injuries in infancy orarly childhood. These patients showed a pronounced loss ofippocampal volume bilaterally, and their neuropsychologicalest performance revealed impairments on verbal and visualecall but not recognition memory, the latter being testedith material that included lists of words, non-words, famil-

ar faces and unfamiliar faces. These findings suggested that,hilst recall of episodic memories was impaired as a result of

hese patients’ hippocampal pathology, recognition memory andemantic memory were spared. More detailed evidence in sup-ort of this in one of these cases was published by Baddeley,argha-Khadem, and Mishkin (2001), using the Doors and Peo-le Test battery (Baddeley, Emslie, & Nimmo-Smith, 1994).oreover, Mayes et al. (2002); (Holdstock et al., 2002; Mayes

t al., 2004) have described in detail an adult-onset patient,R, who suffered selective bilateral lesions to the hippocampi.cross 43 recognition memory tests, YR showed significant

mpairment relative to controls, but the impairment was veryinor (mean Z = −0.5) and clinically significant (>2S.D.) in

nly 10% of tests. By contrast, YR showed a severe and dispro-ortionate impairment on recall tests (mean Z = −3.6), whichas clinically significant in 95% of tests (Mayes et al., 2002).urther investigations showed that YR was unimpaired on aorced-choice object recognition memory test, but was clearlympaired at an equivalently difficult yes/no object recognition

est (Holdstock et al., 2002), and she was also impaired at recog-ition of associations between different kinds of information,ven when tested by forced-choice tasks (Mayes et al., 2004).astin et al. (2004) and Aggleton et al. (2005) have reported a

r2(i

ologia 45 (2007) 1232–1246 1233

imilar cases, and Holdstock, Mayes, Gong, Roberts, and Kapur2005) a patient in whom non-verbal (but not verbal) recognitionemory was relatively spared, possibly related to asymmetricalPECT findings. Interestingly, Henke et al. (1999) described aatient with hypoxic bilateral hippocampal damage whose ini-ial recall and recognition memory impairment evolved throughime to a more selective recall deficit. Moreover, Yonelinas etl. (2002) reported that 56 cardiac arrest patients with presumedypoxic brain damage involving the hippocampi showed dis-roportionate impairment on a word-list recall test, relative toecognition memory performance, standardised according to Z-cores. In addition, some functional imaging investigations haveroduced evidence of differential medial temporal activationsuring tasks involving recollection or familiarity processes, con-istent with this hypothesis (Davachi, Mitchell, & Wagner, 2003;ldridge, Knowlton, Furmanski, Bookheimer, & Engel, 2000;anganath et al., 2004).

There is, however, an older tradition, which argues thatisproportionate impairment in recall memory or recollectiverocesses is characteristic of amnesic patients in general, andhat memories based on familiarity alone are relatively pre-erved in amnesia (Giovanello & Verfaellie, 2001; Hirst et al.,986; Hirst, Johnson, Phelps, & Volpe, 1988; Huppert & Piercy,976, 1978; Warrington & Weiskrantz, 1982; Yonelinas, Kroll,obbins, Lazzara, & Knight, 1998). For example, Huppert andiercy (1976, 1978) found that amnesic patients made memory

udgements purely on the basis of ‘trace strength’ or familiarity,ven when they had been asked to make more specific evalua-ions about item recency or frequency. Hirst et al. (1986, 1988)howed that, after matching amnesic patients’ performance tohat of healthy subjects in two different ways on a recognition

emory test, the amnesic group’s recall scores were dispro-ortionately impaired, relative to the controls. Giovanello anderfaellie (2001) employed a very similar design to that of Hirstt al. (1986, 1988), finding that they replicated Hirst et al.’s resultn one task, but not the other. These authors argued that amnesicatients and healthy participants performed the two tasks inifferent ways, and that this was consistent with a differentialmpairment of recollective memory in the amnesic patients.

The third view – namely, that (verbal and visual) recall andecognition memory are proportionately impaired in amnesia –as been advocated by Squire and colleagues in a series of pub-ications (Haist, Shimamura, & Squire, 1992; Manns, Hopkins,eed, Kitchener, & Squire, 2003; Manns & Squire, 1999; ReedSquire, 1997; Stark, Bayley, & Squire, 2002; Stark & Squire,

003). These authors have argued that patients with damagehought to be limited to the hippocampal region consistentlyhow impairments on tests, such as the Recognition Memoryest, especially if a delay is introduced (Reed & Squire, 1997),

he Doors and People Test (Manns & Squire, 1999), the recog-ition component of the Rey Auditory Verbal Learning TestManns et al., 2003), as well as on a wide variety of other recog-ition memory tests, whether tested by forced-choice or yes/no

ecognition procedures (Reed & Squire, 1997; Stark & Squire,003). Consistent with these findings, Kopelman and Stanhope1998) used a variant of Hirst et al. (1988) technique, match-ng performance on recognition memory testing and avoiding

1 psych

‘emcettemoKpo

paoei1l(wsro&o

1eltQtmpaap

asafbopcl1hrsr(bmtmmlr

2

2

2

ltnitahw

TB

NMN

M

F

234 M.D. Kopelman et al. / Neuro

ceiling’ and ‘floor’ effects: these authors found, unlike Hirstt al., that there was no evidence of disproportionate recallemory impairment in memory-disordered patients with dien-

ephalic, temporal lobe or frontal lesions. Moreover, Coleshillt al. (2004) have shown that unilateral electrical stimulation tohe left or right hippocampus produced material-specific disrup-ion of yes/no recognition memory performance, and Kramert al. (2005) have recently employed MRI volume measure-ents to show that hippocampal volumes are the best predictor

f both delayed recall and recognition memory discriminability.opelman et al. (2001) also found that MRI measures of hip-ocampal volume were the most consistent volumetric correlatesf both recall and recognition memory.

Hence, considerable uncertainty remains concerning whichatients will show a disproportionate recall memory impairment,nd under what circumstances. The most persuasive descriptionsf disproportionate recall memory impairment have occurredither in developmental cases (Vargha-Khadem et al., 1997) orn single case-reports of adult acquired lesions (e.g. Henke et al.,999; Mayes et al., 2002). Other investigations have includedarger numbers, but have lacked either detailed neuro-imagingYonelinas et al., 2002) or appropriate ‘matching’ procedures onhich recall/recognition comparisons rely. Moreover, there are

uggestions that the delay between stimulus presentation andecall/recognition testing (Kopelman & Stanhope, 1997, 1998)r the interpolation of an inter-item distractor task (Giovanello

Verfaellie, 2001) might be critical in determining the patternf findings obtained.

In the present investigation, we have examined this issue in9 memory-disordered patients, whose amnesia resulted fromither lesions confined to the medial temporal lobes, or fromesions extending more laterally from the medial temporal lobeo the lateral temporal cortex, or from focal frontal pathology.uantitative structural MRI brain measurements from these par-

icipants were available, and, in particular, it was possible toake a comparison between a subgroup from the medial tem-

oral group of three patients (H−) in whom the hippocampilone were atrophied, relative to healthy control values, andsubgroup of two patients (H+) in whom the parahippocam-

al structures (including perirhinal and entorhinal cortex) were

ppsps

able 1ackground cognitive test scores

Controls Frontal

Mean S.D. Mean S.D.

9 7ean age 49.4 18.1 53.3 11.2ART-R IQ 117.6 13.0 107.4 17.3

emoryWMS-R GM index 119.0 11.9 94.1 21.7WMS-R DM index 120.8 14.5 88.0 21.0

rontal/executiveFAS verbal fluency 53.4 13.3 29.0 16.3Card-sort categories 6.0 0.8 3.4 2.3Card-sort persev’ns 0.8 1.4 6.3 5.4

ologia 45 (2007) 1232–1246

lso atrophied (see Bright et al., 2006, for findings in these twoubgroups at retrograde amnesia tasks). We again employedmodification of Hirst et al. (1988) technique, which allows

or appropriate ‘matching’ of recognition memory performanceetween amnesic patients and healthy participants, but, unlikeur earlier investigation (Kopelman & Stanhope, 1998), com-arison of the findings was made across three different delayonditions (30 s, 2 and 10 min)—a period over which our ear-ier studies (Green & Kopelman, 2002; Kopelman & Stanhope,997) as well as those of others (Isaac & Mayes, 1999a, 1999b)ave suggested that critical differences in forgetting rates onecall memory might occur. Secondly, we have examined thecatter of our participants’ recall scores plotted against theirecognition scores in a manner analogous to Yonelinas et al.2002). Thirdly, we sought differential patterns of correlationetween hippocampal and parahippocampal volumes with oureasures of recall and recognition memory performance across

he total patient group, and we compared the pattern of perfor-ance of our H+ and H− subgroups on our recall/recognitionemory measures. Finally, we examined whether the interpo-

ation of an inter-item distractor task influences the pattern ofesults by examining this issue in healthy participants.

