• Hippocampus;
  • Functional magnetic resonance imaging;
  • Memory;
  • Epilepsy


  1. Top of page
  2. Abstract
  6. Acknowledgments

Summary: Purpose: Previous research suggests that the hippocampus is modulated both by stimulus novelty and by the extent to which relational processing (formation of associations) occurs during episodic encoding. The aim of this study was to compare hippocampal activation patterns measured by functional magnetic resonance imaging (fMRI) during encoding protocols emphasizing either novelty or relational processing.

Methods:fMRI was performed on 32 healthy volunteers while they encoded complex visual scenes or unrecognizable scrambled versions of the same scenes. In the Novelty contrast, encoding of novel scenes was compared with encoding of a repeated pair of scenes. In the Relational Processing contrast, semantic encoding of novel scenes was compared with structural encoding of scrambled scenes.

Results: Both protocols elicited bilateral hippocampal activation. Overall mean activation values were similar for the two protocols, but the Relational Processing protocol resulted in a larger volume of hippocampal activation. The pattern of activation along the longitudinal hippocampal axis differed for the two protocols. The Novelty contrast produced stronger activation in the posterior hippocampus, whereas the Relational Processing contrast produced stronger activation in the anterior hippocampus.

Conclusions: Hippocampal activation is determined by both stimulus novelty and degree of relational processing during encoding. Given the importance of anterior hippocampal pathology in temporal lobe epilepsy, an approach emphasizing modulation of relational processing may be preferable for clinical fMRI of the medial temporal lobes.

Assessment of the morphologic and functional status of the medial temporal lobes (MTL) is a clinically important aspect of the presurgical evaluation of patients with temporal lobe epilepsy (TLE). Asymmetry of MTL anatomy and function has been used to predict the side of seizure focus (1–7), the likelihood of seizure control (3–5,8–11), and the probability of memory decline after temporal lobe resection (12–18). Techniques currently in common use for MTL assessment include EEG, structural MRI, interictal positron emission tomography (PET), single-photon emission tomography, Wada memory testing, and psychometric testing. Several initial studies using functional magnetic resonance imaging (fMRI) suggest that this technique may also provide helpful adjunctive information about MTL function in TLE (11,19–24).

In developing fMRI for this application, it will be critical to evaluate a range of alternative imaging protocols to determine an optimal approach. For the purpose of clinical applications, a procedure is needed that robustly and reliably modulates the blood oxygenation level–dependent (BOLD) signal in targeted MTL structures of clinical interest. Because the majority of temporal lobe seizure foci arise in the hippocampus (25), a prime concern should be activation of the hippocampal formation itself rather than surrounding parahippocampal areas. Investigations in normal participants using episodic memory encoding and retrieval tasks have been notable for a relative lack of observed activation in the hippocampus, yet many reports of successful hippocampal activation exist (26–39). A number of factors might account for these variable results, including the fact that the hippocampus is a relatively small structure, the visualization of which can be adversely affected by macroscopic susceptibility artifacts in fMRI (29,40). What is clear from existing data, however, is that the particular characteristics of the memory activation task and baseline state used during imaging also play a large role in determining the extent and location of hippocampal activation [for excellent reviews, see (41–44)].

Because of the complexity of episodic memory processes, the number of these potential task variables is large, yet all need to be considered in designing an optimal fMRI protocol for hippocampal activation. The hippocampus is likely to play a role in both encoding (initial memory storage) and retrieval (recall from storage) aspects of episodic memory, so one basic issue is whether an encoding or a retrieval task is preferable. Although a few studies have shown hippocampal activation during retrieval (30,32), encoding tasks have generally produced more robust results (41–44). Encoding tasks can differ along a number of dimensions, such as the type of material being encoded, the novelty or familiarity of the material, and the type of task (if any) performed during encoding. For example, several PET and fMRI studies have shown that MTL activation is left-lateralized for word stimuli and more symmetric for pictorial stimuli (28,33,45,46), probably reflecting the fact that pictures can be encoded both verbally and nonverbally. If the aim, therefore, is to design a task that produces bilateral hippocampal activation in the normal brain, a reasonable first choice might be a task involving encoding of pictures.

Stimulus novelty is an important variable that has been manipulated in a number of MTL studies. Electrophysiological studies show that the hippocampus responds more strongly to novel than to repeated stimuli (47–50), thus the contrast between novel and repeated stimuli is expected to show hippocampal activation. Although hippocampal activation has been observed in a few of the imaging studies by using a novelty contrast, the activation associated with novelty occurs more often in the posterior parahippocampus and adjacent fusiform gyrus than in the hippocampus proper (26,31,35,40,51–53). When observed, hippocampal activation is typically located in more posterior aspects of the hippocampus (26,31).

Another very important factor is the degree to which the encoding task encourages associative or “relational” processing. Recent models of the MTL propose that the hippocampus “binds” distributed cortical activity during perception, comprehension, and response to a stimulus event or “episode.” Binding of activity in these systems creates a complex, unique spatiotemporal representation of the event “configuration,” composed of the salient stimulus elements (including the environment or context in which the stimulus occurs), stored knowledge (e.g., semantic or spatial information) associated with these elements, and behavioral (including emotional) responses by the participant to the stimulus, creating a unitary representation of the episode for later retrieval from long-term memory (54–57). According to this model, hippocampal activity depends on how much co-occurring neural activity is elicited by an episode (i.e., how complex the episode is in terms of evoked sensory and associative processing). Stimuli that evoke elaborative associative processing by virtue of being recognizable and meaningful should therefore elicit greater hippocampal activation than nonsense stimuli, and tasks that require activation of such associations (e.g., conceptual, associative, or semantic tasks) should elicit stronger hippocampal activation than tasks that do not.

