Domain-specific retrieval of source information in the medial temporal lobe

Domain-specific retrieval of source informationin the medial temporal lobe

Jan Peters,1,2 Boris Suchan,1,2 Odo Koster3 and Irene Daum1,2

1International Graduate School of Neuroscience, Ruhr-University of Bochum, Germany2Institute of Cognitive Neuroscience, Department of Neuropsychology, Ruhr-University of Bochum, Universitatsstraße 150, D-44780Bochum, Germany3Institute of Diagnostic and Interventional Radiology and Nuclear Medicine, St Josef Hospital of the Ruhr-University Bochum,Germany

Keywords: fMRI, MTL, parahippocampal cortex, perirhinal cortex, recollection, source memory

Abstract

Memory for context information (source memory) has been reported to rely on structures in the medial temporal lobe (MTL).Perirhinal cortex (anterior MTL) and parahippocampal cortex (posterior MTL) have distinct connectivity patterns with sensoryneocortex, suggesting a possible modality-dependent organization of memory processes. The present study investigated the neuralsubstrates of two different types of source information of newly encoded material using functional magnetic resonance imaging:auditory (speaker voice) and visual (texture and colour). Source judgements during retrieval were reliably above chance level for bothmodalities and performance did not differ between the auditory and visual condition. During encoding, activity predictive ofsubsequent source recollection was observed in the anterior hippocampus ⁄ parahippocampal gyrus, irrespective of source modality.During retrieval, on the other hand, a regional dissociation emerged: bilateral parahippocampal cortex discriminated between correctand incorrect auditory but not visual source judgements, whereas left perirhinal ⁄ entorhinal cortex showed the reverse pattern. Thesefindings are consistent with recent lesion evidence of disrupted auditory but intact visual source memory following damage to theparahippocampal cortex. Results are discussed with respect to anatomical models of corticoparahippocampal connectivity and thefunctional organization of the MTL.

Introduction

In recognition memory, a distinction is commonly drawn betweenmemory for an item and memory for additional contextual informationof the study episode (source memory). Experimental variations offeatures of the study episode and subsequent forced-choice tests ofsource recollection are commonly used to obtain objective measuresof source memory (Cansino et al., 2002; Davachi et al., 2003; Kahnet al., 2004; Ranganath et al., 2004).

Accumulating evidence suggests that subregions of the medialtemporal lobe (MTL) support dissociable functions in recognitionmemory (Murray & Wise, 2004; Davachi, 2006; Eichenbaum, 2006).Recollective recognition is thought to depend on the hippocampus,whereas familiarity-based recognition is thought to depend on therhinal cortices (Brown & Aggleton, 2001). Current theories emphasizethe role of the anatomical connections of MTL subregions (Eichen-baum et al., 2007). Perirhinal cortex is connected predominantly toinferior temporal regions of the ventral visual processing streamwhereas parahippocampal cortex has strong connections withregions of the dorsal visual pathway and auditory association cortices(Suzuki & Amaral, 1994; Lavenex et al., 2002). Lesion studies yieldedresults consistent with these anatomical findings: while parahippo-campal cortex lesions in monkeys impair spatial memory functions,

perirhinal cortex lesions impair object memory (Alvarado &Bachevalier, 2005; Nemanic et al., 2004).Functional imaging studies also implicated regions of the posterior

parahippocampal cortex in the perception (Epstein & Kanwisher,1998), encoding (Davachi et al., 2003) and retrieval (Cansino et al.,2002; Kahn et al., 2004) of spatial (source) information. Perirhinalcortex, on the other hand, is more involved in single-item encoding(Davachi et al., 2003; Ranganath et al., 2004) and familiarity-basedrecognition (Henson et al., 2003).We directly tested an anatomically motivated model of MTL

functioning by applying a source memory task using auditory (speakervoice) and visual (background texture and colour) source informationthought to be relayed to the parahippocampal and perirhinal cortices,respectively (Suzuki & Amaral, 1994). In support of the notion ofdomain specificity (Davachi, 2006), the present paradigm has recentlyrevealed a dissociation of auditory and visual source memoryfollowing ischemic damage to posterior but not anterior medialtemporal lobe (Peters et al., 2007).Reports of modality-specific interactions of the MTL with the

neocortex specifically during memory retrieval (Kohler et al., 1998a)and of a backward-spreading retrieval signal from the perirhinal cortexto area TE in the monkey during retrieval of object information (Nayaet al., 2001) led us to expect domain-specific responses in theparahippocampal gyrus (PHG) during source retrieval. Anterior PHGactivation (thought to reflect perirhinal and lateral entorhinal process-ing; see Eichenbaum et al., 2007) was expected during visual sourceretrieval, whereas posterior PHG activation (thought to reflect

Correspondence: Jan Peters, 2Institute of Cognitive Neuroscience, as above.E-mail: [email protected]

Received 25 April 2007, revised 2 July 2007, accepted 6 July 2007

European Journal of Neuroscience, Vol. 26, pp. 1333–1343, 2007 doi:10.1111/j.1460-9568.2007.05752.x

ª The Authors (2007). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing Ltd

parahippocampal and medial entorhinal processing; see Eichenbaumet al., 2007) was expected during auditory source retrieval.Given previous reports of hippocampal activation during source

retrieval and recollection (Eldridge et al., 2000; Cansino et al., 2002;Daselaar et al., 2006), hippocampal activation was expected to bedomain-general during source retrieval.

Materials and methods

Subjects

Twenty-one subjects participated in the experiment. Data from threesubjects had to be excluded because of technical problems duringdata acquisition. Three further subjects were excluded because ofbehavioural performance at chance level or false-alarm rates in bothmodalities > 2 SD above the mean. In the remaining 15 subjects(mean age ¼ 25, range 20–35 years; seven female), handedness wasassessed using the Edinburgh Handedness Inventory (Oldfield,1971). Fourteen participants were right-handed (mean LQ ¼ 90)and one participant was left-handed (LQ ¼ )83.33). Exclusion ofthe left-handed participant from the analysis did not significantlyalter the pattern of results. All participants had normal or corrected-to-normal vision and gave informed written consent prior to theirparticipation. The study procedure was in accordance with theDeclaration of Helsinki, and approved by the Ethics Committee ofthe Medical Faculty of the Ruhr-University, Bochum, Germany.