. Method

.1. Participants—clinical and MRI description

.1.1. Medial temporal lesion groupFive patients were selected on the basis of significant anterograde memory

oss and MRI evidence that regional brain atrophy was restricted to the medialemporal lobe structures: the former was defined as clinical evidence of sig-ificant memory impairment and a NART-R minus WMS-R Delayed Recallndex discrepancy of at least 15 points (range 17–64 points). Table 1 showshe mean for WMS-R general and delayed recall indexes. The atrophy wasttributable to acute hypoxic episodes in three of these patients. A fourth patientad experienced an acute encephalopathy of uncertain origin at 13, associatedith presumed hypoxia and subsequent left-sided mesial temporal sclerosis and

artial seizures. The fifth patient had suffered complex partial seizures over aeriod of many years. In all cases, the atrophy was bilateral. Fig. 1 shows coronalections from the brains of these patients revealing medial temporal lobe atro-hy, confined to the hippocampi (top row) and also involving parahippocampaltructures (bottom row, left).

Medial temporal Temporal ANOVA

Mean S.D. Mean S.D.

5 741.8 7.1 41.6 12.5 N.S.

114.2 6.3 104.1 13.8 N.S.

80.4 7.2 65.9 14.3 p < 0.000167.4 16.8 70.0 15.7 p < 0.0001

40.6 13.8 36.1 8.9 p < 0.025.8 0.8 4.3 2.7 p < 0.011.4 1.5 2.3 2.4 p < 0.05

M.D. Kopelman et al. / Neuropsychologia 45 (2007) 1232–1246 1235

Fig. 1. Top row: Coronal sections showing hippocampal atrophy only (H−) in DL, JB and DH (cerebral hypoxia). Bottom row, left: Parahippocampal and hippocampala medii sion a

2

gN1dplmafednodebsIlpihmls

2

u

‘datmrrwlbshM

la

2

filt(a

2

trophy (H+) in JM (cerebral hypoxia). Centre: Axial sections showing bilateraln SM (herpes encephalitis) and (right) bilateral frontal pathology in JW (contu

.1.2. Temporal lobe lesion groupThese patients were chosen on the basis of their all having significant antero-

rade memory impairments (based again on clinical evidence and minimumART-R minus WMS Delayed index difference of at least 15 points (range5–63 points, see Table 1 for mean values)), in association with MRI evi-ence of extensive medial and antero-lateral temporal lobe damage. In thisaper, these patients will sometimes be referred to as the ‘lateral’ temporalobe group to distinguish them from those with pathology confined to the

edial temporal lobes, but it should be understood that this group’s pathologylso involved medial temporal lobe structures. Of the seven patients selectedor this group, five had been diagnosed with (antibody confirmed) herpesncephalitis. In four of these patients, there was evidence of temporal lobeamage in both hemispheres, although the extent of damage was predomi-antly left lateralised in three patients and predominantly right lateralised inne patient; the remaining patient (DJ) showed unilateral left temporal lobeamage, as previously described by Stanhope and Kopelman (2000). In allxcept DJ, the signal alteration on MRI implicated the medial temporal lobesilaterally (in DJ unilaterally), involving the hippocampi and parahippocampaltructures including the entorhinal, perirhinal and parahippocampal cortices.n the more affected hemisphere, the signal alteration involved the antero-ateral temporal lobe cortex (see Fig. 1, bottom row, middle). Two furtheratients were included in this group. One patient had suffered an encephaliticllness at 20, resulting in residual temporal lobe epilepsy. The other patientad had a temporal lobe abscess at 17 resulting in (predominantly) verbalemory impairment. An MRI carried out when she was 34 showed a large

eft temporal CSF-filled lesion, involving medial and lateral temporal lobetructures.

.1.3. Frontal lesion patientsSeven patients with focal frontal lesions and deficits on measures of exec-

tive function were recruited (e.g. Fig. 1, bottom row, right). All showed some

owH

al temporal temporal lobe pathology and extensive right antero-lateral pathogynd haemorrhage).

frontal’ behavioural symptoms, such as apathy, irritability, emotional lability orisinhibition. In two patients, the pathology resulted from acute head injury andssociated contusions and haematomas, worse on the right than the left. Anotherwo patients had undergone surgery for removal of tumours: one a left frontal

eningioma arising from the planum sphenoidale, which had been only partiallyesected, the other a transfrontal craniotomy for removal of a pituitary tumouresulting in right anteromedial frontal damage. There were a further two casesith frontal infarcts. In one of these patients, the damage was restricted to the

eft hemisphere, but the other patient showed bilateral frontal signal alteration:oth showed pronounced ‘frontal’ behavioural changes. Finally, one patient haduffered a large right frontal cerebral abscess, following a tooth infection, ande showed extensive residual signal alteration in the right prefrontal cortex onRI.

None of the patients in any of the groups had any known psychiatric prob-ems, evidence of substance abuse or other conditions, which might have affectedbility to understand instructions or to complete the tasks.

.1.4. ControlsTwo sets of healthy control participants were recruited for this study. The

rst set (Controls A) (N = 9) were recruited from a local further education col-ege as well as non-clinical staff in the hospital, matched as closely as possibleo the patients for age, sex, NART-R and years of education. The second setControls B) (N = 12) were recruited from non-clinical hospital staff, and weregain matched as closely as possible in terms of the same variables.

.2. Quantitative structural MRI

MRI scans were axially acquired on a 1.5T Philips scanner, using a protocolf T1 and T2 weighted gradient and PD echo 3D volume datasets. Slice thicknessas 1.5 mm and the matrix size 256 × 256, giving a voxel size of 1.3 mm3. AP735 graphics workstation was used to segment (delineate) brain structures of

1 psychologia 45 (2007) 1232–1246

isiitltla(

peotlatlws(Agttt

2

TtR(gmaadneptom

(vahil

3

rwge

Fpc

236 M.D. Kopelman et al. / Neuro

nterest across sequential MR slices. The data were analysed using a hierarchicalegmentation program, allowing detailed volumetric assessment. The programncorporates visualisation, manipulation and storage/retrieval functions in itsnterface, and segmentation tools include a multi-slice 2D hierarchical segmen-ation program, a 2D polyline tool for drawing a sequence of connected straightines and a 3D plane cutting tool. Quantitative structural MRI measurements ofhe left and right temporal lobes, antero-lateral temporal lobes, medial temporalobes and hippocampi were taken from planimetric measurements determinedccording anatomical definitions and segmentation criteria described elsewhereColchester et al., 2001; Kopelman et al., 2003).

Fig. 2 shows total, lateral and medial temporal lobe mean volumes in theatient groups, relative to 10 volunteers in a reference control sample (Colchestert al., 2001; Kopelman et al., 2003) who did not differ significantly from either ofur control groups in terms of mean age, sex ratio or NART-R IQ. It shows thathe temporal lobe lesion group showed significant atrophy across total temporalobe, total lateral temporal and total medial temporal volumes. The frontal lesionnd medial temporal lesion groups did not differ significantly from controls inerms of total temporal lobe or lateral temporal volumes. The medial temporalesion group showed a mean medial temporal lobe volume approximately halfay between the controls and the temporal lobe lesion group: they differed

ignificantly from controls in terms of mean medial temporal volume on a t-testt = 2.86, p < 0.025), but not on a Bonferroni post hoc test following one-wayNOVA across all four groups. Fig. 3 shows that the medial temporal lesionroup and the temporal lesion group both showed highly significant atrophy inerms of left and right hippocampal volumes. These quantitative MRI data showhat, despite the variability in underlying aetiology, the allocation of patients tohese groups is valid in terms of regional brain volumes.

.3. Background neuropsychological findings

Background cognitive test scores were collected, and are summarised inable 1. Statistical comparisons are given between the patient groups and the

otal control group (N = 21). On a measure of estimated premorbid IQ (NART-) (Nelson & Willison, 1991), there were no differences among the groups

F(3,36) = 1.22, N.S.). However, there were significant differences across theroups for the general memory index (F(3,36) = 14.74, p < 0.0001), delayedemory index (F(3,36) = 17.87, p < 0.0001), as well as the individual visual

nd verbal memory indexes (p < 0.0001). In terms of Bonferroni post hoc tests,ll patient groups performed significantly more poorly than controls on theelayed memory index (p < 0.02), and both temporal lobe lesion groups (butot the frontal lobe group) performed significantly worse than controls on gen-ral memory (p < 0.01). For general memory, the ‘lateral’ temporal lobe lesionatients performed more poorly than the frontal lesion patients (p < 0.02) but thewo temporal lesion groups did not differ significantly from each other. Nonef the patient groups differed significantly from one another on the delayedemory index.