Support for this model of hippocampus function comes from a number of imaging studies showing stronger hippocampal activation for meaningful relative to meaningless stimuli and associative/semantic relative to nonsemantic tasks (19,33,34,36–39,58–68). Examples of task contrasts used in these studies include encoding of complex visual scenes versus unrecognizable “scrambled” versions of the same scenes, processing object pictures vs. meaningless shapes, processing words versus nonwords, performing semantic judgments versus phonologic or orthographic judgments, and learning new associations between stimuli. Although the precise location of these activations is not yet clear, results from our laboratory (19,59,68) and others (33,37–39,58,60,61,65–67) suggest greater involvement of the anterior compared to the posterior MTL. In a meta-analysis of episodic encoding studies, Schacter and Wagner (41) also suggested that MTL activations tend to be more anterior when stimulus and task contrasts emphasize differences in the degree of relational processing.

A final consideration involves the use of a “resting” or “passive” baseline in hippocampal activation studies (the latter term refers to conditions in which sensory stimuli are presented, but no task is required). Some authors have expressed the view that the conscious “resting” state may be associated with conceptual-processing, memory-encoding, and memory-retrieval processes that activate the hippocampus (28,35,64,69). Detection of hippocampal activation, according to this view, would require a baseline state that engages the participant in an active “structural” task (i.e., a task that does not involve associative or semantic processing) to “interrupt” this ongoing memory encoding and retrieval. In an important empirical test of this notion, Stark and Squire (35) demonstrated that the hippocampus and parahippocampus both show higher BOLD signals during “rest” than during active perceptual discrimination tasks. Activation of these MTL regions during encoding of pictures was detected by using the perceptual discrimination tasks as a baseline, but not when “rest” was used as a baseline.

Table 1 summarizes some of these general effects of stimulus and task factors on hippocampal activation. A consideration of these factors suggests at least two rather different task contrasts that would be expected to (and have been reported to) produce hippocampal modulation. The first of these emphasizes stimulus novelty, using a contrast between novel and repeating pictures. For both novel and repeating conditions, the stimuli are meaningful, and an associative task is required; thus the conditions differ only in terms of stimulus novelty. The second approach emphasizes relational processing, by using a contrast between associative processing of pictures and structural processing of nonsense stimuli. In both conditions, the stimuli are novel; thus the conditions differ in terms of the extent to which relational processing occurs. The aim of the current study was to compare these two approaches to hippocampal activation in the same participants, using a large enough sample to ensure stable activation patterns, and focusing specifically on activation in the hippocampus proper. Our larger goal was to assist in the eventual design of an optimal strategy for hippocampal assessment with fMRI in the presurgical evaluation of patients with TLE.

Table 1. Stimulus and task characteristics affecting hippocampal activation
 High, Bilateral Activation Low Activation
Stimulus Novelty NovelFamiliar, repeating
Stimulus Type Meaningful, pictorialNonsense
Task Type Associative (semantic)Active structural


  1. Top of page
  2. Abstract
  6. Acknowledgments


Thirty-four right-handed volunteers between the ages of 18 and 35 years participated. Two were excluded from analyses because of uncorrectable amounts of head movement, leaving 32 participants (16 women) in the final data set. All participants reported normal neurologic histories and showed no gross anatomic anomalies on MRI. Participants provided informed consent according to institutional guidelines before fMRI.

Behavioral tasks

Before scanning, participants were trained on four behavioral tasks without explicit instruction to remember any stimuli. Data from one of these, a delayed match-to-sample task involving nonsense stimuli, is not reported here. The Novel Pictures and Repeating Pictures tasks required participants to discriminate indoor from outdoor environmental scenes. Stimuli (Fig. 1) were selected from a commercial collection of digitized color photographs (PhotoDisc, Seattle, WA, U.S.A.). Each image was cropped to 336 × 336 pixels and subtended 4.8 degrees of horizontal and vertical visual angle in the scanner. All words (e.g., store name signs) and persons were removed from the pictures. Stimuli for the Repeating Pictures task included only two pictures, one indoor and one outdoor, whereas all stimuli used in the Novel Pictures task were presented only once.


Figure 1. Example stimuli from the three tasks. In the Novel Pictures task, participants saw novel color photographs and categorized these as indoor or outdoor scenes. In the Repeating Pictures task, the same indoor/outdoor judgment was performed on a repeating set of two stimuli. In the Novel Scrambled task, participants judged whether the two halves of a scrambled image were identical.

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The Novel Scrambled task required participants to decide whether the left and right halves of scrambled nonsense images were identical. These stimuli were created by randomly rearranging 12-pixel square segments of the indoor and outdoor pictures. Halves of these scrambled images (336 × 168 pixels) were either combined with another retiling of the same picture to create nonmatching halves (nontargets) or duplicated to produce matching halves (targets). A red line bisected each stimulus to define the medial border of the hemifields. All stimuli in the Novel Scrambled set were presented only once.

The procedure was identical for all tasks. Stimuli were presented on a white background for 2,500 ms and were separated by 500-ms blank interstimulus intervals. Stimuli were blocked by task into epochs lasting 24 s, with eight trials of a given task in each epoch. Each epoch included three target stimuli and five nontargets. A 24-s period of visual fixation occurred before and after each task epoch. Eight epochs were administered for each task, with the order of these epochs pseudo-randomized and counterbalanced across four functional scanning series. Participants responded by pressing a keypad with the index finger of the nondominant hand when a target was detected. Targets for the Novel Pictures and Repeating Pictures tasks were defined as indoor pictures for two of the scanning series and as outdoor pictures for the other two series.

Immediately after scanning, participants were given a surprise recognition test involving the Novel Pictures and Novel Scrambled stimuli while still in the scanner, using the same stimulus presentation apparatus. For each type of stimulus, 32 items that had been presented during scanning were presented along with an equal number of items that had not been presented previously. Participants indicated whether they recalled seeing the stimuli during scanning.