General procedure

Participants were scanned during both an encoding session and asubsequent recognition test. After encoding, participants left thescanner for a break of �10–15 min. Behavioural pilot studies haveshown that a break of this length results in source memoryperformance reliably above chance while ceiling effects are avoided,allowing us to obtain a sufficient number of both source-correct and

source-incorrect trials. T1-weighted anatomical scans were acquired atthe end of the recognition session. Stimuli and instructions wereprojected onto a screen in front of the magnetic resonance imaging(MRI) scanner, which subjects viewed through a head coil-mountedmirror. Auditory stimuli were presented binaurally via MR-compatibleheadphones (MR-Confon; http://www.mr-confon.de; Magdeburg,Germany). A foam cushion was used for additional scanner noiseattenuation. The paradigm was implemented using the experimentalrun-time system (BeriSoft, http://www.erts.de; Frankfurt, Germany).

Stimulus material

A set of 230 items was used. For objects taken from a standardisedset of line drawings (Snodgrass & Vanderwart, 1980), new auditoryand visual versions were constructed in our lab. Visual items weregreyscale photographs of common objects and auditory items werethe corresponding spoken words. Words were recorded from a maleand a female speaker in stereo at a sampling rate of 44.1 kHz.Visual items were presented against either a flat ‘lawn’ or a ‘clouds’background, which differed in both texture and colour (Fig. 1).During the recognition session, targets and distracters werepresented in a contextually neutral format: pictures were shownagainst a grey background and spoken words were presented in aneutral voice (‘robot’ voice). The neutral voice was constructed byfrequency modulation of recordings of a second male speaker,created using the GoldWave software package (http://www.goldwave.com). The exact spoken duration of all words rangedfrom 800 to 1100 ms.For each participant, 80 items were randomly selected to serve as

auditory targets and 80 items were randomly selected to serve as visualtargets. The remaining 70 items served as distracters during therecognition phase. During the encoding session, auditory and visualtargets were randomly assigned to either source condition (male orfemale voice for auditory items, lawn or clouds background for visualitems), yielding 40 items for each source condition in each modality.

Fig. 1. (A) Schematic outline of encoding and retrieval trials in both modalities. (Ai) During encoding, pictures were presented either against a flat ‘lawn’ or a‘clouds’ background texture. Words were spoken by a female or a male speaker. (Aii) During retrieval, distractors and targets were presented in a contextually neutralformat: pictures were shown against a grey background and words were spoken in a neutral ‘robot’ voice (see Materials and methods). Participants made ‘old’ or‘new’ decisions followed by source judgements. (B) Mean ± SEM percentage of hits with correct source (n ¼ 15). Source memory was significantly above thechance level of 50% (dotted line) for both modalities and not different between auditory and visual trials (P > 0.2). ***P < 0.005; n.s., not significant.

1334 J. Peters et al.

ª The Authors (2007). Journal Compilation ª Federation of European Neuroscience Societies and Blackwell Publishing LtdEuropean Journal of Neuroscience, 26, 1333–1343

Task

Encoding

Participants were instructed to memorise the spoken words and thepictures for a later memory test, but no mention was made of the factthat memory for visual or auditory source would later be tested. Item-based encoding was emphasised and participants were instructed touse a rote-rehearsal strategy. To ensure that participants adequatelyprocessed source information, they were prompted to indicate thespeaker voice (male or female) or the background texture (lawn orclouds) after each item presentation. There was no practice session.Voice and background information should therefore have beenencoded incidentally, minimising the likelihood of a verbal strategywhich may contaminate any material specific effects (Fan et al., 2003).

The sequence of events during encoding is depicted in Fig. 1A.Trials were separated by blank-screen intertrial intervals and theirduration was randomly varied between 1000 and 3000 ms in steps of400 ms, in order to increase the efficiency of the event-related design(Dale, 1999). Furthermore, auditory and visual trials were randomlyintermixed, resulting in a mean interval between two successiveauditory or visual trials of � 12.5 s. The encoding session lasted�18 min.

Retrieval

During recognition, 160 old items and 70 new items (distracters) werepresented in a neutral format (see stimulus material), half in eachmodality. Subjects were first prompted to make an ‘old’ or ‘new’decision followed by the prompt to indicate the voice (male or female)or the background picture (lawn or clouds) of the item duringencoding. For technical reasons, the prompt to indicate the voice orbackground was also shown when participants indicated that theythought the item was new. In these cases, subjects were instructed notto respond to the source prompt. The sequence and duration of eventsduring recognition is depicted in Fig. 1A. The relatively long responsetime windows were chosen because, in behavioural pilot studies,source memory performance was reduced with shorter response timewindows. Due to the fact that subjects were instructed to respond onlywhen prompted to make ‘old’ vs. ‘new’ and source judgements, andbecause accuracy was emphasised over speed, reaction times are notreadily interpretable and are therefore not reported. The recognitionsession lasted � 45 min.

Image acquisition and preprocessing

Anatomical and functional images were acquired on a 1.5-T SiemensSymphony scanner. During the encoding and retrieval session, 620and 1540 volumes were acquired, respectively, with a repetition timeof 1.75 s and an echo time of 30 ms. Such short response timesminimise signal drop-out from the anterior temporal lobes (Ojemannet al., 1997). Each volume comprised 24 axial slices with an in-planeresolution of 3.0 mm · 2.2 mm. A 160-mm field of view waspositioned to cover the hippocampus, PHG and fusiform gyrusbilaterally. The approximate region from which functional scans wereacquired is depicted in Fig. 2. The first five volumes were discarded toallow for T1 stabilisation. A high-resolution T1-weighted image wasacquired for anatomical labelling. Imaging data were processed andanalysed using SPM2 (http://www.fil.ion.ucl.ac.uk/spm/). Volumes ofeach session were slice-time corrected, realigned, normalized to avoxel size of 2 · 2 · 2 mm into the Montreal Neurological Institute(MNI) standard anatomical space and smoothed with a 6-mm full-width half-maximum isotropic Gaussian kernel.