Table 1 also shows significant differences in card-sorting categoriesF(3,36) = 4.49, p < 0.01) and perseverations (F(3,36) = 3.27, p < 0.05), and onerbal fluency (F(3,36) = 4.17, p < 0.02) with the control group performing bestnd the frontal lesion group performing worst in each case. On Bonferroni postoc tests the frontal lesion group performed significantly worse than controlsn each case (p < 0.05). Neither the ‘lateral’ temporal nor the medial temporalesion group differed significantly from the controls.

. Experiment 1: Analysis 1

This experiment examined performance on recall memory,

elative to recognition, at delays of 30 s, 2 and 10 min to examinehether a differential pattern of performance across the patientroups (frontal, medial temporal and ‘lateral’ temporal) mightmerge at the longer delays.

ig. 2. Volumetric measures of temporal lobe structures for controls and eachatient group. Figures in square brackets show mean percentage deviation fromontrol group volumes.

M.D. Kopelman et al. / Neuropsych

Flm

3

abrhAnl1fpeg

1trmil2attww

mehf

www

3

aPiwbdtw

wwlc3tiS(s

tituistwsflao

dmmnmch

cfc

3

ig. 3. Left and right hippocampal volumes for controls and the two temporalobe groups (temporal and medial temporal). Figures in square brackets show

ean percentage deviation from control group volumes.

.1. Materials

The materials used in this study were adapted from Kopelmannd Stanhope (1998). Three sets of 32 words of 1 or 2 sylla-les were selected, within each of which half of the words wereelated, and belonged to one of two categories, and the otheralf were unrelated (stimulus details are provided in Appendix). The words were selected from Battig and Montague (1969)orms. The mean word frequency of both the related and unre-ated words was 128 occurrences per million (Francis & Kucera,982) and the three sets of words were matched for wordrequency and syllable length. A different set of words wasresented to subjects at each time interval, with the order ofxposure to each set counterbalanced within and across subjectroups.

Each set of 32 words was divided into 2 (matched) lists of6 words (A and B), 1 of which would be used for the recallask. Within each list there were eight unrelated words and fourelated words from two categories, and the words in each wereatched for frequency and syllable length. Words were typed

n large font on to 15 cm × 10 cm cards. The 16 words in eachist to be presented were divided into 4 blocks, 2 related and

unrelated, and were arranged so as the two types of blocklternated. Each block was preceded by a card on which wasyped either “unrelated” or the name of the category from whichhe related words were taken, e.g. “colours”. Within each block,ord order was randomised, and the order of block presentationas counterbalanced across participants.For the forced-choice recognition test, the words from the

atched list, which had not been used in the recall task weremployed as distractors. Each “target” word, i.e. a word thatad been presented in the recall task, was paired with a wordrom the same category from the distractor list. The two words

rt

ologia 45 (2007) 1232–1246 1237

ere typed side by side on 15 cm × 10 cm cards. Lists A and Bere employed equally as often as targets and distractors bothithin and across the participants.

.2. Procedure

The procedure follows that employed originally by Hirst etl. (1988) and subsequently by Kopelman and Stanhope (1998).articipants were presented with one of the word-lists consist-

ng of 16 items. The experimenter told the participants that theyould be presented with two blocks of related words, and twolocks of unrelated words, and that each block would be intro-uced with a card on which was written either “unrelated” orhe category from which the words were drawn. The participantsere told to read each word aloud and remember it.In order to match recognition memory scores, exposure times

ere titrated across groups. The exposure time to each stimulusas 7 s in the frontal lobe group, 10 s in the medial temporal

obe group and 12 s in the temporal lobe group. Our initialontrol group (Controls A) was given an exposure time ofs per stimulus. These exposure times were determined on

he basis of extensive pre-study piloting, which, in turn, wasnformed by the findings of an earlier study (Kopelman &tanhope, 1998). Subsequently, we tested a second control groupControls B), who were given an exposure time of 0.5 s perlide.

It has been pointed out, however, that in such designs theotal duration of the presentation phase of the task, and the meantem-to-test delay, is longer for the memory-impaired patientshan the healthy controls (Mayes, 1986). This may lead to annderestimation of the patients’ performance. Consequently, asn the Kopelman and Stanhope (1998) investigation, an inter-timulus task was employed to match the inter-item delay acrosshe groups. The inter-stimulus task consisted of counting back-ards in multiples of three until the next stimulus was presented,

tarting from a number between 100 and 1000 indicated on aash card (see also Experiment 2, below). This procedure gaven inter-item delay of 12 s in each group from initial presentationf each item until presentation of the next.

Following presentation of the last word, a 30 s, 2 or 10 minelay (filled with normal conversation) preceded free recallemory testing, in which participants were asked to recall asany words as they could in any order. When they could recall

o further words, a forced-choice recognition memory task com-enced, in which the experimenter held up the forced-choice

ards described earlier, and asked which of the two words theyad seen before.

This procedure was conducted at each of the three delayonditions (30 s, 2 and 10 min) using a different set of wordsor each condition. The word-sets for use at each delay wereounterbalanced across subjects.

.3. Results

In order to assess any disproportionate impairment in recallelative to recognition in the patient groups, it was first necessaryo check whether the groups were matched in terms of recog-

1 psychologia 45 (2007) 1232–1246

ncltptttFobaswmbFccnmww

ttawobcgtebdrts

aoaiw(

(aggdWt(iw

Fig. 4. Recall and recognition performance for each patient group at each testdelay compared with Control B (0.5 s exposure, solid line and + symbol) andCc

wctttdso

mwm

238 M.D. Kopelman et al. / Neuro

ition scores at each time interval. First, we compared the twoontrol groups (A and B) finding that, following their more pro-onged exposure time, Controls A performed significantly betterhan Controls B at 30 s (t = 4.98, p < 0.0001), 2 min (t = 3.27,< 0.005) and 10 min (t = 3.88, p = 0.001). However, when the

wo control groups were compared with the three patient groups,here were no significant differences on one-way ANOVAs inerms of recognition memory score at either 30 s (Controls A:= 0.76, Controls B: F = 1.39), 2 min (A: F = 0.53, B: F = 1.13)

r 10 min (A: F = 2.43, B: F = 2.17). However, there were a num-er of subjects scoring at ceiling (16/16) on the recognition taskt each time-delay, although none of the controls at a 0.5 s expo-ure (Controls B) did so. As in Kopelman and Stanhope (1998),e then excluded participants with perfect scores on recognitionemory, finding that there were still no significant differences

etween the groups at 30 s (A: F = 1.53, B: F = 0.24), 2 min (A:= 1.16, B: F = 0.15) or 10 min (A: F = 2.68, B: F = 0.99). This

onfirmed that, following our manipulation of the patient versusontrol exposure times, our two control groups did not differ sig-ificantly from the three patient groups in terms of recognitionemory. Having ‘matched’ the groups on recognition memory,e then examined their performance at recall memory for theords.Fig. 4 shows the recognition and recall performance of the

hree patient groups and Control Group B at each of the threeime-periods after excluding subjects at ceiling. Controls A arelso shown as a dotted line. Comparing the patient groupsith Controls B, there was a highly significant main effectf (recognition/recall) condition (F(1,18) = 462.50; p < 0.001),ut the main effect of group failed to reach statistical signifi-ance (F(3,18) = 1.42, N.S.), and of particular importance theroup by condition interaction (F(3,18) = 1.25) was not sta-istically significant. However, there was a significant mainffect of delay (F(2,36) = 3.63, p < 0.05) and significant groupy delay (F(2,36) = 6.02, p < 0.01) and group by condition byelay (F(6,36) = 3.16, p < 0.05) interactions. This reflected theelatively superior performance of the frontal group at recall athe 2 min delay (confirmed by individual ANOVAs at each delay,howing a significant effect at this delay only).

When all patients were analysed (including those at ceiling),nd compared with Control Group B, neither the main effectf group (F(3,26) = 2.70), nor the group by condition inter-ction (F(3,26) = 2.87), nor the group by condition by delaynteraction (F(6,52) = 2.10) were statistically significant. Thereas a significant main effect of (recognition/recall) condition

F(1,26) = 379.2; p < 0.0001).Statistical comparisons between the three patient groups and

the less well-matched) Control Group A also failed to findny evidence of a recall–recognition discrepancy across theroups. When subjects at ceiling were excluded, neither theroup by condition (F(3,8) = 1.24) nor the group by condition byelay (F(6,16) = 1.23) interactions was statistically significant.hen all subjects were analysed (including those at ceiling),

he group by condition interaction was statistically significantF(3,23 = 3.42, p < 0.05), but not the group by condition by delaynteraction (F(6,46 = 2.67, N.S.). However, when all subjectsere analysed in the 10 min condition taken in isolation (in

lWet

ontrol A (3 s exposure, dotted line), after eliminating subjects performing ateiling on recognition testing.

hich fewer subjects were at ceiling than in the 30 s and 2 minonditions), the group by condition interaction was not statis-ically significant (F(3,24) = 1.45, N.S.). In other words, whenhe subjects were away from ceiling in the recognition condi-ion (either by examining scores at the longest delay only or aftereliberately excluding those with ‘perfect’ recognition memorycores), there was no evidence of a differential effect of groupn recall relative to recognition memory performance.

