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Delayed Verbal Memory Retrieval: A Functional MRI Study in Epileptic Patients with Structural Lesions of the Left Medial Temporal Lobe
NeuroImage 14, 995–1003 (2001) doi:10.1006/nimg.2001.0908, available online at http://www.idealibrary.com on
Delayed Verbal Memory Retrieval: A Functional MRI Study in Epileptic Patients with Structural Lesions of the Left Medial Temporal Lobe Sophie Dupont,* ,† ,‡ Yves Samson,† ,§ Pierre-Franc¸ois Van de Moortele,† Se´verine Samson,* Jean-Baptiste Poline,† Claude Adam,* ,‡ Ste´phane Lehe´ricy, ¶ Denis Le Bihan,† and Michel Baulac,* ,‡ *Unite´ d’Epileptologie and §Department of Urgences Ce´re´bro-vasculaires, Clinique Neurologique Paul Castaigne, ¶Department of Radiology, and ‡LENA, CNRS UPR640, Hoˆpital de la Pitie´-Salpeˆtrie`re, Paris, France; and †CEA–SHFJ, 91406 Orsay, France Received December 27, 2000
In a previous functional magnetic resonance imaging (fMRI) study, we suggested that in left medial temporal lobe epilepsy (LTLE) poor verbal episodic memory performances were sustained by abnormal neocortical and mesiotemporal activations. In the present study, we attempted to examine the evolution of these abnormal neocortical and mesiotemporal activations over 24 h. We thus observed the fMRI brain regions activated during the 24-h-delayed retrieval of a word list in the same sample of healthy control subjects and LTLE patients. In control subjects, a similar left occipitotemporofrontal network was activated during both immediate and 24-h-delayed retrieval conditions. In addition, the 24-h-delayed retrieval also activated a larger parietal region and the right hippocampus. This distributed neocortical and mesiotemporal network was very poorly activated during the 24-h-delayed retrieval in LTLE patients, suggesting the inability to reactivate areas that are keys to retrieving stored information. © 2001 Academic Press
INTRODUCTION In a previous paper (Dupont et al., 2000), we used functional magnetic resonance imaging (fMRI) to identify neocortical and mesiotemporal regions involved in encoding and immediate retrieval of a word list in control subjects and patients with left medial temporal lobe epilepsy (LTLE). In both encoding and immediate retrieval tasks, control subjects activated a distributed neocortical network mainly involving the left occipitotemporofrontal ventral cortex. Mesiotemporal activations were found only during the immediate retrieval task and were restricted to the parahippocampal gyri, with a predominant rightsided lateralization. No hippocampal activation was detected. In LTLE patients, neocortical and mesiotemporal activations were modified. Neocortical occipitotemporofrontal ventral activation was less marked than in control subjects and we noticed the
emergence of a new dramatic activation of the dorsolateral frontal cortex. Parahippocampal activation was decreased bilaterally. In this study, however, as in most retrieval studies performed during PET or fMRI experiments (Henson et al., 1999; Schacter et al., 1997; Squire et al., 1992), word retrieval was only assessed a few minutes after the encoding processing. To our knowledge, a single neuroimaging study (Andreasen et al., 1995) examined both immediate and 1-week recall of an overlearned word list in healthy normal volunteers. They found that similar regions were activated in both immediate and delayed retrieval conditions: large right frontal areas, biparietal areas, and the left cerebellum. In the present study, we planned to confirm these results in control subjects by examining the evolution of the normal cerebral networks sustaining episodic memory after a 24-h time delay. We also wanted to determine whether a similar consolidation of the cerebral activations would occur in LTLE patients. Therefore, we scanned all the subjects (control subjects and epileptic patients) with the same blocked fMRI recognition paradigm after a 24-h-delayed period including a full night of sleep. MATERIAL AND METHODS Subjects The study population included 7 patients (4 women and 3 men; median age 37 years; range 18 –53 years) with medial temporal lobe epilepsy who were undergoing presurgical evaluation for anterior temporal lobectomy at the Pitie´-Salpeˆtrie`re Epilepsy Unit. They were matched with a control group, consisting of 10 healthy volunteers (8 women and 2 men; median age 24 years; range 23–31 years). All subjects gave informed written consent in accordance with the Declaration of Helsinki, and the Local Ethics Committee approved the study. Six patients underwent presurgical evaluation (Adam et al., 1996) in-
