Preserved Hippocampal Novelty Responses Following Anterior Temporal-Lobe Resection That Impairs Familiarity But Spares Recollection

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1 HIPPOCAMPUS 21: (2011) Preserved Hippocampal Novelty Responses Following Anterior Temporal-Lobe Resection That Impairs Familiarity But Spares Recollection Ben Bowles, 1 Edward B. O Neil, 1 Seyed M. Mirsattari, 1,2 Jordan Poppenk, 3,4 and Stefan Köhler 1,3 * ABSTRACT: Although it is well established that the integrity of the medial temporal lobe (MTL) is critical for declarative memory, the functional organization of the MTL remains a matter of intense debate. One issue that has received little consideration so far is whether the hippocampus can function normally in the presence of a lesion to perirhinal cortex that produces noticeable memory impairments. This question is intriguing as the MTL forms a hierarchical system, in which perirhinal cortex represents one of the critical nodes in the reciprocal projections between neocortical association areas and the hippocampus. Here, we used functional magnetic resonance imaging to examine whether NB, an individual who underwent surgical resection of the left anterior temporal lobe that included large aspects of perirhinal and entorhinal cortex but spared the hippocampus, exhibits intact hippocampal novelty responses to auditory sentences. Our results revealed such evidence in NB s left and right hippocampus. They complement previous behavioral work in NB, indicating that recollective processes considered to rely on hippocampal integrity are also preserved. Further analyses revealed intact novelty responses in structures that provide neuroanatomical input to the hippocampus, including remaining perirhinal cortex and surgically spared parahippocampal cortex. These findings point to viable neuroanatomical mechanisms as to how functional integrity in the hippocampus may be maintained in the face of widespread, but incomplete removal of its input structures. VC 2010 Wiley-Liss, Inc. KEY WORDS: entorhinal cortex; epilepsy; medial temporal lobe; perirhinal cortex; recognition memory INTRODUCTION It is firmly established in cognitive neuroscience that the integrity of the primate medial temporal lobe (MTL) is vital for declarative memory functioning (Milner et al., 1998). The MTL consists of several structures that can be distinguished based on their cytoarchitectonic composition 1 Department of Psychology, University of Western Ontario, London, Ontario, Canada; 2 Department of Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada; 3 Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada; 4 Department of Psychology, University of Toronto, Toronto, Ontario, Canada Ben Bowles and Edward B. O Neil contributed equally to this work. Grant sponsors: Canadian Institutes of Health Research (CIHR), Savoy Foundation, Natural Sciences and Engineering Research Council (NSERC). *Correspondence to: Stefan Köhler, Department of Psychology, University of Western Ontario, London, ON, N6A 5C2 Canada. stefank@uwo.ca Accepted for publication 28 February 2010 DOI /hipo Published online 20 May 2010 in Wiley Online Library (wileyonlinelibrary.com). and patterns of connectivity (Amaral and Insausti, 1990; Lavenex and Amaral, 2000). At present, it remains controversial whether the computations and cognitive processes supported by the hippocampus (including fields CA 1 3, the dentate gyrus, and the subiculum) can be discerned from those of structures in the adjacent parahippocampal region, specifically perirhinal cortex (Davachi, 2006; Eichenbaum et al., 2007; Squire et al., 2007). One issue that has received little consideration in this debate is whether the hippocampus can function normally in the presence of a lesion to perirhinal cortex that produces specific memory impairments. This question is intriguing from a neuroanatomical perspective given that the MTL forms a hierarchically organized system, in which perirhinal cortex represents a critical node in the convergent, reciprocal projections between neocortical association areas and the hippocampus (Lavenex and Amaral, 2000). An influential model of MTL organization that captures a large body of evidence in support of division of labor posits that the hippocampus is specialized for the encoding and recollection of contextual details about episodes, such as a stimulus encounter (Aggleton and Brown, 1999; Yonelinas, 2002; Eichenbaum et al., 2007). Perirhinal cortex, by contrast, supports encoding and retrieval of information that allows for the assessment of stimulus familiarity. In a recent single-case study, we showed that a rare resection of the left anterior temporal lobe for the treatment of intractable epilepsy, which included large aspects of perirhinal cortex but spared the hippocampus, produced a verbal familiarity impairment with preserved recollection (Bowles et al., 2007). This pattern, which had not been reported previously in association with a focal temporal-lobe lesion, was revealed in four experiments conducted with three different behavioral paradigms. Importantly, when considered together with the findings of isolated recollection impairments following selective hippocampal lesions (e.g., Mayes et al., 2002; Aggleton et al., 2005), it points to a double dissociation. At present, however, evidence that suggests preserved hippocampal processing in this individual (NB) is only indirect. As the findings we reported were purely behavioral in nature, we do not know whether NB s left hippocampus does indeed show functional integrity in the presence of partial de-afferentiation. VC 2010 WILEY-LISS, INC.