In a further analysis, we examined whether these findingsight relate: (i) to the fact that overall medial temporal volumeas lower in the lateral temporal group (7578 mm3) than theedial temporal group (10,872 mm3) or (ii) to the fact that the

ateral temporal group had greater atrophy on the left (Fig. 3).

e chose three patients from each group with approximately

qual medial temporal volumes (mean volume for lateralemporal subset: 8520 mm3; for medial temporal subset:

psych

9acdNmvtt(FcMe

wtdt1pbe

3

miwptsme

4r

roa(

4

rtmcdmv12

tmtw

4

ZtihZs

lawr

(ttNoppstdp

rTtdlp

tzqhti(oitiric

M.D. Kopelman et al. / Neuro

095 mm3). The recognition/recall discrepancies showed onlytrend difference at 30 s (F(1,4) = 3.78, p > 0.10), and were

losely similar, not approaching significance, at subsequentelays (2 min: (F(1,4) = 0.07, N.S.; 10 min: (F(1,4) = 0.02,.S.). We then compared three lateral temporal patients withore evenly matched left and right medial temporal mean

olumes (left: 3719 mm3; right: 4094 mm3) with three medialemporal patients (left: 4470 mm3; right: 4625 mm3). Again,he recognition–recall difference did not approach significance30 s: F(1,4) = 0.10, N.S.; 2 min: F(1,4) = 1.66, N.S.; 10 min:(1,4) = 0.84, N.S.). Given the small sample sizes, we alsoomputed the same six comparisons with the non-parametricann–Whitney test for independent samples. The results were

ntirely consistent with the parametric analyses (p > 0.10).In comparing performance across related and unrelated

ords, there was a non-significant trend for the frontal groupo show a greater related-unrelated difference in the recall con-ition (i.e. better performance in recalling related words) thanhe two temporal lobe groups (compare Kopelman & Stanhope,998). However, neither the group by condition interaction (allarticipants: F = 0.32; excluding ceiling: F = 0.71) nor the groupy condition by delay interaction (all participants: F = 0.49;xcluding ceiling: F = 0.72) were statistically significant.

.4. Summary

These results indicate that none of the patient groups (frontal,edial temporal or ‘lateral’ temporal) showed a disproportionate

mpairment on recall relative to recognition memory comparedith healthy controls, after matching for recognition memoryerformance as closely as possible by manipulating exposureimes and after excluding subjects at ceiling in some of the analy-es. Nor did this finding appear to result from differences in meanedial temporal lobe volumes between the groups, laterality

ffects or differences between related and unrelated words.

. Experiment 1: Analysis 2—scatterplots of recall andecognition scores

In order to investigate the relationship between recall andecognition memory more thoroughly, we examined the scatterf individuals’ recall scores plotted against recognition scorest each time-point in a manner similar to that of Yonelinas et al.2002).

.1. Method

To standardise the scales along each axis, each subject’secall and recognition scores were converted to Z-scores at eachime-point. For these analyses, the Z-scores were based on the

eans and standard deviations (expressed as percentages) in theombined control group (A plus B) in order that the standardeviation in the controls at each delay should approximately

atch that of the patients’ (Recognition, C versus P, 30 s: 10.9%

ersus 13.4%; 2 min: 10.3% versus 10.7%; 10 min: 12.6% versus2.0%; Recall, 30 s: 28.6% versus 21.0%; 2 min: 29.6% versus7.3%; 10 min: 28.9% versus 29.8%). After inspecting the scat-

0tve

ologia 45 (2007) 1232–1246 1239

erplots at each delay separately, we decided it was legitimate toerge the plots into a scatter of 56 points (3 points for each of

he 19 patients, one at each delay, 1 missing datum) to compareith Yonelinas et al.’s (2002) scatter of 56 points.

.2. Results

As a first step, we compared control-referenced mean-scores for the whole patient group on recall and recogni-

ion memory (56 ‘paired’ observations), analogous to Fig. 1an Yonelinas et al.’s (2002). Unlike their investigation ofypoxic patients, we obtained highly similar mean Z-recall and-recognition scores (recognition = 0.18, recall = 0.05; paired-amples t = 1.15, N.S.).

Where the medial temporal group were examined in iso-ation (15 paired observations), analogous to Yonelinas etl.’s (2002) study of hypoxic patients, the mean Z-scoresere still closely similar (mean Z-recognition = 0.04, mean Z-

ecall = −0.04; paired −t = 0.46, N.S.).Kopelman and Stanhope (1998) included a group of five

different) hypoxic patients tested on this same task, but athe 30 s delay only. These participants were closely matchedo the present medial temporal group in terms of mean age,ART-R and memory indexes. In order to enlarge the sizef the present hypoxic group to N = 10, we converted theseatients’ recall and recognition scores to Z-scores, using theresent controls’ values at this delay as the reference means andtandard deviations. When this was done, the mean Z-values inhis group of 10 hypoxic patients were again not significantlyifferent (mean Z-recognition = 0.14, mean Z-recall = −0.25;aired −t = 0.64, N.S.).

Fig. 5a shows the scatter of Z-recall scores against Z-ecognition scores for all 56 paired observations in the patients.he line plots where the points would fall if Z-recall was equal

o Z-recognition for each obtained value. The data-points wereistributed approximately equally either side of our ‘idealised’ine, consistent with neither recall nor recognition being dispro-ortionately impaired in this patient group.

Fig. 5b shows the scatter for the entire group (con-rols + patients combined), and it also indicates lines through theero intercepts. The distribution of these data-points across theuadrants has been influenced by the fact that the exposure timesave been manipulated to match patients’ performance to con-rols’; where Z-scores for patients were referenced to controls An isolation, more patients fell into the bottom left-hand quadrantindicating impairments in both recall and recognition mem-ry) and many fewer in the top right-hand column (the quadrantndicating relatively spared recall and recognition memory athese exposure times). The values in the scattergram were putnto a multiple regression examining the predictive value of Z-ecognition and group membership on Z-recall. As we werenterested in differences in performance between the healthyontrol and patient samples, group membership was entered as

for control, 1 for patient. The product of this binary value and

he recognition score was then computed to produce a dummyariable. This dummy variable was entered as a further regressornabling a test of parallelism to be carried out, as outlined by

1240 M.D. Kopelman et al. / Neuropsych

Fig. 5. Control-referenced Z-recall and recognition scores: (a) pattern of perfor-mance for each patient group shown with a line of idealised fit; (b) combinedsci

KaZnNwdr

omtwt1

4

w

ctawifat

5m

psqarppctisdqa

5

t(btscdshsTawpn(

totow

catterplot of both controls and patients, showing dotted lines through zero inter-epts. These scatters show one point for each subject at every test delay, resultingn three points per subject.

leinbaum, Kupper, Muller, and Nizam (1988). This test for par-llelism revealed a highly significant effect of the regression of-recall against Z-recognition (t = 8.15, p < 0.0001), but no sig-ificant effect of group (patient/control) membership (t = −0.37,.S.) or group by condition interaction (t = −1.34, N.S.). In otherords, this analysis confirms that, as recognition memory scoresiminished, recall memory scores showed a proportionate fall,egardless of group.

The important quadrant in Fig. 5b is the bottom right-handne, which was the quadrant indicating disproportionate recallemory impairment with preserved recognition memory at

hese exposure times. There were 19 data-points which fellithin this quadrant: 10 were from control participants, 6 from

he temporal lobe lesion group, 2 from frontal patients and onlyfrom the medial temporal group.

.3. Summary

In summary, when the patients’ recall and recognition scoresere converted to Z-scores, based on the means and S.D.s of the

phao

ologia 45 (2007) 1232–1246

ombined control groups (A and B) for recall and recognition,here was no overall evidence of significantly disproportion-te recall (or recognition) memory impairment in either: (i) thehole patient group, (ii) the medial temporal group, taken in

solation or (iii) the medial temporal group ‘pooled’ with thatrom Kopelman and Stanhope (1998). Only one data-point frommedial temporal lobe patient fell within the quadrant on a scat-

ergram indicating disproportionate recall memory impairment.