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1053-8119/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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cluding medical, neurological, and neuropsychological examinations, video-EEG monitoring, brain MRI, FDG–PET examinations, and an intracarotid amytal test. The 7th patient underwent the same investigation, with the exception of the neuropsychological examination and the intracarotid amytal test. The inclusion criteria for our study were the following: right-handed lateralization, surface EEG recordings consistent with left-sided medial temporal lobe seizure onset, left hippocampal sclerosis diagnosed on volumetric MRI without any other structural abnormalities, and/or left temporal lobe hypometabolism on interictal FDG–PET. All patients were otherwise healthy. fMRI Procedures
Session 1 (Day 0) This block fMRI recognition paradigm has already been described in a previous paper (Dupont et al., 2000). Briefly, subjects were visually instructed to recall silently a supraspan of 17 abstract words that they had learned 20 min before. At the end of the session, subjects were tested to establish the efficiency of the retrieval of the verbal information and were asked to recall out loud the words that they had previously learned. For the first session (encoding, immediate retrieval), it was clearly explained to the subjects before and during the experiment that they had to learn and recall the words. At the end of the first session, we told the subjects that the second session would be totally different in order to avoid rehearsal of the word list between the interval.
Imaging parameters and acquisition procedures were identical to those described in a previous paper (Dupont et al., 2000). Blood oxygenation-level-dependant fMRI data were acquired on a 3-T Bruker system equipped with a prototype fast-gradient system and the standard quadrature head coil. Subjects were placed in a supine position in the MRI scanner. Their heads were immobilized with cushions to reduce motion artifact. The stimuli were projected onto a mirror located at the end of the scanner bore. Subjects were equipped with prism glasses that allowed them to see the projection in central vision without image distortion. For each subject, conventional structural images were first collected to provide detailed anatomic information. Following the acquisition of these sagittal and axial inversion recovery turbo-flash T1-weighted localizer images, gradient-echo echoplanar fMRI was performed in 22 contiguous 5-mm axial slices (repetition time 6 s, 64 ⫻ 80 matrix, 22-cm 2 field of view) covering the whole brain. The entire session, including both structural and functional sequences, lasted 45 min the first day and 50 min the following day.
fMRI data were analyzed on SPARC workstations (Sun Microsystems, Mountain View, CA). Statistical analysis was performed in MATLAB (Mathworks, Natick, MA) using a statistical parametric mapping software package (SPM96) (Friston et al., 1995).
Memory Task Procedures
Statistical Analysis
Memory tasks included verbal episodic memory retrieval tasks. The aim of the present experiment was to create two retrieval conditions that differed in relation to immediate retrieval or 24-h-delayed retrieval. Two sessions were performed on consecutive days. A sequential task-activation paradigm was employed, alternating between an experimental condition and a baseline condition. The baseline condition was the same for all the experiments and consisted of the fixation of the letter A. Scanning was performed over a 324-s block. Each block included five control and four experimental conditions beginning with the control condition. The study words were exposed for 2 s at four times alternating with the baseline condition.