2 848 BOWLES ET AL. Here, we conducted a functional magnetic resonance imaging (fmri) study to directly probe whether hippocampal functioning, in particular, in the left hemisphere, is preserved in NB. We used a novelty paradigm in combination with a block design, because this approach represents one of the most robust means to elicit reliable hippocampal responses with fmri in individual participants (Narayan et al., 2005; Westmacott et al., 2008). Moreover, novelty signals in the hippocampus have specifically been linked to processing of the types of relationships between stimuli and their context that are critical for episodic recollection, i.e., the process that operates normally in NB (Ranganath and Rainer, 2003; Nyberg, 2005; Kumaran and Maguire, 2009). By focusing our analyses not only on the hippocampus but also on structures in the parahippocampal region, we sought to explore which neuroanatomical pathways might still provide cortical input that would permit preserved hippocampal processing in the face of partial de-afferentiation. MATERIALS AND METHODS Patient NB: Case Profile and Lesion Analyses NB is a right-handed, university-educated female who underwent a left unilateral lesionectomy as treatment for intractable epilepsy, which was caused by a mass in the left amygdala [for further case details, see Bowles et al. (2007)]. Her surgical resection involved the most anterior extent (1.7 cm) of the lateral and medial temporal cortex in the left hemisphere and provided full relief from seizures postsurgically. Volumetric analysis of remaining MTL tissue showed that, when compared with intact right hemisphere structures, the surgery resulted in removal of 83% of the amygdala as well as 43% of perirhinal cortex and 59% of entorhinal cortex (Bowles et al., 2007). The hippocampus and parahippocampal cortex were spared by the resection. Neuropsychological examination following surgery revealed clinically normal cognitive functions in all domains including episodic memory (97th percentile for Wechsler Memory Scale III Auditory Delayed Index, Recall). Critically, as reported in our original investigation, more detailed experimental probing of recognition memory functions revealed a consistent familiarity impairment with preserved recollection. This deficit manifested not as a phenomenological absence of feelings of familiarity, but as an impaired discrimination process with reduced accuracy that was observed in the context of overall normal recognition performance. At the time of this study, NB was 24 years old. Control Participants Nine right-handed healthy university students (4 females), between 20 and 28 years (M years, SD 5 2.3), served as control participants in the study. They had normal, or corrected-to-normal vision, and no history of psychiatric or neurological disorders. All participants gave written informed consent and were compensated for their participation. This study received approval from the Health Sciences Research Ethics Board at the University of Western Ontario. METHODS Thirty-three sentences were selected from a larger stimulus set that had been used previously to examine novelty signals in the MTL (Poppenk et al., 2008). Each sentence described a unique episode (e.g., At the conclusion of the provocative comedian s outstanding performance, the enthusiastic crowd applauded with a standing ovation). All sentences were presented auditorily, with sentence lengths ranging from 4.99 s to 6.98 s (M s). Thirty sentences were selected as novel stimuli and randomly assigned to 10 blocks of three sentences each. The remaining three sentences served as old stimuli and were repeated in each of 10 blocks. Participants were pre-familiarized with these old sentences before scanning. Sentence order was fixed within and across participants in all blocks. Experimental Procedure During scanning, participants were asked to judge, using a four-point rating scale, the valence of each episode described in the sentences presented. This task was chosen so as to encourage semantic processing of sentence content. The experiment was administered using E-Prime (Psychology Software Tools). A digital projector displayed instructions on a screen viewed through a mirror by the participants. Sentences were presented through MR-safe headphones. Each sentence presentation was preceded by visual presentation