. Experiment 1: Analysis 3—recall and recognitionemory scores and medial temporal MRI measures

In order to examine the relative contribution of hippocam-al and parahippocampal (including entorhinal and perirhinal)tructures to recall and recognition memory, we employed ouruantitative structural MRI measurements of the hippocampind the parahippocampal gyri to examine for correlations withecall and recognition memory performance within the totalatient group. Secondly, we examined the findings from the fiveatients in the medial temporal group in more detail in order toompare performance in subjects whose atrophy was confined tohe hippocampi (H− subgroup) with those whose pathology alsonvolved the parahippocampal gyri (H+ subgroup). This analy-is was initially conducted using the exposure times and dataescribed above, but, in addition, the H− subgroup were subse-uently re-tested at a shorter (5 s) exposure time and a furthernalysis conducted.

.1. Method

Separate segmentations were carried out on coronal sec-ions to measure hippocampal volumes and medial temporalcombined hippocampal and parahippocampal) volumes. Ouroundary definitions for the hippocampi were closely similar tohose described by Mori et al. (1997), except that we included theubiculum as part of the hippocampus. Anteriorly, the alveolarovering of the hippocampus provided a border with the amyg-ala. The posterior limit of the hippocampus was the coronallice in which the fornix clearly emerged from the fimbria of theippocampus, just anterior to the splenium of the corpus callo-um. These margins were checked in sagittal and axial sections.he medial temporal measurements employed the same anteriornd posterior margins but, in the coronal plane, segmentationsere taken from the subiculum across the cortical surface of thearahippocampal gyrus, and then deep into the collateral (rhi-al) sulcus until it met the inferolateral point of the hippocampussee Colchester et al., 2001; Kopelman et al., 2003).

Inspection of the quantified MRI measurements revealed thathe medial temporal group could be subdivided into a subgroupf three patients (H−) in whom the hippocampi alone appearedo be atrophied, relative to healthy control values, and a subgroupf two patients (H+) in whom the parahippocampal structuresere also atrophied. Table 2 shows the mean hippocampal and

arahippocampal volumes in these two subgroups, relative toealthy controls. F-values from one-way analyses of variancend their significance values are shown, together with the resultsf (C versus H− and H− versus H+) Bonferroni post hoc tests.

M.D. Kopelman et al. / Neuropsychologia 45 (2007) 1232–1246 1241

Table 2Mean hippocampal and parahippocampal volumes in H+ and H− subgroups and controls (figures in square brackets indicate % difference from controls’ mean)

Controls H− group H+ group F p C vs. H− H− vs. H+

P 3 ] 3741 (± 1983) [−43%] 12.48 <0.001 N.S. <0.001H ] 3590 (± 1482) [−54%] 21.30 <0.001 <0.002 N.S.

N arahippocampal structures were also atrophied.

npssc(s(nv

5

spIana

mrbcpacdh

tsfefi

TC

TTT

*

arahippocampal volume (mm ) 6553 (± 960) 8368 (± 250) [+28%ippocampal volume (mm3) 7772 (± 1008) 4864 (± 293) [−37%

ote: H−: patients with focal hippocampal atrophy; H+: patients in whom the p

The table shows that the H− subgroup did not differ sig-ificantly from the controls in terms of total (left and right)arahippocampal volume, but that the H+ subgroup showedignificantly smaller parahippocampal volumes than the H−ubgroup (p < 0.001); the H+ group also differed signifi-antly from controls in terms of total parahippocampal volumep < 0.02). By contrast, both H+ and H− subgroups showedignificantly smaller total hippocampal volumes than controlsp < 0.001, p < 0.002, respectively), but they did not differ sig-ificantly from each other with respect to total hippocampalolumes.

.2. Results

Table 3 shows correlations between recall and recognitioncores and ‘total’ (left and right) hippocampal, parahippocam-al and medial temporal volumes across the total patient group.ncluded in the table are the findings for recall and recognitiont all delays, and also for the mean Z-scores for recall and recog-ition averaged across delays, using the data from Analyses 1nd 2 above.

Contrary to the prediction that recall memory impairmentight be specifically associated with hippocampal atrophy, and

ecognition memory impairment with parahippocampal atrophy,oth recall and recognition memory scores were significantlyorrelated with parahippocampal volumes but not with hip-ocampal volumes at the 30 s delay and when Z-scores wereveraged across all delays. Although there were no signifi-ant correlations at 2 and 10 min, the trends were in the sameirection, i.e. stronger relationships with parahippocampal thanippocampal volumes.

Fig. 6 shows the findings from the H+ and H− subgroupsaken in isolation. The findings for H+ and H− at 10 s expo-ure per stimulus is shown, but, in addition, there is a curve

or the H− subgroup when re-tested over 4 years later at 5 sxposure. Controls A (3 s exposure) and B (0.5 s) are shownor comparison. If the H− group were specifically impairedn recall, but not recognition, that group would show a steeper

Fig. 6. Recall and recognition memory performance at each time interval forthe H+ and H− subgroups of the medial temporal group at 10 s exposure perstimulus. Performance is shown at each of the three delays in comparison withControls A (3 s/stimulus) and B (0.5 s). Also shown are the findings at each delayon subsequent re-testing of the H− subgroup at 5 s. per stimulus.

able 3orrelations between recall/recognition scores and MRI volumes of medial temporal structures

Recall(30 s)

Recog.(30 s)

Recall(2 min)

Recog.(2 min)

Recall(10 min)

Recog.(10 min)

Mean Z-recall:all delays

Mean Z-recog.all delays

otal hippocampal volumes 0.23 0.40 0.10 0.07 −0.03 0.14 0.10 0.26otal parahippocampal volumes 0.75*** 0.56** 0.43 0.23 0.32 0.28 0.53* 0.44*

otal medial temporal volumes 0.57** 0.53* 0.31 0.18 0.19 0.24 0.37 0.39

** p < 0.001 (one-tailed).** p = 0.01 (one-tailed).* p < 0.05 (one-tailed).

1 psych

rulgstag

awviNcotd3rt

sFcadgaotdaa

ttotpmHGosaa

5

plafan

bgwnrawstr

6

ticnrikocrgtm

awsi

6

4tI

ugsp

6

ooWcant (F(1,20) = 48.67, p < 0.001), neither the main effect of

242 M.D. Kopelman et al. / Neuro

ecognition/recall gradient than the H+ group. In fact, the fig-re shows that, at each time-delay, the H+ subgroup (with thearger lesions) performed somewhat worse than the H− sub-roup (when each subgroup received a 10 s exposure time pertimulus), but that there was no difference in the slopes of thewo subgroups’ curves. The curves were approximately parallelnd, if anything, the H+ group showed a (minimally) steeperradient, contrary to prediction.

Statistical analysis was initially conducted comparing the H+nd H− subgroups, each at 10 s exposure per stimulus. Thereas an overall significant effect of condition, i.e. recognitionersus recall (Wilcoxon test, Z = −2.0, p < 0.05), but no signif-cant effects of (H+ versus H−) group on either recall (Z = 1.8,.S.), recognition (Z = −1.7, N.S.) or recognition–recall dis-

repancy (Z = −1.2, N.S.). There were also no significant effectsf delay on recall (Friedman test, χ2 = 5.4, N.S.) or on recogni-ion (χ2 = 2.0, N.S.), although there was on recognition–recalliscrepancy (χ2 = 6.6, p < 0.05). Subtracting 10 min scores from0 s scores, the groups did not differ in terms of either recall,ecognition or recognition–recall discrepancy scores as a func-ion of delay (Wilcoxon, Z > −1.6, p > 0.1 in all cases).

Because such statistical comparisons lack power in smallubgroups, we also compared individual patients with controls.ig. 6 shows that the H− group’s scores at 10 s exposure werelosely matched with Controls A, especially at 30 s and 10 min,nd that the H+ group’s were very similar to Controls B at allelays. Comparing the individual patients in the H− and H+ sub-roups with ‘their’ respective control group, using the Crawfordnd Garthwaite (2005) Revised Standardised Difference Test,ne H− patient differed significantly from Controls A on a one-ailed test at 30 s only (t = 2.01, p < 0.05), but this patient did notiffer from Controls A at 2 or 10 min. The other H− patients andlso the H+ patients did not differ significantly from controls atny delay.

Because of the possibility that a ceiling effect on recogni-ion might have obscured the presence of a steeper gradient inhe H− subgroup, the same three participants were re-testedn the same material using a shorter (5 s) exposure test morehan 4 years after their original testing. Fig. 6 shows that theerformance of the H− subgroup at this exposure time closelyatched that of Controls B (0.5 s/stimulus) and also that of the+ subgroup given a 10 s exposure. Using the Crawford andarthwaite (2005) Revised Standardised Difference Test, nonef the individual H− participants at this exposure time differedignificantly from Controls B at any delay. In short, H− patientst 10 s/stimulus did not differ significantly from Controls A (3 s),nd H− at 5 s did not differ from Controls B (0.5 s).