For each subject, we performed a stereotaxic reorientation of the images along the bicommissural line. Images were then coregistered and resliced to correct movement and further spatially transformed to standard stereotaxic coordinates to correct for anatomical variance across subjects. The standard reference space used in SPM96 is based on the Talairach and Tournoux stereotaxic atlas (Talairach and Tournoux, 1988). The resulting images were convolved with a three-dimensional Gaussian filter to suppress noise. The data were then analyzed statistically on a voxelby-voxel basis using a two temporal basis functions model. We first performed an individual analysis for each subject and then a multisubject analysis using
Postsleep Session (Day 1) The following day, after a full night of sleep, subjects were visually instructed to recall silently the list of words that they had learned the previous day (24-hdelayed retrieval). Subjects were told that they had to recall the list that they had learned the previous day just 2 s before the functional scanning began. At the end of the session, subjects were again tested to establish the efficiency of the 24-h-delayed retrieval and were therefore asked to recall out loud the words that they had previously learned. We also checked at this time that the patients did not have seizures between the two experiments. Image Analysis
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We also conducted a two-way ANOVA (group ⫻ immediate and delayed retrievals) using retrievals as repeated measures. The results confirmed that there was a significant difference between the patients group and the control group (F ratio ⫽ 14.76; P ⫽ 0.0016) and also evidenced a significant difference between immediate and delayed retrieval (F ratio ⫽ 4.84; P ⫽ 0,0438) in the whole group (patients ⫹ controls). No interaction was found. Within-Group Comparisons of Hemodynamic Response
FIG. 1. Memory test longitudinal performances in controls and patients.
a similar method. Since our aim was to investigate the global changes in neocortical activations in relation to the hippocampal damage, we focused our study on the group analysis. For this multisubject analysis, a given voxel was considered to be significantly activated if, on comparison with a reference task, there was an increase in the hemodynamic response function at P ⬍ 0.0001 (P ⬍ 0.01 corrected for multiple comparison). These values correspond to Z scores of 3.72 and above in this study. A region was considered to be activated if a spatially contiguous set of voxels were all independently significant at a level of P ⬍ 0.003. RESULTS Memory Test Performance As expected, the retrieval performances of the control subjects were broadly similar over 24 h. Control subjects recalled 9.9 ⫾ 4.3 words (mean ⫾ SD) (median 11 words, range 2–16 words) during the 24-h-delayed retrieval and 10.3 ⫾ 4.4 words (median 11 words, range 2–16 words) during the immediate retrieval experimental condition.. The difference between the two retrievals in the two separate groups was not statistically significant. LTLE patients’ retrieval performances tended to decrease after the 24-h-delayed period but the difference did not reach significance (2.4 ⫾ 3.6 words during the 24-h-delayed retrieval (median 1 word, range 0 –10 words) versus 3.1 ⫾ 2.5 words recalled during the immediate retrieval (median 2 words, range 1– 8 words)) (see Fig 1). As expected, LTLE patients’ performances were significantly worse than those of control subjects during both immediate and 24-h-delayed retrieval (P ⬍ 0.0007 and P ⬍ 0.0014, respectively).