Image analysis

Data were modelled for each subject and session (encoding andrecognition) by convolving the canonical haemodynamic responsefunction (HRF) with the event train of stimulus onsets. Blood oxygenlevel-dependent (BOLD) responses to hits with and without correctsource, misses, false alarms and correct rejections were modelledseparately. Given that regional specificity of neuronal responses duringsource memory was our primary objective, further analyses wererestricted to trials in which participants correctly recognized the item(recognition session) or subsequently correctly recognized the item(encoding session).Planned contrasts of parameter estimates were then computed for

each subject using SPM2. We compared hits associated with correctand incorrect source judgements in each modality by computingbidirectional contrasts (auditory hit: source correct vs. auditory hit:source incorrect) and (visual hit: source correct vs. visual hit: sourceincorrect) for each subject and separately for encoding and retrieval.These contrasts were then taken to a second-level random-effectsanalysis. Because of our clear a priori hypotheses about the role ofanterior and posterior PHG in this task, all bidirectional statisticalparametric maps were thresholded at P < 0.01 (two-tailed, uncor-rected for multiple comparisons) with an extent threshold of8 voxels, yielding a one-tailed significance of P < 0.005. Note thatthis threshold is commonly adopted in event-related functional MRimaging (fMRI) studies of the MTL (Strange et al., 2002; Duzelet al., 2003; Weis et al., 2004; Daselaar et al., 2006). Given the lowsignal-to-noise ratio in the anterior MTL (Ojemann et al., 1997) andour a priori hypotheses about the role of perirhinal and parahippo-campal cortices in this task, based on anatomical considerations(Suzuki & Amaral, 1994) and recent lesion evidence (Peters et al.,2007), this uncorrected threshold represents an acceptable trade-offbetween sensitivity and reliability, and all MTL activations showinggreater activity for correct than for incorrect source encoding andretrieval are addressed in the Results section.We aimed to investigate whether the activations in the MTL

identified in these contrasts show a regionally specific dissociationbetween auditory and visual source memory. To address this question,regions of interest were constructed from activated clusters inthe bidirectional contrasts of interest described above (i.e. auditorysource correct vs. auditory source incorrect during encoding or

Fig. 2. Sagittal view of the MNI reference brain (x ¼ )20). Lines indicate theapproximate position and orientation of acquired functional scans.

Domain-specific retrieval in the MTL 1335


retrieval; accordingly for the visual modality) and percent signalchange was calculated across all activated voxels in a given cluster asactivation relative to implicit baseline using MarsBar (Brett et al.,2002). Signal change data were then exported to SPSS 12.0 forstatistical analysis. We conducted separate anovas for the encodingand retrieval phases. Signal change data were submitted to region ·modality (auditory or visual) · source (correct or incorrect) anovaswith Greenhouse–Geisser correction. Additionally, signal changetime-courses were obtained using MarsBar for visualization purposes.All statistical parametric maps were projected onto the mean

T1-weighted image of all participants. For additional anatomicalanalyses, we overlaid the group activations on each subject’sindividual normalized structural scan. All coordinates are reported inMNI space. Anatomical localization was performed by convertingthe coordinates into the Talairach anatomical space (Talairach &Tournoux, 1988) using an algorithm suggested by Brett (http://www.mrc-cbu.cam.ac.uk/Imaging/mnispace.html).

Results

Behavioural data

Proportions of trials associated with source and item memory successas well as proportions of false alarms, misses and correct rejections arelisted in Table 1 for each modality. Corrected item recognition scores(Pr ¼ hit rate ) false alarm rate; Snodgrass & Corwin, 1988) werecomputed for each modality (mean ± SEM auditory 0.36 ± 0.03,visual 0.58 ± 0.06) and statistically analysed. Pr was significantlyabove chance level for both auditory (t1,14 ¼ 11.209, P < 0.001) andvisual (t1,14 ¼ 10.033, P < 0.001) trials. Auditory Pr was lower thanvisual Pr (t1,14 ¼ 4.464, P ¼ 0.001). To assess source memoryperformance, the percentage of hits with correct source judgementswas calculated (see Fig. 1B). This measure was significantly abovechance level for both auditory (t1,14 ¼ 4.633, P < 0.001) and visual(t1,14 ¼ 4.065, P ¼ 0.001) trials and, importantly, did not differbetween the auditory and visual conditions (t1,14 ¼ 0.367; n.s.). Thispattern indicates that (i) participants’ source memory was reliablyabove chance level, but a sufficient number of errors were made toallow contrasting of correct and incorrect trials, and (ii) that the sourcememory task was of similar difficulty in auditory and visual trials.We used relatively long response time windows and subjects were

instructed to respond only when prompted (see Materials and methods).Reaction times were therefore not analysed and are not reported.

fMRI data: encoding

FMRI data were analysed in two steps. Firstly, we identified regionsshowing activation differences during successful compared to unsuc-cessful source encoding, separately for auditory and visual trials.Analysis was thus limited to those trials on which subjects success-

fully recognized the item (i.e. the spoken word or the object). Asimaging data were acquired from a reduced field of view principallycovering PHG and hippocampus bilaterally (see Fig. 2), region-of-interest analysis was focused on activations in the MTL (see Materialsand methods). The complete list of activations for each modality canbe found in Table 2.One region that could be localized to the MTL was identified,

although it was anatomically somewhat ambiguously located at theborder of right hippocampus and PHG (Fig. 3A and D; see alsoDiscussion). This cluster [x ¼ 36, y ¼ )14, z ¼ )24, peakz-score ¼ 2.94, k ¼ 18 voxels; Brodmann area BA20 ⁄ hippocampus]was found to show greater BOLD signal for successful than forunsuccessful visual source encoding. In a second step, we assessedwhether activity related to source encoding success in this regionwas domain-general (i.e. present for successful auditory and visualsource encoding) or domain-specific (i.e. only present for visualsource encoding). Percent signal change was averaged over allactivated voxels in this cluster (see Materials and methods) andsubmitted to a source (correct or incorrect) · modality (auditory orvisual) anova. This analysis revealed greater activity for correctthan for incorrect source encoding irrespective of modality (maineffect of source, F1,14 ¼ 9.073, P ¼ 0.009) and greater activation forvisual than for auditory trials (main effect of modality,F1,14 ¼ 10.007, P ¼ 0.007) but no interaction (F1,14 ¼ 0.230,P > 0.2). The main effects are illustrated in Fig. 3B and the timecourses are plotted in Fig. 3C.At the initial extent threshold of 8 voxels, no additional