.3. Summary

Use of the quantitative structural MRI hippocampal andarahippocampal volumes allowed us to examine the corre-ation of these measures with recall and recognition scores,

nd to differentiate a ‘hippocampal only’ (H−) subgrouprom a ‘hippocampal plus parahippocampal’ (H+) subgroupmong the medial temporal patients. Overall recall and recog-ition measures correlated significantly with parahippocampal,

g(cr

ologia 45 (2007) 1232–1246

ut not hippocampal, measurements within the total patientroup. Although the H+ subgroup at 10 s exposure performedorse than the H− subgroup at 10 s per stimulus, there wereo significant group differences between them in terms ofecognition–recall discrepancy (or in recognition–recall discrep-ncy as a function of delay). Moreover, when the individualsithin the H+ subgroup at 10 s and H− subgroup at 5 s expo-

ure were compared with Controls B (0.5 s/stimulus), none ofhese participants differed from the controls in terms of theecognition–recall difference at any delay.

. Experiment 2

In the above investigation, we employed an inter-item dis-ractor task to match mean delays-to-testing of individualtems across the groups. While the present data were beingollected, Giovanello and Verfaellie (2001) criticised this tech-ique arguing that it might eliminate recollection/familiarity orecall/recognition differences across groups, because it “likelynterfere(s) with the establishment of inter-item associationsnown to benefit recollection . . . [leading to] suboptimal rec-llection [recall] in control participants.” On the other hand, itan be argued that the inter-item distractor task prevents activeehearsal and gives a better matching of exposure times acrossroups (Mayes, 1986), and that there is no empirical evidencehat it affects the relationship between recall and recognition

emory.In order to test whether or not the distractor task would indeed

ffect the relationship between recall and recognition memory,e compared a group of healthy subjects using the same expo-

ure time as Controls A, but with an unfilled gap between stimuli,.e. no distractor task.

.1. Method

We compared a group of 13 healthy participants (mean age,8.2 ± 15.0; mean NART-R IQ = 108.5 ± 8.2) with our 9 par-icipants in Controls A (mean age, 49.4 ± 18.1; mean NART-RQ = 117.5 ± 13.0) on the recall/recognition task.

The exposure time and presentation conditions of the stim-li were identical across the two groups, except that the ‘new’roup of healthy subjects had an unfilled gap between the pre-entation of individual items, whereas the ‘old’ group of controlserformed the distractor task between items as described above.

.2. Results

Fig. 7 shows that the two groups were matched in termsf mean recognition memory scores, and that there wasnly minimal difference in terms of mean recall scores.hilst the recall/recognition difference was highly signifi-

roup (F(1,20) = 0.16) nor the group by condition interactionF(1,20) = 0.31) approached significance. Excluding subjects ateiling, the group by condition (recall/recognition) interactionemained non-significant (F = 0.06).

M.D. Kopelman et al. / Neuropsych

Fi

6

tirEma

7

ap(rcmaopti(dfthgwp

t

sZaawfvoectrwowpt

prihptemnsscotC(tap

rhrm2tas2Kemaat

ig. 7. Effect of filled and unfilled intervals upon recognition and recall scoresn healthy controls.

.3. Summary

The findings of this experiment do not support the view thathe use of an inter-item distractor task interferes with recollectionn such a way as to affect the relationship between recall andecognition memory. Therefore, our use of a distractor task inxperiment 1 above (and in Kopelman & Stanhope, 1998) isost unlikely to have influenced the relationship between recall

nd recognition memory.

. General discussion

In this paper, we have examined the relationship of recallnd recognition memory impairments in memory-disorderedatients in a number of different ways. We employed Hirst et al.1988) technique of titrating exposure times in order to ‘match’ecognition memory performance across participant groups aslosely as possible, and then making a comparison of recallemory performance. We found that, when ceiling effects were

voided, each of the patient groups showed a fall in recall mem-ry performance (relative to recognition scores), which wasroportionate to that seen in healthy participants. Moreover,here was no significant interaction with the delay until testing:n other words, contrary to the speculation in our earlier paperKopelman & Stanhope, 1998), a recall/recognition dissociationid not emerge as the delay until testing increased (a differencerom findings in forgetting rate studies presumably relating tohe differing procedures and material employed). These findingseld good both when the patients were compared with a controlroup given a 3.0 s exposure per word (Controls A), and also

hen comparison was made with controls given a 0.5 s exposureer word (Controls B).

When we converted the patients’ scores to Z-scores, based onhe mean and standard deviation of the combined control groups’

ritr

ologia 45 (2007) 1232–1246 1243

cores, there was no significant difference between their mean-recall and Z-recognition scores. The distribution of points onscatterplot of the patients’ Z-scores (Fig. 5a) was plotted insimilar manner to that of Yonelinas et al. (2002), except thate used an ‘idealised’ line to indicate where the points would

all if Z-recall were equal to Z-recognition for each obtainedalue, whereas Yonelinas et al. employed a regression line basedn their controls’ data. The data-points were distributed fairlyvenly either side of this line. When the data-points from theombined control group (A and B) and the patients were plot-ed, and lines through the zero intercepts superimposed (Fig. 5b),elatively few data-points fell in the bottom right-hand quadrant,hich was the quadrant indicating disproportionate recall mem-ry impairment. More particularly, 10 of these latter data-pointsere from control participants, 6 from ‘lateral’ temporal lobeatients, 2 from frontal patients, and only 1 from the medialemporal group.

Examination of MRI correlates indicated that it was totalarahippocampal, rather than hippocampal, volumes which cor-elated significantly with both recognition and recall memoryn this study. Moreover, although the subgroup with combinedippocampal and parahippocampal (H+) atrophy consistentlyerformed worse than the subgroup whose atrophy was confinedo the hippocampi (H−), when both were given a 10 s/stimulusxposure time, there was no evidence of disproportionate recallemory impairment in the latter group. This was analysed in a

umber of ways, including direct comparison of the H− and H+ubgroups, as well as comparison of the individuals within eachubgroup (using the Crawford & Garthwaite, 2005, test) with alosely matched control group (A and B, respectively). More-ver, when the H− subgroup was re-tested at a shorter exposureime (5 s/stimulus), their performance closely matched bothontrols B (0.5 s/stimulus) and the H+ subgroup (10 s/stimulus)

Fig. 6). Taken together, these findings argue strongly againsthe view that hippocampal amnesia is always characterised bydisproportionate impairment in recall memory, at least on thisarticular test.

Moreover, these findings were obtained using a forced-choiceecognition memory test, a design which at least some studiesave indicated is more likely to show preserved verbal and visualecognition memory performance (and disproportionate recallemory impairment) in hippocampal patients (Holdstock et al.,

002). The purpose of the ‘titration’ experimental design waso match recognition memory performance across the groupss closely as possible, as has previously been employed ineveral of the better designed studies (Giovanello & Verfaellie,001; Huppert & Piercy, 1976, 1978; Hirst et al., 1986, 1988;opelman & Stanhope, 1998): in the absence of such an

xperimental design, comparison of recall and recognitionemory performance, even after statistical manipulations such

s the use of Z-scores, is fraught with difficulty. The use ofn interpolated distractor task allows the delay until testingo be matched across the participant groups whilst preventing

ehearsal between stimuli. An empirical test (Experiment 2)ndicated that the interpolation of an inter-stimulus distractorask does not influence the relationship between recall andecognition memory performance, as had previously been sug-

1 psych

gioeSVcottbe

dt2rtsmaiYsioFfmsrcmKSfttobopr(oroso

emdrds2

oegiahtiuptvoytisabwftaolhsTatpd

tflepvhatv(itfiwrbtd

244 M.D. Kopelman et al. / Neuro

ested (Giovanello & Verfaellie, 2001). A potential criticisms that we tested recall and recognition memory in successionn the same word-lists. However, this design was based on thatmployed by Hirst et al. (1988), and was also used by Janowsky,himamura, Kritchevsky, and Squire (1989), Giovanello anderfaellie (2001) and Yonelinas et al. (2002), who obtainedontrasting results. As was also true of those investigations, onlyne experimental task was employed, and it is certainly arguablehat the present findings need to be replicated using differentypes and modalities of stimuli, and that a design using counter-alanced lists for recall and recognition could also usefully bemployed.