Tables 1 and 2 indicate the coordinates of the areas of significant activation (P ⬍ 0.0001, corrected for multiple comparison) during immediate and 24-h-delayed retrievals for both hemispheres in control subjects and LTLE patients. A peak of activation consists of voxels that survived a voxel-wise multiple-comparison correction of P ⬍ 0.001 (Z ⬎ 3.72) using a two basis function model. For each comparison, we tested the following thresholds: height threshold P ⬍ 0.05, P ⬍ 0.01, P ⬍ 0.0001; and extent threshold P ⫽ 0.000, P ⫽ 0.000, P ⫽ 0.013 (P corrected ⬍ 0.05) and found similar results. Control Subjects Activation Minus Baseline Hippocampal and parahippocampal activations. As shown in Table 2, a robust hippocampal activation (coordinates 24, ⫺39, 3; Z ⫽ 7.12) was detected in the posterior part of the right hippocampus (see Fig. 2). A left parahippocampal activation was also seen during the 24-h-delayed retrieval. This activation was located within 6 mm of one of the two peaks of activation detected during the immediate retrieval. Similarly, right parahippocampal activation very close to those found during the immediate retrieval was observed during the 24-h-delayed retrieval. But there again, a single peak was detected during the 24-h-delayed retrieval while four peaks were detected during the immediate retrieval. Neocortical activations. Figure 3 shows the SPM cortical activation maps during the two retrieval tasks for the 10 healthy volunteers. The network of neocortical regions activated during the 24-h-delayed retrieval shared similarity with the one activated during the immediate retrieval, including the following regions: the left occipital cortex, the lingual gyrus, the left lateral parietal cortex (Brodmann’s areas 7 and 40), the left superior temporal gyrus (Brodmann’s area 22), and the ventrolateral frontal cortex (Brodmann’s areas 44 and 45) bilaterally. However, there were notable differences. There was a dramatic decrease in the occipitotemporofrontal activations in terms of number of activation peaks and Z scores (see Table 1): only two peaks of activation were seen during the 24-h-delayed
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TABLE 1 Activation Foci in Normal Control Subjects and Epileptic Patients during Immediate and 24-h-Delayed Retrieval Tests (Stereotaxic Coordinates Are Expressed in mm) (Left Hemisphere) Controls Immediate retrieval Region Occipital cx Primary occipital cortex Occipitotemporal cx (BA 37/41/42) Fusiform gyrus Lingual gyrus Parietal cx (BA 40/7)
Superior temporal cx (BA 22)
Frontal cx Ventrolateral frontal cortex (BA 44/45)
LTLE patients 24-h-delayed retrieval
Immediate retrieval
24-h-delayed retrieval
x
y
z
Z value
x
y
z
Z value
x
y
z
Z value
⫺18 ⫺18 ⫺42 ⫺51 ⫺45 ⫺30
⫺78 ⫺66 ⫺60 ⫺27 ⫺24 ⫺54
15 21 6 15 3 0
5.28 4.74 4.77 4.83 5.1 7.18
⫺18
⫺78
18
6.58
⫺12
⫺66
15
6.61
4.87 7.01
⫺57
6
7.77
⫺12 ⫺51 ⫺42 ⫺39 ⫺33 ⫺33 30 ⫺30
⫺57 ⫺36 ⫺36 ⫺36 ⫺51 ⫺60 ⫺33 ⫺45
⫺54 ⫺54
3 3
⫺12
⫺30 ⫺21 3 27 36 45 48 48 48 42
7.46 4.29 4.40 6.24 7.34 7.61 5.03 6.68
⫺36 ⫺45
⫺45 ⫺66
42 24
5.02 7.18
⫺45
5.57
⫺33
⫺63
21
⫺57
9
5.95 ⫺57 ⫺54 ⫺39 ⫺42 ⫺45
15 21 21 36 51
15 3 9 0 12
6.78 5.72 5.16 4.55 5.07
⫺57 ⫺51 ⫺48 ⫺48 ⫺39 ⫺48 ⫺42 ⫺51 ⫺45
27 30 33 45 51 18 6 9 33
24 30 21 18 24 30 30 36 36
4.73 5.84 5.32 5.03 3.96 6.69 6.27 4.78 5.50
⫺9 ⫺3 ⫺18
18 6 ⫺45
45 66 3
5.32 7.57 4.81
⫺30 ⫺36
⫺63 ⫺39
48 48
6.23 5.21
⫺66 ⫺63 ⫺57 ⫺45 ⫺54 ⫺42 ⫺42 ⫺48 ⫺45 ⫺42
⫺33 ⫺36 ⫺33 ⫺45 24 18 27 12 21 9
9 18 6 18 6 3 3 21 18 30
6.04 4.66 6.69 8.08 4.8 5.87 6.62 7.11 6.09 5.95
⫺45 ⫺39
21 24
21 12
5.31 7.29
Dorsolateral frontal cortex
Cingulate cortex Anterior (BA 32) Posterior (BA) Medial frontal cx (BA 6/8)
⫺21 ⫺15
Mesiotemporal Parahippocampal gyrus
⫺12 ⫺33
36 30
⫺48 ⫺39
18 15
⫺6 ⫺6
x
y
z
Z value
⫺9
⫺60
6
5.20
⫺51 ⫺42
18 12
36 39
5.70 4.00
⫺12 ⫺3 ⫺3
⫺66 6 15
15 69 60
7.50 5.30 7.30
4.22 4.37
7.56 6.73
⫺15
⫺42
retrieval in the left occipital cortex versus seven during the immediate retrieval, one peak versus five peaks were found in the left superior temporal cortex during respectively 24-h-delayed and immediate retrievals, and finally two peaks versus six peaks were found in the left ventrolateral frontal cortex. Conversely, there was an apparent increase in the spatial extent of the activated left parietal cortex (Brodmann’s areas 7 and 40, seven peaks during the 24-h-delayed retrieval versus two peaks during the immediate retrieval), with the emergence of a new sym-
0
4.74
metrical activation, although less extensive, in the contralateral parietal region. Immediate versus Delayed Retrieval The direct comparison between immediate and delayed retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) confirmed the clear decrease in the 24-h-delayed retrieval activations located in the left temporal and ventrolateral frontal regions (see Fig. 3).