hippocampal activation predictive of subsequent source recollection

Table 1. Behavioural measures for both modalities

Trials

Old items New items

Hits withsource

Hitswithoutsource Misses

Correctrejections

Falsealarms

Auditory 0.38 ± 0.04 0.21 ± 0.02 0.42 ± 0.05 0.79 ± 0.04 0.21 ± 0.04Visual 0.42 ± 0.05 0.24 ± 0.02 0.34 ± 0.05 0.93 ± 0.02 0.07 ± 0.02

Values are proportions of trials (mean ± SEM); n ¼ 15 subjects.

Table 2. Task-related activations from the encoding session

RegionApproximateBA area

Numberof voxels

MNIcoordinates

z-valuex y z

AuditoryR inferior temporalgyrus

37 15 44 )50 )2 3.66

L putamen – 11 )24 10 8 3.30L fusiform gyrus 37 10 )40 )54 )12 3.19L PHG� 19 8 )32 )52 )6 2.94R superior temporalgyrus ⁄ insula

29 ⁄ 13 16 32 )34 10 2.91

L inferior temporalgyrus

37 10 )52 )54 )10 2.68

VisualL cerebellum – 75 )4 )38 )12 3.99L hippocampus� – 13 )30 )46 8 3.38R superior temporalgyrus

38 17 34 12 )28 3.31

R PHG� 36 10 18 )48 )18 3.17R middle temporalgyrus

21 11 58 )36 )4 3.16

R brainstem – 21 12 )12 )14 3.01L PHG� 19 ⁄ 37 25 )18

)20)50)50

)6)16

3.002.73

R PHG–hippocampus 20 18 36 )14 )24 2.94L superior temporalgyrus

38 8 )40 16 )20 2.78

Correct > incorrect source encoding (P < 0.01, two-tailed, extent threshold8 voxels). Regions correspond to the nearest grey matter as provided by theTalairach Daemon. L, left; R, right. �Activation fell �10 mm beyond the greymatter of the hippocampus and was therefore not considered to reflect a hip-pocampal signal. �Activation was too posterior to reflect an MTL signal.



was observed. As clearer hippocampal effects were expected, weexplored subthreshold MTL effects. When using a more liberalextent threshold of 3 voxels, we additionally observed a smallcluster in the right posterior hippocampus showing a greater BOLDsignal for correct than for incorrect auditory source encoding(x ¼ 28, y ¼ )38, z ¼ )4, peak z-score ¼ 2.84, k ¼ 3 voxels).This region showed source encoding success-related activity forauditory but not visual source (source · modality interaction,F1,14 ¼ 7.451, P ¼ 0.016; paired comparison, t1,14 ¼ 3.351,P < 0.005, one-tailed).

fMRI data: recognition

Analysis of the fMRI data from the recognition phase proceeded inanalogy to the encoding phase. For the recognition phase, we againfocused on activations in the MTL. Given that we motivated ourapproach by focusing on MTL connections with sensory cortices,we additionally analysed subthreshold activity in sensory regionsoutside the MTL. The complete list of activations is shown inTable 3.Clusters in left (x ¼ )24, y ¼ )46, z ¼ )16, peak z-score ¼ 3.24,

k ¼ 26 voxels; BA37) and right (x ¼ 28, y ¼ )42, z ¼ )12, peakz-score ¼ 3.05, k ¼ 13 voxels; BA36) parahippocampal cortex

Fig. 3. (A) Perirhinal cortex activation in the contrast correct vs. incorrectvisual source encoding (P < 0.01, two-tailed, 8-voxel extent threshold).Contrast was increased in the magnified section for visualization purposes.HC, hippocampus; PHG, parahippocampal gyrus; dashed line, collateralsulcus. (B) Mean ± SEM cluster signal change relative to implicit baselinefor correct vs. incorrect auditory or visual source encoding. This regionshowed source encoding success-related activity (main effect of source,P < 0.01) regardless of modality (source · modality interaction, P > 0.2).**P< 0.01.(C) Mean ± SEM signal change time course for the auditory (left)and the visual (right) condition. Each data point corresponds to one scan.(D) The activation from the group analysis overlaid onto each participant’sindividual normalized structural scan.

Fig. 4. (A) Left perirhinal and entorhinal cortex activation in the bidirectionalcontrast correct vs. incorrect visual source retrieval (P < 0.01, two-tailed,8-voxel extent threshold). Contrast was increased in the magnified section forvisualization purposes. HC, hippocampus; PHG, parahippocampal gyrus;dashed line, collateral sulcus. (B) Mean ± SEM signal change time-coursesfor correct vs. incorrect auditory (left) and visual (right) source retrieval. Eachdata point corresponds to one scan. This region differentiated selectivelybetween correct and incorrect visual but not auditory source retrieval(source · modality interaction, P ¼ 0.054). **P < 0.01; n.s., not significant.(C) Results from the group analysis overlaid onto each subject’s individualnormalized structural scan.