Although a series of recent publications have pointed toifferential patterns of activation in medial temporal lobe struc-ures during recollection or familiarity processes (Davachi et al.,003; Eldridge et al., 2000; Ranganath et al., 2004), and caseeports of individual patients or small groups clearly indicatehat some patients with pathology confined to the hippocampihow disproportionate verbal and visual recall memory impair-ent (Aggleton et al., 2005; Bastin et al., 2004; Henke et

l., 1999; Mayes et al., 2002), the only larger study purport-ng to show this (known to the present authors) is that byonelinas et al. (2002). In that study, the volumes of braintructures were not actually measured, which places severe lim-tations on the interpretation of the findings, and impositionn their Fig. 1b of zero intercept lines, comparable with ourig. 5b, would indicate that the majority of their subjects inact showed combined recall and recognition memory impair-ents. By contrast, there are other investigations which have

hown proportionate effects upon verbal and visual recall andecognition memory in groups of patients with pathology eitheronfined to the hippocampi or more extensively distributed inedial temporal and thalamic structures (Haist et al., 1992;opelman & Stanhope, 1998; Manns et al., 2003; Reed &quire, 1997). Kopelman et al. (2001) and Kramer et al. (2005)ound that it was MRI hippocampal volumes which showedhe most consistent correlations with both recall and recogni-ion memory. This latter finding is at odds with the presentbservation that parahippocampal volumes best correlated withoth recall and recognition memory performance, but both setsf findings argue against a differential contribution of hip-ocampal/parahippocampal (perirhinal) pathology to recall andecognition memory impairments, respectively. Coleshill et al.2004) have shown that unilateral electrical stimulation to the leftr right hippocampus produced material-specific disruption ofecognition memory. Moreover, Adlam (2003) has found that 11ut of 12 adolescents or young adults with developmental amne-ia failed to show disproportionate recall memory impairmentn the Doors and People Test.

This brings us to the important question posed by Holdstockt al. (2002)—namely, under what conditions is recognitionemory spared relative to recall after selective hippocampal

amage in humans? One possibility is that disproportionate

ecall memory impairment simply reflects a milder memoryisorder, as clinical observation and comparison of amnesiaeverity across some published studies suggest (Kopelman,002). However, this cannot account for all the published

A

S

ologia 45 (2007) 1232–1246

bservations (Kopelman, 2002). Similarly, the duration of timelapsed (or the degree of functional or strategic cognitive reor-anisation) since acute hypoxic brain damage may also be asmportant, as Henke et al. (1999) indicated. (The present firstuthor has unpublished data on at least two similar cases). Again,owever, this is unlikely to account for all the discrepancies inhe literature. As already alluded to, Holdstock et al. (2002)ndicated that forced-choice object recognition memory wasnimpaired in their hippocampal amnesic patient, whereas hererformance on an equivalently difficult yes/no object recogni-ion memory task was impaired when the targets and foils wereery similar. Their patient was also impaired on recognition ofbject-location associations, whether tested by forced-choice ores/no memory tasks (Holdstock et al., 2002) and at recogni-ion of other types of association between differing kinds ofnformation (Mayes et al., 2004). Nevertheless, these latter dis-ociations occurred within a single patient, and they do notccount for the discrepancies in the findings on simpler ver-al and visual recognition memory tasks across other patientsith apparently similar pathology. Other possible explanations

or these discrepancies in the literature could include varia-ion in the type, location or extent of hippocampal pathologynd/or variation in the type, location and extent of pathologyr dysfunction beyond the hippocampi and medial temporalobes (Mayes et al., 2004). For example, patients with knownippocampal atrophy and/or sclerosis (in epilepsy) have beenhown to have concurrent thalamic hypometabolism (Kapur,hompson, Kartsounis, & Abbott, 1999) or combined thalamicnd retrosplenial hypometabolism (Reed et al., 1999). However,here is no clear evidence, either in the literature or from theresent investigation, that aetiological differences underlie theseiscrepancies.

At present, we do not have the relevant information availableo choose between these alternative explanations for the con-icts in the literature, which may not necessarily be mutuallyxclusive or equally applicable to all comparisons. However, theresent findings serve as an antidote to the argument, based onery few case reports or functional imaging studies alone, thatippocampal amnesia or amnesia in general is typically char-cterised by disproportionate recall memory impairment, andhat contiguous and closely inter-connected structures subserveery different memory functions. This may be another instancecompare the literature on retrograde amnesia), where the find-ngs from functional imaging studies in healthy participants andhose from neuropsychological investigations in patients withocal lesions point in different directions. The present find-ngs suggest that many patients with medial temporal or moreidespread temporal lobe damage show proportionate recall and

ecognition memory impairments, and that, where discrepanciesetween recall and recognition memory exist, it will require fur-her fine-grained cognitive and neuro-imaging investigations toisentangle their basis.

cknowledgements

The research was funded by the Special Trustees of Guy’s &t Thomas’s Hospital.

psych

A

R

U

R

A

A

A

A

B

B

B

B

B

C

C

C

D

E

F

G

G

H

H

H

M.D. Kopelman et al. / Neuro

ppendix A. Stimulus lists

elated wordsProperties of buildings

Wall DoorBasement StairsHall RoofWindow Floor

ColoursGreen OrangePink GreyBrown BlueYellow White

VehiclesCar LorryTaxi TrainAirplane CoachFerry Van

ClothingScarf CollarJacket TieSock TrousersSkirt Slipper

BirdsFalcon ThrushRobin SwallowPigeon MagpieSeagull Raven

VegetablesCorn ParsnipOnion BeanCabbage LettuceBeetroot Carrot

nrelated wordsUnrelated 1

Spring TailWine PrettyStreet GameTown Picture

Unrelated 2Breakfast LimitLetter MachineHorse MoneyOil Club

Unrelated 3Speaker PartnerCareful MarshHammer RubberMarker Athlete

Unrelated 4Clear PolePlastic SuitcaseFuse ColumnPlanet Wine

Unrelated 5Iron CushionCarry WaveSunshine DrawingRecord Scissors

Unrelated 6

Key ShoulderCloud MarbleHeavy TablePaper Watch

H

ologia 45 (2007) 1232–1246 1245

eferences

dlam, A. R. (2003). Associations in Memory: A Study of Developmental Amne-sia. Ph.D. thesis. University of London.

ggleton, J. P., & Brown, M. W. (1999). Episodic memory, amnesia, andthe hippocampal-anterior thalamic axis. Behavioral & Brain Sciences, 22,425–489.

ggleton, J. P., & Shaw, C. (1996). Amnesia and recognition memory: A re-analysis of psychometric data. Neuropsychologia, 34, 51–62.

ggleton, J. P., Vann, S. D., Denby, C., Dix, S., Mayes, A. R., Roberts, N.,et al. (2005). Sparing of the familiarity component of recognition memoryin a patient with hippocampal pathology. Neuropsychologia, 43(12), 1810–1823.

addeley, A. D., Emslie, H., & Nimmo-Smith, I. (1994). The Doors and PeopleTest. Bury St. Edmunds, UK: Thames Valley Test Company.

addeley, A., Vargha-Khadem, F., & Mishkin, M. (2001). Preserved recognitionin a case of developmental amnesia: Implications for acquisition of semanticmemory? Journal of Cognitive Neuroscience, 13, 357–369.

astin, C., Van der Linden, M., Charnallet, A., Denby, C., Montaldi, N., Roberts,N., et al. (2004). Dissociation between recall and recognition memory per-formance in an amnesic patient with hippocampal damage following carbonmonoxide poisoning. Neurocase, 10, 330–344.

attig, W. F., & Montague, W. E. (1969). Category norms of verbal items in 56categories. A replication and extension of the Connecticut category norms.Journal of Experimental Psychology, 80, 1–46.

right, P., Buckman, J., Fradera, A., Yoshimasu, H., Colchester, A. C. F., &Kopelman, M. D. (2006). Retrograde amnesia in patients with hippocampal,medial temporal, temporal lobe or frontal pathology. Learning and Memory,13, 545–557.

olchester, A., Kingsley, D., Lasserson, D., Kendall, B., Bello, F., Rush, C., et al.(2001). Structural MRI volumetric analysis in patients with organic amnesia,1: Methods and comparative findings across diagnostic groups. Journal ofNeurology Neurosurgery & Psychiatry, 71, 13–22.

oleshill, S. G., Binnie, C. D., Morris, R. G., Alarcon, G., Van Emde Boas,W., Demetrios, V. N., et al. (2004). Material-specific recognition memorydeficits elicited by unilateral hippocampal electrical stimulation. Journal ofNeuroscience, 24, 1612–1616.

rawford, J. R., & Garthwaite, P. H. (2005). Testing for suspected impair-ments and dissociations in neuropsychology. Evaluations of alternativesusing Monte Carlo simulations and revised tests for dissociations. Neuropsy-chology, 19, 318–331.

avachi, L., Mitchell, J. P., & Wagner, A. D. (2003). Multiple routes to memory:Distinct medial temporal lobe processes build item and source memories.Proceedings of the National Academy of Sciences, United States of America,100, 2157–2162.

ldridge, L. L., Knowlton, B. J., Furmanski, C. S., Bookheimer, S. Y., & Engel,S. A. (2000). Remembering episodes: A selective role for the hippocampusduring retrieval. Nature Neuroscience, 3, 1149–1152.

rancis, W. N., & Kucera, H. (1982). Frequency analysis of english usage:Lexicon and grammar. Boston: Houghton Mifflin Co.

iovanello, K. S., & Verfaellie, M. (2001). The relationship between recall andrecognition in amnesia: Effects of matching recognition between patientswith amnesia and controls. Neuropsychology, 15, 444–451.

reen, R. E. A., & Kopelman, M. D. (2002). Contribution of recollection andfamiliarity judgments to rate of forgetting in organic amnesia. Cortex, 38,161–178.

aist, F., Shimamura, A. P., & Squire, L. R. (1992). On the relationship betweenrecall and recognition memory. Journal of Experimental Psychology, 18,691–702.

enke, K., Kroll, N. E. A., Behniea, H., Amaral, D. G., Miller, M. B., Rafal,R., et al. (1999). Memory lost and regained following bilateral hippocampaldamage. Journal of Cognitive Neuroscience, 11, 682–697.

irst, W., Johnson, M. K., Kim, J. K., Phelps, E. A., Risse, G., & Volpe, B.