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DELAYED MEMORY RETRIEVAL IN TEMPORAL LOBE EPILEPSY
TABLE 2 Activation Foci in Normal Control Subjects and Epileptic Patients during Immediate and 24-h-Delayed Retrieval Tests (Stereotaxic Coordinates Are Expressed in mm) (Right Hemisphere) Controls Immediate retrieval Region Occipital cortex Primary occipital cortex Occipitotemporal cx (BA 37/41/42) Fusiform gyrus Lingual gyrus
x
y
6 15
⫺60 ⫺60
z
3 0
24-h-delayed retrieval
Z value
54 39
18 27
15 9
x
y
z
Z value
7.58 4.52
Parietal cortex (BA 40/7) Superior temporal cortex (BA 22) Frontal cortex Ventrolateral frontal cortex (BA 44/45) Dorsolateral frontal cx (BA 9/10/46)
LTLE patients
6.01 7.72
42 36 36
⫺39 ⫺39 ⫺24
36 45 6
5.12 5.98 7.14
51 39
24 27
6 9
5.96 7.59
Posterior cingulum (BA 23/30/31) Medial cortex (BA 6/8) Mesiotemporal cortex Parahippocampal gyrus
12 27 21 24
Hippocampus
⫺42 ⫺45 ⫺42 ⫺54
3 ⫺3 3 3
5.81 7.72 6.66 7.31
15
⫺42
3
7.36
24
⫺39
3
7.12
Immediate retrieval
24-h-delayed retrieval
x
y
z
Z value
3
⫺60
6
5.80
36 45 48 9 24 3 6
24 21 0 ⫺60 ⫺60 30 18
36 42 39 6 15 51 48
4.58 6.63 6.10 7.84 7.38 5.44 6.86
21 27
⫺45 ⫺54
3 3
6.34 6.49
x
y
z
Z value
Note. Areas are named after Brodmann (Brodmann, 1909), coordinates are according to the atlas of Talairach and Tournoux (Talairach and Tournoux, 1988). Immediate retrieval data have been previously reported (Dupont et al., 2000).
Delayed versus Immediate Retrieval The direct comparison between delayed and immediate retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) clearly confirmed the increase of the parietal activation depicted during the delayed retrieval condition. LTLE Patients Activation Minus Baseline The most striking finding was the reduction of the number of overall cerebral peaks of activation (7 peaks of activation in LTLE patients versus 20 peaks of activation in control subjects). Hippocampal and parahippocampal activations. No activation was detected (see Fig. 2). Neocortical activations. Figure 4 shows the SPM cortical activation maps during the two retrieval tasks for the seven MTLE patients. The single peak of activation that was similar to those found in control subjects was located in the left lingual gyrus. All the other areas detected in LTLE patients during the
24-h-delayed retrieval were not activated in control subjects. These areas included the left dorsolateral frontal cortex, the left medial frontal cortex (supplementary motor area), the right lingual gyrus, and the left posterior cingulate cortex. A broadly similar left dorsolateral and medial frontal activation was detected during the immediate retrieval in LTLE patients but the activation located within the dorsolateral cortex was much more extensive during the immediate retrieval condition (nine peaks of activation) than during the 24-h-delayed retrieval (two peaks of activation). Immediate versus Delayed Retrieval The direct comparison between immediate and delayed retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) confirmed that the network of left neocortical regions activated during the immediate retrieval condition was significantly more activated during the immediate retrieval than during the delayed retrieval.