showed greater BOLD responses, for correct than for incorrectauditory source retrieval (see Fig. 5), whereas a region in the leftperirhinal ⁄ entorhinal cortex (x ¼ )20, y ¼ )16, z ¼ )32, peakz-score ¼ 2.73, k ¼ 14 voxels) showed a greater BOLD responsefor correct than for incorrect visual source retrieval (see Fig. 4).To assess domain specificity in the these regions during source

retrieval, mean signal change of these clusters was submitted to aregion (left parahippocampal cortex, right parahippocampal cortex,left perirhinal and entorhinal cortex) · source (correct or incor-rect) · modality (auditory or visual) anova. This yielded a region-dependent effect of the stimulus modality (region · modalityinteraction, F2,28 ¼ 13.390, P < 0.001). Critically, the three-wayinteraction was also significant (region · source · modality,F2,28 ¼ 6.646, P ¼ 0.016). To resolve this interaction, separatesource · modality anovas were conducted for each of the threeMTL clusters. For left parahippocampal cortex (Fig. 5, i), thisanalysis revealed a main effect of the stimulus modality(F1,14 ¼ 17.56, P ¼ 0.001). Furthermore, activity in this regionreliably differentiated between correct and incorrect auditory but notvisual source judgements (source · modality interaction,F1,14 ¼ 15.803, P ¼ 0.001; paired comparison, t1,14 ¼ 4.425,P ¼ 0.001, two-tailed). An identical pattern of results was observedin the right parahippocampal cortex (Fig. 5, ii): a main effect ofmodality was observed (F1,14 ¼ 21.997, P < 0.001) but this region,too, only reliably differentiated between correct and incorrectauditory source judgements (source · modality interaction,F1,14 ¼ 6.481, P ¼ 0.023; paired comparison, t1,14 ¼ 4.637,P < 0.001, two-tailed). Responses in bilateral parahippocampalcortex during auditory correct rejections were not different fromzero (left, t1,14 ¼ 0.312, P > 0.4; right, t1,14 ¼ )0.832, P > 0.4),whereas responses to visual correct rejections were not significantlydifferent from the responses in these regions to visual correct orincorrect source judgements (all P > 0.05).Left perirhinal ⁄ entorhinal cortex, on the other hand, discriminated

between correct and incorrect visual but not auditory source judge-ments (source · modality interaction, F1,14 ¼ 4.428, P ¼ 0.054;paired comparison, t1,14 ¼ 2.931, P ¼ 0.011, two-tailed), though theinteraction was only marginally significant. Responses in this region tocorrect rejections were not significantly different from zero (auditory,t1,14 ¼ 0.337, P > 0.4; visual, t1,14 ¼ )1.646, P > 0.1). Takentogether, the perirhinal and parahippocampal MTL activity observed

in the recognition phase showed the expected anterior–posteriordissociation between successful voice and texture–colour sourcememory.Sensory cortices are frequently reported to be engaged in a

material-dependent fashion during vivid remembering (e.g. Wheeleret al., 2000). Activity in a cluster in the inferior temporal cortex(x ¼ )50, y ¼ )38, z ¼ )20, peak z-score ¼ 3.68, k ¼ 5 voxels;BA20) showed BOLD signal differences between correct andincorrect visual source retrieval, whereas a region in the left superiortemporal gyrus (x ¼ )48, y ¼ )26, z ¼ 2, peak z-score ¼ 2.81,k ¼ 6 voxels; BA 22 ⁄ 41) showed a signal difference betweencorrect and incorrect auditory source retrieval. Note, however, thatboth clusters were only observed at a slightly lower extent threshold(5 voxels) than in the previous analyses (8 voxels). While theinferior temporal cortex region showed a nonsignificant trendtowards specificity for visual source retrieval (source · modalityinteraction trend, F1,14 ¼ 3.9, P ¼ 0.077; paired comparison,t1,14 ¼ 3.25, P ¼ 0.003, one-tailed), the cluster in the left auditoryassociation cortex showed greater activity for auditory trials(modality main effect, F1,14 ¼ 7.169, P ¼ 0.018) and correct sourcejudgements (source main effect, F1,14 ¼ 6.3, P ¼ 0.025) but nointeraction (P > 0.1).Hippocampal activation is often (but not always) reported to

accompany recollective remembering. At our initial threshold ofP < 0.01 (two-tailed) we observed no hippocampal activation ineither the auditory or the visual source memory contrast. Althoughprocedural differences such as the use of a purely incidentalencoding paradigm and the fact that perceptual rather than semanticassociations were retrieved may account for this finding (seeDiscussion), lowering the threshold to P < 0.01 (one-tailed) yieldedanterior hippocampal activation in the auditory source correct >incorrect contrast (peak coordinates x ¼ )22, y ¼ )8, z ¼ )22,peak z-score ¼ 2.51, k ¼ 2 voxels), showing a trend for increa-sed activation during correct source retrieval (source maineffect, F1,14 ¼ 3.407, P ¼ 0.086) irrespective of modality (source ·modality interaction, P > 0.2).

Discussion

The present results suggest several dissociations between memoryprocesses and MTL subregions in the human brain. During encoding,an anterior hippocampal–parahippocampal region showed increasedactivity for successful compared to unsuccessful encoding of sourceinformation irrespective of source modality. During retrieval, on theother hand, bilateral posterior parahippocampal cortex reliablydifferentiated correct from incorrect auditory but not visual sourceretrieval. In contrast, left perirhinal ⁄ entorhinal cortex differentiatedcorrect from incorrect visual but not auditory source retrieval. Wewill discuss in turn the pattern of behavioural performance, issues ofanatomical localization of the observed clusters and finally thesignificance of the present findings to current theories of thefunctional organization of the human medial temporal lobe.

Task and behavioural performance

The source memory task was of similar difficulty in the two modalitiesand the average accuracy of � 64% allowed the comparison of trialsassociated with correct and incorrect source memory. Auditory sourcememory performance was somewhat lower than in a previouslyreported lesion study (Peters et al., 2007), a finding that is probablydue to the scanning environment, i.e. the background noise may have

Table 3. Task-related activations from the retrieval session

RegionApproximateBA area

Numberof voxels

MNI coordinates

z-valuex y z

AuditoryL parahippocampal 37 26 )24 )46 )16 3.24–fusiform gyrus )30 )42 )20 2.92R PHG 36 13 28 )42 )12 3.05R inferior temporalgyrus

20 10 50 )28 )16 2.92

VisualL claustrum–insula – 24 )30 16 6 2.86L PHG 35 14 )20 )16 )32 2.73R middle temporalgyrus

22 9 64 )32 4 2.71

L PHG 37 13 )12 )4 )12 2.70

Correct > incorrect source encoding (P < 0.01, two-tailed, threshold extent8 voxels). Regions correspond to the nearest grey matter as provided by theTalairach Daemon. L, left; R, right.



affected auditory trials. Item memory performance differed betweenmodalities, a finding that is probably due to the fact that visual trialsbenefit more from dual coding than do auditory trials (Paivio, 1991),as all pictures were easily verbalizable. Analysis focused on trials inwhich the item was correctly recognized; therefore, differential itemmemory performance can be assumed to be cancelled out in thereported contrasts.