T. (1986). Recognition and recall in amnesics. Journal of ExperimentalPsychology: Learning, Memory, & Cognition, 12, 445–451.

irst, W., Johnson, M. K., Phelps, E. A., & Volpe, B. T. (1988). More on recogni-tion and recall in amnesics. Journal of Experimental Psychology: Learning,Memory, & Cognition, 14, 758–762.

1 psych

H

H

H

H

I

I

J

J

K

K

KK

K

K

K

K

M

M

M

M

M

M

N

R

R

R

S

S

S

V

W

Y

246 M.D. Kopelman et al. / Neuro

oldstock, J. S., Mayes, A. R., Gong, Q. Y., Roberts, N., & Kapur, N. (2005).Item recognition is less impaired than recall and associative recognition ina patient with selective hippocampal damage. Hippocampus, 15, 203–215.

oldstock, J. S., Mayes, A. R., Roberts, N., Cezayirli, E., Isaac, C. L., O’Reilly,R. C., et al. (2002). Under what conditions is recognition spared relative torecall after selective hippocampal damage in humans? Hippocampus, 12,341–351.

uppert, F. A., & Piercy, M. (1976). Recognition memory in amnesic patients:Effects of temporal context and familiarity of material. Cortex, 12, 3–20.

uppert, F. A., & Piercy, M. (1978). The role of trace strength in recency andfrequency judgements by amnesic and control subjects. Quarterly Journalof Experimental Psychology, 30, 347–354.

saac, C. L., & Mayes, A. R. (1999a). Rate of forgetting in amnesia: I. Recalland recognition of prose. Journal of Experimental Psychology: Learning,Memory, & Cognition, 25, 942–962.

saac, C. L., & Mayes, A. R. (1999b). Rate of forgetting in amnesia: II. Recalland recognition of word lists at different levels of organization. Journal ofExperimental Psychology: Learning, Memory, & Cognition, 25, 963–977.

acoby, L. L., Toth, J. P., & Yonelinas, A. P. (1993). Separating consciousand unconscious influences of memory: Measuring recollection. Journalof Experimental Psychology: General, 122, 139–154.

anowsky, J. S., Shimamura, A. P., Kritchevsky, M., & Squire, L. R. (1989).Cognitive impairment following frontal lobe damage and its relevance tohuman amnesia. Behavioral Neuroscience, 103, 548–560.

apur, N., Thompson, P., Kartsounis, L. D., & Abbott, P. (1999). Retrogradeamnesia: Clinical and methodological caveats. Neuropsychologia, 3, 27–30.

leinbaum, D. G., Kupper, L. L., Muller, K. E., & Nizam, A. (1998). Appliedregression analysis and other multivariable methods (3rd Ed.). Belmont,CA, US: Brooks, Cole Publishing Co.

opelman, M. D. (2002). Disorders of memory. Brain, 125, 2152–2190.opelman, M. D., & Stanhope, N. (1997). Rates of forgetting in organic amnesia

following temporal lobe, diencephalic, or frontal lobe lesions. Neuropsychol-ogy, 11, 343–356.

opelman, M. D., & Stanhope, N. (1998). Recall and recognition memory inpatients with focal frontal, temporal lobe and diencephalic lesions. Neu-ropsychologia, 36, 785–796.

opelman, M. D., Lasserson, D., Kingsley, D., Bello, F., Rush, C., Stanhope,N., et al. (2001). Structural MRI volumetric analysis in patients with organicamnesia, 2: Correlations with anterograde memory and executive tests in 40patients. Journal of Neurology, Neurosurgery & Psychiatry, 17, 23–28.

opelman, M. D., Lasserson, D., Kingsley, D. R., Bello, F., Rush, C., Stan-hope, N., et al. (2003). Retrograde amnesia and the volume of critical brainstructures. Hippocampus, 13, 879–891.

ramer, J. H., Howard, J. R., An-Tao, D., Schuff, N., Odell, C., Delis, D. C., et al.

(2005). Dissociations in hippocampal and frontal contributions to episodicmemory performance. Neuropsychology, 19(6), 799–805.

anns, J. R., Hopkins, R. O., Reed, J. M., Kitchener, E. G., & Squire, L. R.(2003). Recognition memory and the human hippocampus. Neuron, 37,171–180.

Y

ologia 45 (2007) 1232–1246

anns, J. R., & Squire, L. R. (1999). Impaired recognition memory on theDoors and People Test after damage limited to the hippocampal region.Hippocampus, 9, 495–499.

ayes, A. R. (1986). Learning and memory disorders and their assessment.Neuropsychologia, 24, 25–39.

ayes, A. R., Holdstock, J. S., Isaac, C. L., Hunkin, N. M., & Roberts,N. (2002). Relative sparing of item recognition memory in a patientwith adult-onset damage limited to the hippocampus. Hippocampus, 12,325–340.

ayes, A. R., Holdstock, J. S., Isaac, C. L., Montaldi, D., Grigor, J., Gummer,A., et al. (2004). Associative recognition in a patient with selective hip-pocampal lesions and relatively normal item recognition. Hippocampus, 14,763–784.

ori, E., Yoneda, Y., Yamashita, H., Hirono, N., Ikeda, M., & Yamadori,A. (1997). Medial temporal structures relate to memory impairment inAlzheimer’s Disease: An MRI volumetric study. Journal of Neurology, Neu-rosurgery & Psychiatry, 63, 214–221.

elson, H. E., & Willison, J. R. (1991). The National Adult Reading Test (2nded.). Windsor: NFER-Nelson.

anganath, C., Yonelinas, A. P., Cohen, M. X., Dy, C. J., Tom, S. M., &D’Esposito, M. (2004). Dissociable correlates of recollection and familiaritywithin the medial temporal lobes. Neuropsychologia, 42, 2–13.

eed, L. J., Marsden, P., Lasserson, D., Sheldon, N., Lewis, P., Stanhope, N.,et al. (1999). FDG-PET analysis and findings in amnesia resulting fromhypoxia. Memory, 7, 599–612.

eed, J. M., & Squire, L. R. (1997). Impaired recognition memory in patientswith lesions limited to the hippocampal formation. Behavioral Neuroscience,11, 667–675.

tanhope, N., & Kopelman, M. D. (2000). Art and memory: A 7 year follow-upof herpes encephalitis in a professional artist. Neurocase, 6, 99–110.

tark, C. E. L., Bayley, P. J., & Squire, L. R. (2002). Recognition memory forsingle items and for associations is similarly impaired following damage tothe hippocampal region. Learning & Memory, 9, 238–242.

tark, C. E. L., & Squire, L. R. (2003). Hippocampal damage equally impairsmemory for single items and memory conjunctions. Hippocampus, 13,281–292.

argha-Khadem, F., Gadian, D. G., Watkins, K. E., & Connelly, A. (1997).Differential effects of early hippocampal pathology on episodic and semanticmemory. Science, 277, 376–380.

arrington, E. K., & Weiskrantz, L. (1982). Amnesia: A disconnection syn-drome? Neuropsychologia, 20, 233–248.

onelinas, A. P., Kroll, N. E. A., Dobbins, I., Lazzara, M. M., & Knight, T.G. (1998). Recollection and familiarity deficits in amnesia: Convergence ofremember-know, process dissociation, and receiver operating characteristic

data. Neuropsychology, 12, 323–339.

onelinas, A. P., Kroll, N. E. A., Quamme, J. R., Lazzara, M. M., Sauve, M.,Widaman, K. F., et al. (2002). Effects of extensive temporal lobe damageor mild hypoxia on recollections and familiarity. Nature Neuroscience, 5,1236–1241.