of a white fixation cross for 900 ms and a blank screen for 100 ms. After sentence presentation, the rating scale appeared for 2,000 ms, at which time participants were required to make their judgment. Following the third sentence of each block, a small variable amount of time (average 5 2,085 ms, range ms) was added to ensure that all blocks were matched in length (30 s). Every participant completedtworuns.eachrunincludedfiverepeatedandfive novel sentence blocks in alternating order, with a repeated (pre-familiarized) block presented first. An additional 15 s of fixation were included at the beginning and end of each run. Following the two experimental runs, an anatomical scan was obtained. To confirm that participants did indeed process sentence content when encountering novel stimuli, a surprise recognition memory test was administered immediately following scanning. Subjects were presented with an intermixed list of 30 old sentences, each presented once during a novel block during scanning, and 30 new sentences not previously heard. The 30 new sentences were selected from the same larger set from which the experimental stimuli were chosen (Poppenk et al., 2008). The 60 sentences were presented auditorily in random

3 NOVELTY RESPONSES FOLLOWING TEMPORAL-LOBE LESION 849 order, and subjects were required to make self-paced old/new judgments. final three volumes of fixation in the second run were removed from NB s data due to a large motion artifact. Functional Data Acquisition Imaging was performed on a 4-tesla whole body magnetic resonance imaging (MRI) system (Varian; Siemens) using a custom head coil. To minimize artifacts and increase the signal-to-noise ratio in the MTL, a semi-automated, localized second-order shimming algorithm was used, combined with a multi-shot, short echo-time imaging sequence. The plane of image acquisition was positioned perpendicular to the longitudinal axis of the hippocampus. For each participant, 25 contiguous 5-mm thick oblique coronal slices were obtained covering the brain from the most anterior extent of the temporal lobe to the occipital pole. The field of view was 19.2 cm cm ( matrix) providing an in-plane resolution of 3 mm. A T2-weighted spiral image acquisition was used for all functional scans (TE 10 ms; TR 750 ms, i.e., volume acquisition time of 3.0 s with four-shot sequence). Each run involved the acquisition of 110 functional image volumes. A T1-weighted anatomical image was collected in the same experimental session using the acquisition plane of the functional scans but covering the entire brain (TR ms; TE ms; 80 slices; 2.5 mm thick; matrix; 0.75-mm in-plane resolution). Image Analysis Functional imaging data were preprocessed using Brain Voyager QX 2.0 software (Brain Innovation). Functional images were resampled into 3-mm isotropic voxels, high-pass filtered, co-registered with the anatomical image, and transformed into standardized Talairach space. Average mean intensity of the volume was included as a covariate-of-no-interest in all statistical analyses. Data were convolved with a double gamma hemodynamic response function and examined using both randomeffects and fixed-effects general linear models. Statistical maps were then interpolated to a resolution of mm 3.To assess novelty responses, we focused on increases in BOLD signal for novel as compared to repeated sentences. For grouplevel analyses (both fixed and random effects), activations were considered significant if peaks at P < were part of aclusterexceeding50mm 3. For examination of data in individual subjects, a more lenient criterion was used of P < Critically, in NB, all reported activations meet the cluster threshold specified at the group level. To allow for a sufficiently large number of participants to be included in subjectby-subject comparisons with NB in terms of localization, the cluster threshold in controls was reduced to a minimum size of 20 mm 3. Localization of novelty responses to distinct MTL structures was guided by established neuroanatomical landmarks provided by Insausti et al. (1998) and implemented in the volumetry protocols established by Pruessner et al. (2000, 2002). A single novel block was excluded from the analysis across all participants due to a stimulus presentation error. In addition, the RESULTS Behavioral Results Both NB and all control