Image acquisition and analysis

Imaging was performed on a 1.5-Tesla General Electric (Milwaukee, WI, U.S.A.) Signa scanner with a three-axis head gradient coil with an insertable transmit/receive radiofrequency coil optimized for echoplanar imaging (Medical Advances, Milwaukee, WI, U.S.A.). Functional imaging of the entire brain was conducted using a gradient-echo echoplanar sequence (TE, 40 ms; TR, 4,000 ms; FOV, 24 cm; matrix, 64 × 64; slice thickness, 7 mm). A series of 106 consecutive image volumes was acquired during each of four functional scans. An additional set of high-resolution, T1-weighted, spoiled gradient-echo anatomic reference images was obtained for localization purposes.

All image processing and statistical analyses were performed with the AFNI software package (70). All echoplanar image volumes were motion-corrected with an automated 3D image-registration program after discarding volumes 1–4 of each series. Mean MRI intensity values were computed at each voxel for each fixation and task epoch. To control for baseline drifts and other artifacts due to gradual head movements and local gradient fluctuations, a baseline-corrected mean was computed at each voxel for each task epoch by subtracting the average MRI intensity during fixation immediately before and after each task epoch from the average MRI intensity during that task epoch. These baseline-corrected images were used to compute both individual activation maps with voxelwise unpaired t tests and group activation maps with repeated-measures analysis of variance (ANOVA). Image volumes were resampled in standard stereotaxic space (71) and spatially smoothed with a 4-mm full-width-half-maximum Gaussian kernel before computing the random-effects group activation maps. Contrasts identified novelty effects (Novel Pictures – Repeating Pictures) and relational processing effects (Novel Pictures – Novel Scrambled). Group activation maps were thresholded at p < 0.05, corrected for multiple comparisons.

Hippocampal region-of-interest (ROI) analyses

Hippocampal ROIs were created for each participant by manually tracing the borders of the hippocampus on high-resolution anatomic images (Fig. 2). Procedures for defining hippocampal boundaries were adapted from Jack et al. (72). An anterior border was set at the most anterior coronal slice in which the temporal horn of the lateral ventricle was visible. A posterior border was placed at the most posterior slice containing the splenium. With a coronal view, hippocampal borders were drawn on each consecutive slice to include the hippocampus proper (CA1, CA2, CA3, dentate gyrus, and lateral subiculum) but to exclude the parahippocampus and entorhinal cortex. After completion of the ROI by filling these boundaries on each slice, a rigid-body transformation was performed so that the anterior and posterior commissures were aligned in the horizontal plane. Anterior hippocampus was then bounded from the posterior hippocampus with a coronal plane through the posterior edge of the interpeduncular cistern. All tracing was performed blind to the functional activation data.


Figure 2. An example hippocampal region of interest (ROI) tracing from one participant, shown in coronal (top) and sagittal views. The anterior ROI is marked in yellow, and the posterior ROI, in red. Green lines, Positions of the sagittal and coronal slices. The left hemisphere is on the reader's right in the coronal views.

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Individual ROIs were used to measure mean voxel values for the novelty contrast (Novel Pictures – Repeating Pictures) and the relational processing contrast (Novel Pictures – Novel Scrambled) separately in anterior and posterior hippocampus of each hemisphere. These were computed for each participant by averaging the t statistics from the appropriate contrast map for all voxels located within each ROI. In addition to the mean voxel value, which provides an estimate of the overall level of activation, the relative spatial extent of activation was computed for each ROI by thresholding the data at uncorrected p < 0.05 and counting the number of surviving voxels.


  1. Top of page
  2. Abstract
  6. Acknowledgments

Task performance

All tasks were performed well. As expected, accuracy and reaction time on the indoor/outdoor task were superior for the Repeating Pictures compared with the Novel Pictures (mean accuracy, 99.0% vs. 94.4%, p < 0.0001; mean reaction time, 1,028 ms vs. 1,707 ms, p < 0.0001), consistent with a repetition priming effect (73). The matching task on Novel Scrambled stimuli was performed less accurately than the indoor/outdoor task on Novel Pictures (86.2% vs. 94.4%; p < 0.0001), although mean reaction time did not differ for these two conditions (1,759 ms vs. 1,707 ms; p = 0.36). Participants later recognized the stimuli from the Novel Pictures condition more accurately than the Novel Scrambled stimuli (84% vs. 62% correct; p < 0.01), confirming more effective encoding of the Novel Pictures into episodic memory.

Group activation maps

Group activation patterns in the MTL and nearby areas are shown in Fig. 3. Novelty effects (Novel Pictures > Repeating Pictures) and relational processing effects (Novel Pictures > Novel Scrambled) were observed in many of the same MTL regions, including fusiform gyrus, posterior parahippocampal gyrus, and retrosplenial cortex bilaterally (green areas in Fig. 3). In contrast to these regions affected by both experimental factors, the anterior and posterior hippocampus showed striking differences in sensitivity to novelty and relational processing. The posterior hippocampus was sensitive primarily to the novelty manipulation (blue areas in Fig. 3), whereas the anterior hippocampus showed primarily relational processing effects (yellow areas in Fig. 3). Other regions showing only novelty effects included much of the lateral occipital lobe bilaterally, posterolateral fusiform gyrus, and a small region at the junction of inferior frontal and ventral precentral sulci. Other regions showing only relational processing effects included the angular gyrus bilaterally (much stronger on the left), pars triangularis and pars orbitalis of the left inferior frontal gyrus, and a small focus in the left superior frontal sulcus. Stereotaxic coordinates of the main activation peaks for each task contrast are provided in Table 2.