Furthermore, we acknowledge that we cannot assume the auditoryand visual conditions of the present task to differ solely in terms ofstimulus modality. It could be argued that the auditory trials may entailverbal rehearsal to a greater extent than the visual trials, for example,which in turn may promote object-level processing to a greater extent.These possible differences between conditions cannot, however,

convincingly account for the domain-specific effect of source memoryaccuracy on responses in the MTL during retrieval.

Localization

Anatomical localization of MTL activations was performed followingthe protocols of Insausti et al. (1998) for perirhinal and entorhinal cortexand the protocols of Pruessner and colleagues for the parahippocampalcortex (Pruessner et al., 2002) and hippocampus (Pruessner et al., 2000).Furthermore, in order to consider individual anatomical variability, weoverlaid the results of the functional group analysis onto each subject’sindividual normalized structural scan (see Figs 3D, 4C and 5C).

Fig. 5. (A) Bilateral posterior parahippocampal cortex activation in the bidirectional contrast correct vs. incorrect auditory source retrieval (P < 0.01, two-tailed,8-voxel extent threshold). Contrast was increased in the magnified sections for visualization purposes. HC, hippocampus; PHG, parahippocampal gyrus; dashed line,collateral sulcus. (B) Mean ± SEM signal change time-courses for correct vs. incorrect auditory (left) and visual (right) source encoding. Each data point correspondsto one scan. (Bi) Left and (Bii) right parahippocampal cortex are depicted. Both regions differentiated selectively between correct and incorrect auditory but notvisual source retrieval as reflected in significant source · modality interactions (left, P < 0.001; right, P ¼ 0.023); **P < 0.01, ***P < 0.005; n.s., not significant.(C) Results from the group analysis overlaid onto each subject’s individual normalized structural scan.



The MTL cluster observed during encoding (Fig. 3) fell anatom-ically somewhat ambiguously onto the border of perirhinal cortex(lateral collateral sulcus) and the hippocampus. Inspection of individ-ual anatomy indicated three patterns: in three subjects, the clustercovered mainly grey matter of the hippocampus and not the collateralsulcus (S3, S9 and S11); in five subjects, the cluster only covered greymatter of the collateral sulcus (S1, S4, S5, S12, S14); and in theremaining seven subjects, the cluster involved both structures. Thisanalysis thus suggests that the cluster mainly reflects perirhinal cortexactivation.Turning to the retrieval data, the right posterior parahippocampal

cluster (see Fig. 5, ii) lay in the parahippocampal cortex, as thehippocampus could still be identified inferolaterally to the lateralventricle (Pruessner et al., 2002) on the average structural scan of allsubjects (Fig. 5A). The inspection of individual structural anatomy(Fig. 5C) confirmed this observation: the hippocampus could beidentified in the coronal section of 12 out of 15 subjects, while it wasnot visible in subjects S4, S8 and S11.The left posterior parahippocampal peak, on the other hand, was

located more posteriorly. Accordingly, hippocampal tissue is notvisible in the group-averaged scan (Fig. 5A). On individual sections(Fig. 5C), the hippocampus is identifiable only in S3 and, less clearly,in S9 and S12. However, the cluster extended anteriorly well into theposterior parahippocampal cortex.The cluster selective for visual source retrieval (Fig. 4) was located

in the anterior PHG. The posterior boundary of the perirhinal cortex islocated �4 mm posterior to the gyrus intralimbicus on coronal MRsections (Insausti et al., 1998; Pruessner et al., 2002). As this gyrusonly disappears �2 mm posterior to the location of the clusterselective for visual source retrieval, this cluster can be classified asperirhinal–entorhinal cortex with respect to the anterior–posteriordimension. Notably, this activation is located more medially than theborders of the perirhinal cortex as reported by Insausti et al. (1998),and may thus reflect entorhinal rather than perirhinal cortex activation.However, it has been suggested that activations in the anterior PHGpredominantly reflect activations of the perirhinal and lateral entorh-inal cortex (Eichenbaum et al., 2007). These regions are stronglyinterconnected both in primates (Suzuki & Amaral, 1994) and inrodents (Burwell & Amaral, 1998). Following Eichenbaum et al.(2007), this activation in the anterior PHG presumably reflects anactivation of the perirhinal cortex and ⁄ or the lateral entorhinal cortex,to which the perirhinal cortex predominantly projects.

Domain-general source-memory effects

Activity in the hippocampus and posterior parahippocampal cortex haspreviously been associated with successful encoding of sourceinformation (Davachi et al., 2003; Ranganath et al., 2004; Uncapher& Rugg, 2005; Uncapher et al., 2006) One recent study, however, alsoimplicated a perirhinal–entorhinal region in source encoding (Goldet al., 2006), and it has recently been reported that perirhinal cortexsupports the encoding of both spatial and object information (Buffaloet al., 2006). In line with these findings, we observed a domain-general effect of source encoding in an anterior hippocampal–parahippocampal region.Although the main projections in the MTL follow the pattern of

parallel processing streams, there are interconnections between thesestreams at the level of the PHG (Suzuki & Amaral, 2004). Morespecifically, there are moderate projections from the parahippocampalcortex (area TF) to the perirhinal cortex in the monkey (Lavenex et al.,2004), suggesting that the perirhinal cortex may be positioned at a

higher level in the hierarchical network that constitutes the MTL.While the data from the encoding phase are in line with the view thatthe perirhinal cortex supports the encoding of different types ofcontextual information, possibly based on input from the parahippo-campal cortex, the data from the retrieval phase of the present studyclearly support the idea of a domain-specific functional specializationin the MTL.Hippocampal activation has frequently been reported during