participants performed with high accuracy on the postscan recognition test (hits minus false alarms in NB: 1.00; control mean: 0.94; control range: ). Given the nature of the stimuli used here (i.e., sentences describing unique episodes) and our previous experimental evidence of fully preserved episodic recollection, NB s high level of behavioral performance on this task is not surprising. MTL Novelty Responses in Control Group Guided by the findings of Poppenk et al. (2008) that were obtained with a variant of the current paradigm, we anticipated that the control group would show robust left-sided MTL activity, particularly, in the hippocampus, for novel as compared to repeated sentences. A random-effect analysis confirmed the expected novelty effect in the hippocampus [t(8) , P < 0.005, 506 mm 3 ]. In addition, we observed a novelty response in a more posterior MTL region in the left parahippocampal cortex [t(8) , P < 0.005, 89 mm 3 ] as well as in a region at the border of the left perirhinal and entorhinal cortex [t(8) , P < 0.005] that met our height threshold at a below-threshold cluster size (23 mm 3 ). We report activity in this region, because it was also present in our fixedeffects analysis and showed high consistency across individuals (see Table 1). MTL Novelty Responses in NB We used a fixed-effects analysis to determine whether NB would exhibit preserved novelty responses in the hippocampus and other MTL structures. This analysis revealed bilateral activation in the hippocampus, perirhinal cortex, and parahippocampal cortex for the contrast between new and repeated sentences at the prespecified threshold (see Fig. 1a and Table 1). In the left hemisphere, these novelty responses were seen in regions comparable to those identified with the random-effects analysis in the control group. Comparison of NB with Control Group In the next step, we aimed to compare NB s left-sided MTL novelty responses with those of the control participants in a more detailed manner. As the first reference point for this comparison, we used a group-level fixed-effects analysis for the controls. This examination revealed a close proximity of the peak voxels of novelty responses in the left hippocampus, perirhinal/ entorhinal cortex, and parahippocampal cortex for NB as compared to controls (see Table 1). Figure 1 shows this close similarity in left-mtl novelty responses. We also examined the

4 850 BOWLES ET AL. TABLE 1. Detailed Characterization of Novelty Responses for NB and Control Participants Group fixed-effects NB Participant averages x y z t Db Cluster size x y z t Db Cluster size x y z Range Db n L HPC R HPC L RHC R RHC L PHC R PHC Coordinates and statistical properties of peak MTL voxels. Db reflects novel-repeated difference of parameter estimates. Participant averages represent only data from control participants who showed evidence of activation (P < 0.01, cluster size > 20). HPC, hippocampus; RHC, rhinal (i.e., perirhinal/entorhinal) cortex; PHC, parahippocampal cortex. overlap of novelty responses in NB and controls in a more formal manner by using an inclusive masking procedure. Figure 2 presents the results from this approach, again highlighting strong similarities in anatomical localization. Additional evidence that supports this conclusion comes from a direct comparison of NB s novelty responses with those of individual control participants. When we calculated the mean of the peak coordinates for all control subjects who showed a significant novelty response, NB s peak coordinates fell within 5mmofthismeaninthex, y, z dimensions in all left MTL FIGURE 1. Novelty responses in left MTL structures in (a) NB and (b) control participants. Images were thresholded to optimize visualization of similarities in localization (NB, P < 0.005; controls fixed-effects, P < 0.001). (c) Remaining tissue in NB s left MTL structures classified based on volumetric analyses reported in Bowles et al. (2007). Sagittal view is in comparable position as functional images to facilitate anatomical localization. Black line indicates position of collateral sulcus. (d) 3D reconstruction of NB s left and right MTL based on same volumetric analyses. Dashed line indicates anterior extent of right MTL and provides estimate of tissue loss in left hemisphere. Note that unilateral resection spared the left hippocampus completely.