Figure 3. A composite image of the thresholded (p < 0.05, corrected for whole-brain comparisons) group activation maps, showing voxels with reliable novelty effects (blue), relational processing effects (yellow), or both (green). Bottom row, Left brain sagittal slices through the hippocampus at x =–21, –25 and –29. Top row, Right brain slices through the hippocampus at x =+18, +22, and +26. Red lines, The stereotaxic y and z axes. A functional dissociation is observed between anterior hippocampus (white arrow), which is modulated by relational processing demands, and posterior hippocampus, which is modulated by novelty.

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Table 2. Stereotaxic locations and z-scores of activation peaks in the group maps
Task ContrastBrain RegionCoordinatesz-score
NoveltyR middle occipital gyrus33, −77, 117.91
L middle occipital gyrus−35, −84, 97.89
L fusiform gyrus−32, −44, −187.89
R collateral sulcus23, −42, −117.71
L collateral sulcus−24, −42, −107.66
R fusiform gyrus32, −45, −157.50
R inferior occipital gyrus36, −79, 07.47
R retrosplenial area18, −54, 96.56
L inferior occipital gyrus−41, −79, −46.56
L posterior hippocampus−26, −32, −16.11
R posterior hippocampus21, −29, −16.07
L retrosplenial area−15, −55, 125.88
R intraparietal sulcus21, −63, 455.05
L intraparietal sulcus−22, −69, 384.73
L inferior precentral sulcus−39, 4, 274.55
Relational ProcessingL collateral sulcus−24, −41, −107.91
R collateral sulcus21, −41, −117.77
L retrosplenial area−10, −56, 126.86
R retrosplenial area18, −52, 96.59
L fusiform gyrus−32, −43, −176.26
L angular gyrus−43, −77, 346.22
R anterior hippocampus21, −14, −146.01
L anterior hippocampus−24, −16, −155.84
L pars orbitalis of IFG−45, 32, −114.81
R angular gyrus42, −72, 184.81
L pars triangularis of IFG−49, 22, 114.63
L superior frontal sulcus−25, 25, 494.54

Hippocampal ROI analyses

To verify that differences observed in the group analysis involved the hippocampus proper and that activation patterns in anterior and posterior hippocampus differed significantly, mean voxel values for the novelty contrast and the relational processing contrast were measured for these regions in each participant. Hippocampal ROIs were identified manually on each participant's high-resolution anatomic images using standardized procedures (see Fig. 2) (72). Resulting total hippocampus volumes (left, 2,984 μl; right, 3,017 μl) approximated those found in prior studies of normal participants (72). Mean voxel values for each task contrast in anterior and posterior hippocampus are depicted in Fig. 4 for each hemisphere. A 2 × 2 × 2 repeated-measures ANOVA [Hemisphere (left vs. right) by Region (anterior vs. posterior) by Contrast (novelty vs. relational processing)] was conducted on these values. A main effect of region was seen, caused by higher values overall in anterior than in posterior hippocampus [F(1, 31) = 6.85, p = 0.014], but no main effects of hemisphere or task. Of note, a highly significant Region × Contrast interaction was observed [F(1, 31) = 56.85; p < 0.001]. As expected, this was due to a stronger relational processing effect in the anterior hippocampus than in the posterior hippocampus (p < 0.001) and a stronger novelty effect in the posterior hippocampus than in the anterior hippocampus (p = 0.006). No other reliable interactions were observed.


Figure 4. Mean effect size values for the relational processing and novelty contrasts in each of the hippocampal regions of interest. Error bars indicate standard error of the mean.

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An identical 2 × 2 × 2 repeated-measures ANOVA examined spatial extent of activation in the individual hippocampal ROIs. Spatial extent was defined by counting the number of voxels in each ROI exceeding an uncorrected threshold of p < 0.05 and converting this number to volume in microliters. Mean volumes for each task contrast in anterior and posterior hippocampus are depicted in Fig. 5 for each hemisphere. Of note, a highly significant main effect of task contrast was seen, caused by an overall larger activation volume in the relational processing contrast than in the novelty contrast [F(1, 31) = 10.22; p = 0.003]. A main effect of hemisphere also was observed, caused by a larger activation volume in the left than in the right hippocampus [F(1, 31) = 6.01; p = 0.02]. A trend toward a region effect was found, with a larger activation volume in anterior than in posterior hippocampus (p = 0.076). Again a highly significant Region by Contrast interaction appeared [F(1, 31) = 19.01; p < 0.001] because of a larger activation volume in the anterior hippocampus than in the posterior hippocampus for the relational processing contrast (p = 0.003), and a larger activation volume in the posterior hippocampus than the anterior hippocampus for the novelty contrast (p = 0.026). No other significant interactions were found.


Figure 5. Mean activation volumes for the relational processing and novelty contrasts in each of the hippocampal regions of interest.

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The final analyses focused on the consistency with which activation in the hippocampus was detected across participants. Activated voxels (uncorrected p < 0.05) were detected in the left hippocampus in 30 of 32 participants with the relational processing contrast and in 31 of 32 participants with the novelty contrast. Activated voxels were detected in the right hippocampus in 29 of 32 participants with either contrast. Figure 6 shows, for each task contrast, a map of the voxels in the hippocampus where ≥50% of the participants showed activation. Voxels with higher overlap across participants are color-coded accordingly. The most consistently detected voxels were in anterior hippocampus with the relational processing contrast.


Figure 6. Group maps indicating overlap within the hippocampus of thresholded (p < 0.05, uncorrected) individual activation maps. The color code indicates the proportion of participants showing activation at each voxel. Top row, The relational processing contrast. Bottom row, the novelty contrast. The coronal slices are, from left to right, at –8, –14, –20, –26, and –32 on the stereotaxic anteroposterior axis.