recollective recognition (see Eichenbaum et al., 2007, for a review).However, there are a considerable number of studies that failed to findreliable hippocampal effects during (source) recollection (Hensonet al., 1999; Kahn et al., 2004; Sharot et al., 2004; Johnson & Rugg,2007). The hippocampal activation that we did observe during therecognition phase was small and showed only a nonsignificant trendtowards a main effect of source recollection. Differences in the type ofinformation that is recollected may be one contributing factor to theseconflicting results. For example, it has been argued that hippocampalactivation may index the retrieval of semantic associations whereasactivation in the PHG regions may index the retrieval of perceptualinformation (Cabeza et al., 2001; Sharot et al., 2004). The fact that thepresent task assessed the retrieval of (incidentally encoded; see below)highly specific perceptual rather than semantic information may thuspartially account for the lack of a stronger hippocampal signal duringsource retrieval. Also, one study that yielded hippocampal activationduring retrieval in a similar task used spatial source information(Cansino et al., 2002). As the hippocampus may be more important formemory processes with a spatial component (Broadbent et al., 2004),spatial source memory tasks may not be directly comparable to thepresent task, in which flat texture patterns with no spatial componentserved as visual source information.Furthermore, one specific feature of the present experimental

procedure was strictly incidental encoding of source information. Thisapproach was adopted to minimise the confounding effects of verbalre-coding of source information (which is difficult to suppress ifparticipants know that memory for source will later be tested). Suchverbal re-coding may contaminate any material-specific effects duringsource retrieval. For this reason, we did not perform several runs ofencoding and retrieval for each participant (Fan et al., 2003), nor didwe include a practice session (Cansino et al., 2002), as both wouldhave informed participants that memory for source information wouldlater be tested. All participants reported that the source memory testwas unexpected; therefore, the reliable above-chance performance insource retrieval can mainly be attributed to retrieval of perceptual andnot verbally re-coded information. The clear dissociations of visualand auditory source memory effects during retrieval support thisinterpretation. Our findings are thus in line with the idea thatparahippocampal regions may support the retrieval of perceptualsource information (Cabeza et al., 2001).

Domain-specific effects during source retrieval

During successful source retrieval, posterior parahippocampal cortexdiscriminated between correct and incorrect source judgementsselectively for the auditory modality. A similar pattern for the visualmodality was observed in perirhinal–entorhinal cortex. These regionaldissociations were reflected in a significant region · source · modal-ity interaction. Importantly, these dissociations reflect differentialeffects of source memory and not item memory, because (i) only trialsin which the item was correctly recognized entered analysis and(ii) effects of source memory success interacted differentially withitem modality.



These findings support our a priori, anatomically motivatedhypothesis. The primate perirhinal cortex receives its strongest corticalprojections from the unimodal ventral visual areas TE and TEO(Suzuki & Amaral, 1994). Parahippocampal cortex, on the other hand,receives strong projections from regions of the dorsal visual stream butalso from auditory association cortices in the superior temporal gyrus(Suzuki & Amaral, 1994). These projections are generally reciprocal(Lavenex et al., 2002). Furthermore, these parallel processing streamsare thought to also be partially segregated at the level of the entorhinalcortex (Hargreaves et al., 2005). The entorhinal region that receives itsinput from the perirhinal cortex has direct cortical connections similarto those of the perirhinal cortex, whereas the entorhinal regionreceiving input from parahippocampal cortex shows direct corticalconnections similar to those of parahippocampal cortex (Burwell,2000). We propose that parahippocampal cortex selectively discrim-inates correct and incorrect auditory source retrieval because of itsconnections with auditory association cortices. Perirhinal ⁄ entorhinalcortex, on the other hand, is more activated for correct vs. incorrectvisual texture–colour source judgements, and we propose that theconnections of this region with inferior temporal visual cortices mayunderlie this selectivity.

Parahippocampal cortex activation during recognition has previ-ously been related to recollection (Eldridge et al., 2000) and successfulretrieval of source information (Cansino et al., 2002; Kahn et al.,2004), although recently it has also been implicated in familiarity(Daselaar et al., 2006). Interestingly, both Cansino and co-workers andKahn and co-workers have used spatial source information in theirstudies: the spatial position of a picture and an imagined scene,respectively. As parahippocampal cortex also receives strong projec-tions from regions of the dorsal visual stream (Suzuki & Amaral,1994), both findings would be consistent with the notion of a domain-specific source retrieval process in parahippocampal cortex. In linewith these connectivity patterns, a region in the posterior parahippo-campal cortex, the parahippocampal place area (PPA), has beenreported to support the perceptual processing of spatial scenes (Epstein& Kanwisher, 1998; Epstein et al., 1999). Although it is unclearwhether the parahippocampal cortex activation in the present studyoverlaps with the individual PPAs of our subjects, our findings suggestthat the function of the posterior parahippocampal cortex may not belimited to spatial processing. A recent report of abnormal perceptualprocessing of music following damage to the parahippocampal cortexlends further support to the idea of an involvement of parahippocam-pal cortex in the processing of certain aspects of auditory information(Gosselin et al., 2006).

Perirhinal cortex, on the other hand, has previously been reported tosupport item memory and familiarity, during both encoding (Davachiet al., 2003; Ranganath et al., 2004; Uncapher et al., 2006) andrecognition (Henson et al., 2003; Montaldi et al., 2006), although onestudy reported an involvement of perirhinal ⁄ entorhinal cortex in sourceencoding (Gold et al., 2006). It should be pointed out that these findingsare not in opposition to the present results. Both familiarity-basedrecognition processes and the retrieval of texture and colour sourceinformation may strongly depend on the interplay of perirhinal cortexwith inferior temporal cortex regions that contain texture- and colour-sensitive neurons (Tanaka et al., 1991) and object-level representations(Ishai et al., 1999). Interestingly, the perirhinal deactivation that iscommonly seen for hits vs. correct rejection contrasts during recognition(and was also observed in the present study; the complete list ofactivations from this contrast is available from the first author uponrequest) is frequently reported to be located somewhat more anteriorthan the present perirhinal–entorhinal cluster (Henson et al., 2003).More data on the role of the perirhinal cortex in processing certain types

of source information is therefore clearly required in order to assesswhether there is consistent functional heterogeneity in this structure.A number of recent studies raised the issue of MTL involvement in

perceptual processes (Lee et al., 2005; Murray et al., 2007). Althoughthis idea is controversial (Shrager et al., 2006), a recent report of adissociation of perceptual processing between semantic dementia andAlzheimer’s (AD) disease patients is in line with the presentanatomically motivated model of MTL functioning (Lee et al.,2006). Semantic dementia patients with presumed perirhinal cortexdamage were impaired at face perception, whereas AD patients withpresumed hippocampal damage were found to be impaired at sceneperception. This is consistent with the previously described anatomicalconnectivity patterns and suggests that domain-specific functionaldissociations in MTL may not be limited to memory but may possiblyextend to the domain of perception.