5 NOVELTY RESPONSES FOLLOWING TEMPORAL-LOBE LESION 851 novelty responses were seen at the fixed-effects level and in individual subjects as well as in NB. DISCUSSION FIGURE 2. (a) Novelty responses in the MTL of NB masked by responses in the control group and superimposed on NB s anatomical image. Slices were selected to illustrate close anatomical overlap of left-sided activity in perirhinal/entorhinal cortex (top panel), the hippocampus (middle panel), and parahippocampal cortex (bottom panel) at the prespecified thresholds. (b) Comparison of NB s hippocampal novelty responses with those of a control participant who also showed bilateral activation (for illustrative purposes both thresholded at P < 0.005). structures (see Table 1). Although in NB, a peak of activation was clearly present in remaining left perirhinal cortex, the peak in controls varied across individuals, sometimes falling into perirhinal cortex, entorhinal cortex, or at the border between the two structures. We also compared NB s fmri data with those of individual controls to examine whether the strength of her novelty response in left-sided MTL structures fell within the normal range. Table 1 shows that the magnitude of her novelty response, as measured by the difference between the parameter estimates for the novel and repeated conditions (Db), clearly fell within the range of those observed in control individuals who showed a significant novelty response. Finally, it is worth noting that we observed right-sided MTL novelty responses in NB that were not present at the group level in the control participants in the random-effects and/or fixed-effects analyses (see Table 1). For the hippocampus, although not present in the random-effects analysis, right-sided In this study, we demonstrate that NB, an individual who underwent a partial surgical resection of the left anterior temporal lobe that included large aspects of entorhinal and perirhinal cortex, exhibits intact novelty responses in her surgically spared left hippocampus; the hippocampal responses are comparable in both location and magnitude to those of controls. In addition, we found that NB exhibits intact novelty responses in MTL structures that are known to provide critical input to the hippocampus, including residual aspects of left perirhinal cortex, the surgically spared parahippocampal cortex, and the right hippocampus. The pattern of preserved novelty responses in these structures offers new insight as to how the hippocampus may maintain normal functioning in the face of extensive removal of some of its input structures. Current models of MTL organization emphasize that structures situated lower in the MTL hierarchy relay signals from widespread neocortical regions as well as fulfill memory functions that are distinct from those of the hippocampus (Lavenex and Amaral, 2000). A large body of findings in human and nonhuman species indicates that the distinction between recollection and familiarity can capture important differences in functional specialization between the hippocampus and perirhinal cortex, respectively [(Aggleton and Brown, 1999; Eichenbaum et al., 2007); but see Squire (2007)]. Most lesion research supporting this view comes from demonstrations that selective hippocampal damage can produce isolated recollection impairments, whereas more widespread MTL damage affects both recollection and familiarity similarly [(Düzel et al., 2001; Mayes et al., 2002; Yonelinas et al., 2002; Bastin et al., 2004; Aggleton et al., 2005; Turriziani et al., 2008); but see (Wais et al., 2003 and Cipolloti et al., 2006)]. In our recent behavioral work in NB, we showed, in line with the dual-process model of MTL organization, that selective familiarity impairments with preserved recollection can also be observed when a focal temporal-lobe lesion includes large aspects of perirhinal cortex but spares the hippocampus (Bowles et al., 2007). Our current work extends this behavioral research by (i) providing direct fmri evidence of preserved hippocampal functioning in NB and by (ii) pointing to viable neuroanatomical mechanisms that could allow for spared hippocampal functioning in the face of partial cortical de-afferentiation. In the primate brain, the majority of hippocampal afferents originate in the entorhinal cortex, which in turn receives most of its input from the perirhinal and parahippocampal cortices (Amaral and Insausti, 1990; Lavenex and Amaral, 2000). Studies of MTL connectivity in nonhuman primates indicate that perirhinal and parahippocampal cortex form nodes of two pathways that are to some extent segregated and provide input from different cortical association areas to the hippocampus