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  1. Top of page
  2. Abstract
  6. Acknowledgments

In this study, we evaluated two task contrasts designed to produce modulation of the BOLD signal in the hippocampus. Although both produced robust bilateral activation, the pattern of activation differed along the anteroposterior hippocampal axis. One contrast emphasized stimulus novelty through a comparison of novel versus repeated pictures, all of which were encoded by using a semantic classification task (“Is the picture indoor or outdoor?”). Hippocampal activation for this contrast was stronger posteriorly. The second contrast emphasized relational processing through a comparison of semantically encoded meaningful pictures versus structurally encoded (“Do the two halves match?”) nonsense stimuli. As expected, identifiable pictures that could be recognized and categorized were better remembered than the spatially scrambled, unidentifiable versions of these images, suggesting more extensive encoding of the meaningful pictures. Activation for this contrast was much stronger in anterior portions of the hippocampus.

Results for the novelty contrast are very consistent with previous PET and fMRI studies showing novelty effects in the posterior MTL, particularly in the posterior parahippocampus, and in surrounding visual extrastriate regions (26,31,35,40,51–53). Novelty effects in extrastriate regions have been attributed to perceptual priming, a process by which repeated stimuli are processed more efficiently and therefore require less neural activity (73–75). In addition to perceptual priming, differences in “top-down” attentional modulation could explain some of the novelty effects, because processing of repeated stimuli (especially stimuli that are repeated many times) should require less attention than processing of novel stimuli. Our data provide further evidence that novelty also modulates activity in the hippocampus proper, although this modulation primarily involved the posterior hippocampus.

Results for the relational processing contrast also are consistent with previous imaging studies (19,33,34,36–39,58–68). In designing a contrast to elicit relational processing effects during encoding, we did not attempt to distinguish task effects from stimulus effects. Consequently, the activation differences observed in the relational processing contrast could be due to differences between the normal and scrambled images in the degree of stimulus meaningfulness, to differences in explicit processing demands between the classification (indoor/outdoor judgment) and discrimination (hemifield-matching) tasks, or to both. According to the relational processing account of hippocampal function, these manipulations should have similar effects, producing more elaborate associative processing either when the stimuli are meaningful or when the explicit task requires retrieval of meaning. If anterior hippocampus activation is dependent on such relational processing, both stimulus and task variables should modulate activity in this region. In this experiment, we manipulated both the stimuli and task to produce as strong a relational processing contrast as possible.

The neurophysiologic explanation for these differences in anterior and posterior hippocampal activation patterns is not yet clear. Some evidence from animal studies supports the general notion of functional differences along the anteroposterior (or, in rats, ventral-dorsal) longitudinal axis in the hippocampus. For example, anatomic studies in cat and monkey indicate a topographic organization of inputs to the dentate gyrus from entorhinal cortex, with anterior dentate gyrus receiving input from anteromedial regions of entorhinal cortex, and posterior dentate gyrus receiving input from posterolateral entorhinal cortex (76). Related studies suggest a relatively greater input from unimodal visual cortex to lateral entorhinal and perirhinal cortices (which have stronger projections to posterior dentate gyrus) and more widespread input from polymodal, temporoparietal, olfactory, and prefrontal areas to medial and anterior entorhinal cortex (which project more strongly to anterior dentate gyrus) (76–78). These connectivity patterns suggest a preponderance of input to posterior hippocampus from the visual system and a more widespread, multimodal input to the anterior hippocampus. Studies in both monkey and rat show that the posterior/dorsal hippocampus is more involved in encoding spatial information than is the anterior/ventral hippocampus (79–81). To our knowledge, however, no studies have yet examined hippocampal functional heterogeneity in experimental animals from the standpoint of nonspatial relational processing.

Several of the results are relevant to clinical fMRI of the medial temporal lobe. Important variables to consider in developing a clinical protocol include the robustness, the hemispheric lateralization, and the intrahemispheric pattern of hippocampal activation. Both of the protocols tested here produced robust activation in the hippocampus proper. The voxel count analysis showed a clear difference between the protocols [i.e., a larger volume of activation for the relational processing contrast (68.7 μl for relational processing vs. 29.6 μl for novelty)]. This difference did not appear in the mean voxel value analysis, suggesting that activation in the relational processing contrast tended to be more focal and of higher intensity, whereas activation in the novelty contrast tended to be of lower intensity and more evenly distributed. The voxel count analysis also showed a larger volume of activation in the left hippocampus, although this difference was relatively small and was not present in the mean voxel value analysis or evident in the group maps. This point is important because the capacity to detect a unilateral abnormality of hippocampal activation is greatly enhanced by computing an asymmetry index (11,20–22,24), which is feasible only when activation is bilateral. Finally, the choice of a relational processing contrast or a novelty contrast depends on whether the anterior or posterior hippocampus is of greater clinical interest. Pathologic, electrophysiologic, and imaging studies suggest that although all regions of the hippocampus can be affected in TLE, the anterior portions are the most consistently involved (82–85). The relational processing contrast, which produces more robust activation and is more sensitive to functioning of the anterior hippocampus, may therefore be the more sensitive protocol for detecting functional abnormalities in TLE.

It should be emphasized that many other variables require careful study before an optimal fMRI protocol for visualizing hippocampal activation is determined. For example, it may be important to include a subsequent item-recognition test as part of the protocol to identify which items presented during scanning are later remembered and which are forgotten. This information can then be used in the analysis of the fMRI response to account for additional variance in MTL activation. This “subsequent memory effect” has been shown in numerous studies to correlate with activation in the MTL, including, in some cases, the hippocampus (27,29,31,33,36,63,86–88). Another potentially critical variable is the specific task used to elicit relational processing. The picture-classification task used here is relatively easy and does not require participants to learn new associations (although implicit formation of new associations between stimuli and context is a defining feature of all episodic encoding, including the task used here). Tasks that make greater demands on semantic retrieval or that require explicit learning of new associations might elicit even stronger hippocampal activation (33,37,39,60,65,67). Finally, although bilateral activation of the hippocampus is a desirable feature for predicting side of seizure focus and seizure outcome, protocols for eliciting material-specific, unilateral activation may be preferable for other applications (22,23).