What is the function of the domain-specific source retrievalsignal?

The question arises why source encoding effects were domain-generalwhereas source retrieval effects in the MTL were mainly domain-specific. One possibility is that the reciprocal connections between theparahippocampus and sensory neocortex (Suzuki & Amaral, 1994;Lavenex et al., 2002) support the re-instatement of aspects of theencoding episode specifically during retrieval. A backward-spreadingsignal from perirhinal cortex to area TE during retrieval of object orpattern information has been described in the primate (Naya et al., 2001).In line with this notion, it has been reported that PHG activity supportsthe re-activation of information after an interruption ofworkingmemoryrehearsal (Sakai et al., 2002; Sakai & Passingham, 2004). Also, domain-specific interactions of MTL with posterior sensory neocortex duringmemory retrieval have been reported in a positron emission tomographystudy (Kohler et al., 1998a,b), although this study did not allow for adifferentiation between different MTL subregions.At the same time, it is frequently reported that sensory cortices are

engaged in a material-dependent fashion during vivid remembering(Nyberg et al., 2000; Wheeler et al., 2000; Vaidya et al., 2002; Kahnet al., 2004; Khader et al., 2005; Prince et al., 2005; Woodruff et al.,2005). We identified regions in the inferior temporal cortex (ITC) andthe superior temporal gyrus that may possibly reflect such sensoryre-activation processes. Area IT in the primate ventral stream containsneurons responsive to colour (Komatsu et al., 1992) and colour–pattern conjunctions (Komatsu & Ideura, 1993). Thus, it is probablethat the visual source information used in the present study wasinitially processed in regions of the ITC. In support of the notion thatthe observed ITC activation may reflect the reconstruction of visualsource information, ITC has recently been implicated in the recon-struction of visual details during remembering (Wheeler et al., 2006).Also, the present ITC activation ()50, )38, )20) is remarkably closeto a region ()52, )36, )12) implicated in colour processing (Chao &Martin, 1999) and to a cluster ()57, )36, )12) activated duringsuccessful encoding of colour information in a recent study (Uncapheret al., 2006). Along similar lines, the region in the left superiortemporal gyrus–planum temporale, close to previously identifiedvoice-selective regions of the auditory association cortex (Belin et al.,2000), was more active for correct than for incorrect auditory sourcejudgements, although the interaction did not reach significance (seeResults). The responses in these sensory regions to false alarms couldnot be investigated due to insufficient numbers of trials.Finally, it should be noted that the present data do not permit an

investigation of the causal relationship between activity in sensory



cortices and perirhinal ⁄ parahippocampal cortex during source retrie-val. Previous reports of a retrieval-related signal that spreadsbackwards from perirhinal cortex to area TE in the primate (Nayaet al., 2001), and findings implicating the parahippocampal regionspecifically in the re-activation of stored representations (Sakai et al.,2002), lend support to our interpretation that the observed domainspecificity in the MTL during retrieval may be related to are-activation of sensory cortex, possibly via parahippocampalback-projections to posterior neocortex (Lavenex & Amaral, 2000).

Limitations

Though participants were scanned during both encoding and retrieval,data from the two phases of the experiment were not directlycompared. Due to trial differences between encoding and retrieval(e.g. trial duration and number of button presses), signal change valueswere not readily comparable. Adopting a source memory test using aone-step rather than a two-step approach may be more feasible infuture studies, although other problems exist with one-step paradigms(Eldridge et al., 2002).It should also be noted that, as in a number of previous reports

(Davachi & Wagner, 2002; Strange et al., 2002; Weis et al., 2004;Daselaar et al., 2006), we identified the different MTL subregionsusing a slightly lower statistical threshold (P < 0.01, two-tailed,corresponding to a one-tailed threshold of P < 0.005) than is commonpractice in event-related fMRI (P < 0.001). Therefore, some cautionshould be taken in interpreting our results. However, we had specificanatomically motivated hypotheses about the role of parahippocampalcortex and perirhinal ⁄ entorhinal cortex in this task. Furthermore, theconvergence of the present findings with recent lesion evidence (Peterset al., 2007) provides additional evidence for the validity of ourconclusions.

Conclusions

Our findings support the idea of domain specificity (Davachi, 2006) inthe parahippocampal and the perirhinal ⁄ entorhinal cortices duringsource memory processing. During retrieval, bilateral parahippo-campal cortex was found to selectively index the successful retrievalof voice but not texture and colour information, whereas the reversepattern was observed in the left perirhinal ⁄ entorhinal cortex. Giventhat damage to the parahippocampal cortex disrupts auditory but notvisual source memory (Peters et al., 2007), these results suggest acausal role of this structure in voice but not texture and colour sourcememory. Both findings are well in line with current anatomical modelsof corticoparahippocampal connectivity (Lavenex & Amaral, 2000)and underline the usefulness of detailed anatomical accounts ingenerating hypotheses about the functional role of different MTLsubregions in human memory processes (Eichenbaum et al., 2007).

Acknowledgements

This research was funded by the International Graduate School of Neurosci-ence, Ruhr-University of Bochum. We thank Sabine Bierstedt for technicalassistance.

Abbreviations

BA, Brodmann area; BOLD, blood oxygen level-dependent; fMRI, functionalMR imaging; MNI, Montreal Neurological Institute; MR, magnetic resonance;MTL, medial temporal lobe; PHG, parahippocampal gyrus.

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Domain-specific retrieval of source information in the medial temporal lobe

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