6 852 BOWLES ET AL. (Suzuki and Amaral, 1994). Recent investigations of slow spontaneous fluctuations in the fmri BOLD signal, a marker of intrinsic functional connectivity, show evidence that points to a similar neuroanatomical organization in humans (Kahn et al., 2008). Taken at face value, the coactivation of parahippocampal cortex and remaining portions of perirhinal cortex in the left hemisphere of NB suggests that both pathways may still provide their distinct sources of input to the hippocampus. It should be noted, however, that the resection included large aspects of the left antero-lateral temporal region that was shown to provide major projections to perirhinal cortex in the research reported by Kahn and his colleagues. Thus, it is possible that even the remaining perirhinal signals in NB are to some extent driven by input provided through projections from parahippocampal to perirhinal cortex, which have been well documented in non-human primate research (Lavenex et al., 2004). Irrespective of whether perirhinal cortex operates on input provided through parahippocampal cortex or through remaining lateral temporal-lobe structures in the current paradigm, the majority of inputs from both pathways are known to project onto entorhinal cortex at the next level in the MTL hierarchy. Thus, it is likely that some entorhinal cortex may need to be preserved to observe spared hippocampal functioning in the presence of a lesion to perirhinal cortex, as is indeed the case in NB. However, more research on cases with varying extent of entorhinal lesions is required to establish such a critical role for entorhinal cortex with certainty. It is also important to consider the possibility that NB s left hippocampus may obtain some of its critical cortical inputs from the intact right MTL via the dorsal hippocampal commissure. Available morphological data from postmortem analyses in epilepsy suggest that the dorsal hippocampal commissure does sustain neural connectivity between the hippocampi of both hemispheres (Gloor et al., 1993). In this study, we observed left-sided as well as right-sided hippocampal activation with our novelty paradigm in NB, consistent with the notion that the dorsal hippocampal commissure may have provided additional cortical input to her left spared hippocampus. Traditionally, memory processing of verbal stimuli has been associated more strongly with MTL functioning of the left than the right hemisphere (Milner, 1972). However, it is well established that any such hemispheric specialization is not absolute and is modulated by numerous task factors, including the specific strategies subjects can bring to bear on the task at hand [for discussion, see Dobbins et al. (1998) and Saling (2009)]. For example, the right hippocampus has been linked to the use of visual imagery in verbal memory tasks (Jones-Gotman and Milner, 1978; Maguire et al., 2003). Furthermore, extant evidence in patients with sections of interhemispheric pathways points to a role of interactions between the left and the right hippocampus in verbal recall (Phelps et al., 1991). Further support for this notion comes from studies showing that deficits in verbal recollection can be observed in association with unilateral left or right-sided hippocampal lesions (Moscovitch and McAndrews, 2002; Peters et al., 2009). Based on these findings, one would predict that, if NB could rely only on a functioning right hippocampus, she would still show an impairment in verbal recollection. However, this is not what we found in our behavioral investigations. Thus, the present fmri findings in NB converge with our previously reported behavioral research to suggest that hippocampal processing is intact in both hemispheres in her case. The preserved left-sided novelty responses in NB s remaining aspects of perirhinal cortex may seem surprising given that she exhibits impairments in familiarity assessment, a process that has been linked to perirhinal-cortex functions in a large body of past research. Specifically, this finding may appear puzzling in light of previous fmri research showing that increases in the perirhinal BOLD response for novel as compared to previously studied items are associated with participants perceived relative familiarity of these items (Henson et al., 2003; Gonsalves et al., 2005; Daselaar et al., 2006; Danckert et al., 2007). Notably, findings from our previous behavioral experiments suggest that NB shows no general deficits in distinguishing between previously studied and novel items. Also, her deficit does not reflect an overall absence of feelings of familiarity, but rather a noisy signal-detection process that is reflected in consistently reduced accuracy of familiarity-based responses to verbal stimuli. The task administered in the current fmri study did not require any familiarity assessment and the novelty versus