  1. Top of page
  2. Abstract
  6. Acknowledgments

Acknowledgment:  This study was supported by Individual National Research Service Award Fellowship 1F32MH11921-01A1, The Charles A. Dana Foundation, National Institute of Neurological Diseases and Stroke grants R01 NS33576 and RO1 NS35929, National Institute of Mental Health grant P01 MH51358, and National Institutes of Health General Clinical Research Center grant M01 RR00058. We thank R.W. Cox, J.S. Hyde, A. Jesmanowicz, R. Reynolds, S.M. Rao, and E. Kapler for discussion and technical assistance.


  1. Top of page
  2. Abstract
  6. Acknowledgments
  • 1
    Spencer SS, McCarthy G, Spencer DD. Diagnosis of medial temporal lobe seizure onset: relative specificity and sensitivity of quantitative MRI. Neurology 1993;43: 211724.
  • 2
    Spencer S. The relative contributions of MRI, SPECT, and PET imaging in epilepsy. Epilepsia 1994;35(suppl 6):S7289.
  • 3
    Perrine K, Westerveld M, Sass KJ, et al. Wada memory disparities predict seizure laterality and postoperative seizure control. Epilepsia 1995;36: 8516.
  • 4
    Cascino GD, Trenerry MR, So EL, et al. Routine EEG and temporal lobe epilepsy: relation to long-term EEG monitoring, quantitative MRI, and operative outcome. Epilepsia 1996;37: 6516.
  • 5
    Bronen RA, Fulbright RK, King D, et al. Qualitative MRI imaging of refractory temporal lobe epilepsy requiring surgery: correlation with pathology and seizure outcome after surgery. AJR Am J Roentgenol 1997;169: 87582.
  • 6
    Spanaki MV, Spencer SS, Corsi M, et al. The sensitivity and specificity of quantitative difference SPECT analysis in seizure localization. J Nucl Med 1999;40: 7306.
  • 7
    Swearer JM, Kane KJ, Phillips CA, et al. Predictive value of the intracarotid amobarbital test in bihemispheric seizure onset. Neurology 1999;52: 40911.
  • 8
    Loring DW, Meador KJ, Lee GP, et al. Wada memory performance predicts seizure outcome following anterior temporal lobectomy. Neurology 1994;44: 23224.
  • 9
    Manno EM, Sperling MR, Ding X, et al. Predictors of outcome after anterior temporal lobectomy: positron emission tomography. Neurology 1994;44: 23316.
  • 10
    Sperling MR, Saykin AJ, Glosser G, et al. Predictors of outcome after anterior temporal lobectomy: the intracarotid amobarbital test. Neurology 1994;44: 232530.
  • 11
    Killgore WDS, Glosser G, Casasanto D, et al. Functional MRI and the Wada test provide complementary information for predicting post-operative seizure control. Seizure 2000;8: 4505.
  • 12
    Trenerry MR, Jack CRJ, Ivnik RJ, et al. MRI hippocampal volumes and memory function before and after temporal lobectomy. Neurology 1993;43: 18005.
  • 13
    Kneebone AC, Chelune GJ, Dinner DS, et al. Intracarotid amobarbital procedure as a predictor of material-specific memory change after anterior temporal lobectomy. Epilepsia 1995;36: 85765.
  • 14
    Loring DW, Meador KJ, Lee GP, et al. Wada memory asymmetries predict verbal memory decline after anterior temporal lobectomy. Neurology 1995;45: 132933.
  • 15
    Davies KG, Bell BD, Bush AJ, et al. Prediction of verbal memory loss in individuals after anterior temporal lobectomy. Epilepsia 1998;39: 8208.
  • 16
    Seidenberg M, Hermann B, Wyler AR, et al. Neuropsychological outcome following anterior temporal lobectomy in patients with and without the syndrome of mesial temporal lobe epilepsy. Neuropsychology 1998;12: 30316.
  • 17
    Chiaravalloti ND, Glosser G. Material-specific memory changes after anterior temporal lobectomy as predicted by the intracarotid amobarbital test. Epilepsia 2001;42: 90211.
  • 18
    Sabsevitz DS, Swanson SJ, Morris GL, et al. Memory outcome after left anterior temporal lobectomy in patients with expected and reversed Wada memory asymmetry scores. Epilepsia 2001;42: 140815.
  • 19
    Bellgowan PSF, Binder JR, Swanson SJ, et al. Side of seizure focus predicts left medial temporal lobe activation during verbal encoding. Neurology 1998;51: 47984.
  • 20
    Detre JA, Maccotta L, King D, et al. Functional MRI lateralization of memory in temporal lobe epilepsy. Neurology 1998;50: 92632.
  • 21
    Jokeit H, Okujava M, Woermann FG. Memory fMRI lateralizes temporal lobe epilepsy. Neurology 2001;57: 178693.
  • 22
    Golby AJ, Poldrack RA, Illes J, et al. Memory lateralization in medial temporal lobe epilepsy assessed by functional MRI. Epilepsia 2002;43: 85563.
  • 23
    Richardson MP, Strange BA, Duncan JS, et al. Preserved verbal memory function in left medial temporal pathology involves reorganisation of function to right medial temporal lobe. Neuroimage 2003;20: S1129.
  • 24
    Rabin ML, Narayan VM, Kimberg DY, et al. Functional MRI predicts post-surgical memory following temporal lobectomy. Brain 2004;127: 228698.
  • 25
    Babb TL, Pretorius JK. Pathologic substrates of epilepsy. In: WyllieE, ed. The treatment of epilepsy: principles and practice. 2nd ed. Baltimore : Williams & Wilkins; 1996: 10621.
  • 26