familiarity of the stimuli administered under scanning in our block design was very obvious, even to NB (as reported anecdotally after scanning). The present findings suggest that NB s remaining left perirhinal cortex still distinguishes between novel and previously encountered stimuli when differences are coarse. However, it remains unclear whether this differential signal has any behavioral relevance for her recognition decisions. We would predict that in a task that did tap fine-grained familiarity processing in the manner assessed in our prior behavioral work, any remaining signals in NB s residual left perirhinal cortex would show a reduced discrimination between novel as compared to previously studied items in a pattern that would mirror her distorted perceived familiarity. The present block design to manipulate novelty was chosen because it represents one of the most robust means to elicit reliable MTL responses with fmri in individual participants (Narayan et al., 2005; Westmacott et al., 2008). This approach allowed us to reveal direct signs of functional integrity in NB s spared left hippocampus and to specify viable neuroanatomical mechanisms that could support hippocampal functioning in the presence of partial de-afferentiation. At the same time, the nature of the paradigm used here has its limitations when interpreting the MTL signals in precise functional terms. For example, although in past group studies with event related designs, novelty signals in the hippocampus have specifically been linked to processing of relationships between stimuli and their context that are critical for episodic recollection (e.g., Köhler et al., 2005; Kumaran and Maguire, 2006; Poppenk et al., 2008), the contrast used in this study would not allow for such a specific functional interpretation. Furthermore, as the old sentences were repeated many times, one might argue that the novelty signal we observed was perhaps modulated by attentional

7 NOVELTY RESPONSES FOLLOWING TEMPORAL-LOBE LESION 853 effects. Although such an interpretation cannot be ruled out entirely, the findings from a study on the trial-by-trial habituation of novelty responses in the hippocampus would speak against it. Yamaguchi et al. (2004) reported that hippocampal novelty responses and their subsequent rapid habituation are comparable across conditions in which the novel stimulus is at the focus of selective visual attention and when it is not. Considering the role of sensory modality, recent evidence suggests that the parahippocampal and perirhinal cortices play distinct roles in source recollection for auditory and visually presented features, respectively (Peters et al., 2007a, b). In light of such findings, one might argue that NB s preserved hippocampal activation may be limited to situations in which cues are presented auditorily, such as the one in this study. However, our previous behavioral work in NB revealed preserved recollection abilities for auditorily (Bowles et al., 2007, Exp. 3) as well as for visually presented words (Bowles et al., 2007, Exp. 1 and 2), making it unlikely that her recollections can only be triggered by auditory cues. Nevertheless, the behavioral methods that we used to examine NB s recollective abilities in our prior work, i.e., the analysis of Receiver Operating Characteristics and the Remember-Know task, did not probe the recollection of sensory-specific contextual attributes. Therefore, it remains to be determined whether NB s preserved recollective abilities do indeed extend to the recovery of specific sensory details from the visual modality. Past work highlighting a role for the left perirhinal cortex in source recollection of the color of object stimuli suggests that she may show impairments on such a task (Staresina and Davachi, 2008; Diana et al., 2009). In sum, the preserved left and right-sided hippocampal novelty responses we observed in NB nicely converge with previously reported behavioral evidence showing intact recollective abilities in this individual. As we also observed coactivation in other remaining MTL structures that were spared by the lesion, this study offers unique new insight into the mechanisms that may allow for preserved hippocampal functioning in the face of widespread but incomplete removal of its input structures. As such, the current findings highlight the importance of considering hierarchical as well as parallel patterns of connectivity within and across hemispheres, when aiming to understand the functional organization of the MTL. Acknowledgments We are grateful to NB for her dedicated participation in this research. We thank Adam McLean, Philippe Chouinard, Joy Williams, and Joe Gati for assisting with data collection and analyses. 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