    Gabrieli JDE, Brewer JB, Desmond JE, et al. Separate neural bases of two fundamental memory processes in human medial temporal lobe. Science 1997;276: 2646.
  • 27
    Fernandez G, Weyerts H, Schrader-Bölsche M, et al. Successful verbal encoding into episodic memory engages the posterior hippocampus: a parametrically analyzed functional magnetic resonance imaging study. J Neurosci 1998;18: 18417.
  • 28
    Martin A. Automatic activation of the medial temporal lobe during encoding: lateralized influences of meaning and novelty. Hippocampus 1999;9: 6270.
  • 29
    Constable RT, Carpentier A, Pugh K, et al. Investigation of the hippocampal formation using a randomized event-related paradigm and z-shimmed functional MRI. Neuroimage 2000;12: 5562.
  • 30
    Eldridge LL, Knowlton BJ, Furmanski CS, et al. Remembering episodes: a selective role for the hippocampus during retrieval. Nat Neurosci 2000;3: 114952.
  • 31
    Kirchhoff BA, Wagner AD, Maril A, et al. Prefrontal-temporal circuitry for episodic encoding and subsequent memory. J Neurosci 2000;20: 617380.
  • 32
    Cabeza R, Rao SM, Wagner AD, et al. Can medial temporal lobe regions distinguish true from false? An event-related functional MRI study of veridical and illusory recognition memory. Proc Natl Acad Sci U S A 2001;98: 480510.
  • 33
    Otten LJ, Henson RNA, Rugg MD. Depth of processing effects on neural correlates pf memory encoding: relationship between findings from across- and within-task comparisons. Brain 2001;124: 399412.
  • 34
    Small SA, Nava AS, Perera GM, et al. Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation. Nat Neurosci 2001;4: 4429.
  • 35
    Stark CE, Squire LR. When zero is not zero: the problem of ambiguous baseline conditions in fMRI. Proc Natl Acad Sci 2001;98: 127606.
  • 36
    Davachi L, Wagner AD. Hippocampal contributions to episodic memory: insights from relational and item-based learning. J Neurophysiol 2002;88: 98290.
  • 37
    Killgore WD, Casasanto DJ, Yurgelun-Todd DA, et al. Functional activation of the left amygdala and hippocampus during associative encoding. Neuroreport 2002;11: 225963.
  • 38
    Kensinger EA, Clarke RJ, Corkin S. What neural correlates underlie successful encoding and retrieval? A functional magnetic resonance imaging study using a divided attention paradigm. J Neurosci 2003;23: 240715.
  • 39
    Zeinah MM, Engel SA, Thompson PM, et al. Dynamics of the hippocampus during encoding and retrieval of face-name pairs. Science 2003;299: 57780.
  • 40
    Fransson P, Merboldt KD, Ingvar M, et al. Functional MRI with reduced susceptibility artifact: high-resolution mapping of episodic memory encoding. Neuroreport 2001;12: 141520.
  • 41
    Schacter DL, Wagner AD. Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval. Hippocampus 1999;9: 724.
  • 42
    Gabrieli JDE. Functional imaging of episodic memory. In: CabezaR, KingstoneA, eds. Handbook of functional neuroimaging of cognition. Cambridge , MA : MIT Press, 2001: 25391.
  • 43
    Paller KA, Wagner AD. Observing the transformation of experience into memory. Trends Cogn Neurosci 2002;6: 93102.
  • 44
    Rugg MD, Otten LJ, Henson RNA. The neural basis of episodic memory: evidence from functional neuroimaging. Phil Trans R Soc Lond B 2002;357: 1097110.
  • 45
    Kelley WM, Miezin FM, McDermott KB, et al. Hemispheric specialization in human dorsal frontal cortex and medial temporal lobe for verbal and nonverbal memory encoding. Neuron 1998;20: 92736.
  • 46
    Golby AJ, Poldrack RA, Brewer JB, et al. Material-specific lateralization in the medial temporal lobe and prefrontal cortex during memory encoding. Brain 2001;124: 184154.
  • 47
    Riches IP, Wilson FAW, Brown MW. The effects of visual stimulation and memory on neurones of the hippocampal formation and neighboring parahippocampal gyrus and inferior temporal cortex of the primate. J Neurosci 1991;11: 176379.
  • 48
    Li L, Miller EK, Desimone R. The representation of stimulus familiarity in anterior inferior temporal cortex. J Neurophysiol 1993;69: 191829.
  • 49
    Knight RT. Contribution of the human hippocampal region to novelty detection. Nature 1996;383: 2569.
  • 50
    Grunwald T, Lehnertz K, Heinze HJ, et al. Verbal novelty detection within the human hippocampus proper. Proc Natl Acad Sci U S A 1998;95: 31937.
  • 51
    Stern CE, Corkin S, González RG, et al. The hippocampal formation participates in novel picture encoding: evidence from functional magnetic resonance imaging. Proc Natl Axad Sci 1996;93: 86605.
  • 52
    Tulving E, Markowitsch HJ, Crail FIM, et al. Novelty and familiarity activations in PET studies of memory encoding and retrieval. Cereb Cortex 1996;6: 719.
  • 53
    Hunkin NM, Mayes AR, Gregory LJ, et al. Novelty-related activation within the medial temporal lobes. Neuropsychologia 2002;40: 145664.
  • 54
    Cohen NJ, Eichenbaum H. Memory, amnesia, and the hippocampal system. Cambridge , MA : MIT Press, 1993.
  • 55
    Alvarez P, Squire LR. Memory consolidation and the medial temporal lobe: a simple network model. Proc Natl Acad Sci U S A 1994;91: 70415.
  • 56
    McClelland JL, McNaughton BL, O'Reilly RC. Why are there complementary learning systems in the hippocampus and neocortex: insights from the success and failures of connectionist models of learning and memory. Psychol Rev 1995;102: 40957.
  • 57
    O'Reilly RC, Rudy JW. Conjunctive representations in learning and memory: principles of cortical and hippocampal function. Psychol Rev 2001;108: 31145.
  • 58
    Vandenberghe R, Price C, Wise R, et al. Functional anatomy of a common semantic system for words and pictures. Nature 1996;383: 2546.
  • 59
    Binder JR, Frost JA, Hammeke TA, et al. Human brain language areas identified by functional MRI. J Neurosci 1997;17: 35362.
  • 60
    Henke K, Buck A, Weber B, et al. Human hippocampus establishes associations in memory. Hippocampus 1997;7: 24956.
  • 61
    Martin A, Wiggs CL, Weisberg JA. Modulation of human medial temporal lobe activity by form, meaning, and experience. Hippocampus 1997;7: 58793.
  • 62
    Mummery CJ, Patterson K, Hodges JR, et al. Functional neuroanatomy of the semantic system: divisible by what? J Cogn Neurosci 1998;10: 76677.
  • 63
    Wagner AD, Schacter DL, Rotte M, et al. Building memories: remembering and forgetting of verbal experiences as predicted by brain activity. Science 1998;281: 118891.
  • 64
    Binder JR, Frost JA, Hammeke TA, et al. Conceptual processing during the conscious resting state: a functional MRI study. J Cogn Neurosci 1999;11: 8093.
  • 65
    Henke K, Weber B, Kneifel S, et al. Human hippocampus associates information in memory. Proc Natl Acad Sci U S A 1999;96: 58849.
  • 66
    Mummery CJ, Shallice T, Price CJ. Dual-process model in semantic priming: a functional imaging perspective. Neuroimage 1999;9: 51625.
  • 67
    Sperling RA, Bates JF, Cocchiarella AJ, et al. Encoding novel face-name associations: a functional MRI study. Hum Brain Mapp 2001;14: 12939.
  • 68
    Binder JR, McKiernan KA, Parsons M, et al. Neural correlates of lexical access during visual word recognition. J Cogn Neurosci 2003;15: 37293.
  • 69
    Andreasen NC, O'Leary DS, Cizadlo T, et al. Remembering the past: two facets of episodic memory explored with positron emission tomography. Am J Psychiatry 1995;152: 157685.
  • 70
    Cox RW. AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 1996;29: 16273.
  • 71
    Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain. New York : Thieme Medical Publishers, 1988.
  • 72
    Jack CR, Theodore WH, Cook M, et al. MRI-based hippocampal volumetrics: data acquisition, normal ranges, and optimal protocol. Magn Reson Imaging 1995;13: 105764.
  • 73
    Schacter DL, Buckner RL. Priming and the brain. Neuron 1998;20: 18595.
  • 74
    Desimone R. Neural mechanisms for visual memory and their role in attention. Proc Natl Acad Sci U S A 1996;93: 134949.
  • 75
    Wiggs CL, Martin A. Properties and mechanisms of perceptual priming. Curr Opin Neurobiol 1998;8: 22733.
  • 76
    Witter MP, Van Hoesen GW, Amaral DG. Topographical organization of the entorhinal projection to the dentate gyrus of the monkey. J Neurosci 1989;9: 21627.
  • 77
    Suzuki WA, Amaral DG. Perirhinal and parahippocampal cortices of the macaque monkey: cortical afferents. J Comp Neurol 1994;350: 497533.
  • 78
    Suzuki WA, Amaral DG. Topographic organization of the reciprocal connections between the monkey entorhinal cortex and the perirhinal and parahippocampal cortices. J Neurosci 1994;14: 185677.
  • 79
    Moser E, Moser M-B, Andersen P. Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J Neurosci 1993;13: 391625.
  • 80
    Jung MW, Wiener SI, McNaughton BL. Comparison of spatial firing characteristics of units in dorsal and ventral hippocampus of the rat. J Neurosci 1994;14: 734756.
  • 81
    Colombo M, Fernandez T, Nakamura K, Gross CG. Functional differentiation along the anterior-posterior axis of the hippocampus in monkeys. J Neurophysiol 1998;80: 10025.
  • 82
    Sommer W. Erkrankung des Ammonshorns als aetiologisches Moment der Epilepsie. Arch Psychiatrie Nervenkr 1880;10: 63175.
  • 83
    Babb TL, Lieb JP, Brown WJ, et al. Distribution of pyramidal cell density and hyperexcitability in the epileptic human hippocampal formation. Epilepsia 1984;25: 7218.
  • 84
    Cook MJ, Fish DR, Shorvon SD, et al. Hippocampal volumetric and morphometric studies in frontal and temporal lobe epilepsy. Brain 1992;115: 10015.
  • 85
    Van Paesschen W, Connelly A, King MD, et al. The spectrum of hippocampal sclerosis: a quantitative magnetic resonance imaging study. Ann Neurol 1997;41: 4151.
  • 86
    Brewer JB, Zhao Z, Desmond JE, et al. Making memories: brain activity that predicts how well visual experience will be remembered. Science 1998;281: 11858.
  • 87
    Buckner RL, Wheeler ME, Sheridan MA. Encoding processes during retrieval tasks. J Cogn Neurosci 2001;13: 40615.
  • 88
    Weis S, Klaver P, Reul J, et al. Temporal and cerebellar brain regions that support both declarative memory formation and retrieval. Cereb Cortex 2004;14: 2567.