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FIG. 2. Mesiotemporal activations during the immediate and 24-h-delayed retrieval task in a control subject and a patient with left medial temporal lobe epilepsy showing (A) a consistent bilateral parahippocampal activation in control subjects during immediate retrieval, (B) a right parahippocampal activation in LTLE patients during immediate retrieval, (C) a right posterior hippocampal activation located in the hippocampus tail in control subjects during delayed retrieval, and (D) the absence of hippocampal or parahippocampal activations in LTLE patients during delayed retrieval.
Delayed versus Immediate Retrieval The direct comparison between delayed and immediate retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) clearly confirmed the dramatic decrease of the neocortical, hippocampal, and parahippocampal activations depicted during the delayed retrieval condition. DISCUSSION This study provides two major findings: first the evidence of a 24-h-delayed memory retrieval sustained by complex distributed neocortical and mesiotemporal networks in normal controls subjects and second the evidence of an alteration of these mesiotemporal and neocortical networks during episodic memory in left medial temporal lobe epilepsy. Memory Retrieval in Normal Subjects The 24-h-delayed retrieval condition was characterized by the reactivation of brain areas that had already been activated during the immediate retrieval condition and by the modification of the medial temporal lobe activations with the emergence of a new activation encompassing the right posterior hippocampus and a dramatic decrease of the parahippocampal activations.
As we noted a memory performance stabilization in the second session, we may hypothesize that these cerebral regions are involved in delayed memory retrieval. These delayed memory retrieval processes seem linked to the reactivation of a left cerebral network that had been previously activated during the immediate retrieval task. Interestingly, the location of the occipitotemporal and ventrolateral frontal regions activated during the immediate and the 24-h-delayed retrievals were very close, with, however, a clear decrease in the 24-h-delayed retrieval activations in terms of number of peaks and Z scores. The dramatic increase of the parietal cortex activation and its bilateralization was much more surprising. The role of the posterior association cortex in memory processes is not well known. Interestingly, the only study that also examined immediate and delayed retrieval conditions (Andreasen et al., 1995) also found a biparietal activation encompassing Brodmann area 40: the left parietal peak of activation was located within 9 mm of one of the nine peaks of activation detected in our study, whereas the right parietal peak of activation was located within 8 mm of one of our two peaks of activation. This may suggest a recoding from the ventral occipitotemporofrontal pathway to the dorsal parietofrontal pathway during the night. An alternative explanation is that control sub-
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FIG. 3. Statistical parametric maps of activation during the immediate and the 24-h-delayed retrieval tasks for control subjects. FIG. 4. Statistical parametric maps of activation during the immediate and the 24-h-delayed retrieval tasks for patients with left medial temporal lobe epilepsy.
jects used different cognitive strategies during the immediate and 24-h-delayed retrievals. We also observed changes in medial temporal lobe activations with a
bilateral decrease of the parahippocampal activations and the emergence of a new right hippocampal activation. Experimental data suggest that sleep states, par-
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ticularly paradoxical sleep or rapid eye movement sleep, could contribute to the effectiveness of memory processing and facilitate memory retrieval in wakefulness (Hennevin et al., 1995). In animal studies, the hippocampal pyramidal cell activity seems specifically correlated with this memory process consolidation (Skaggs and McNaughton, 1996, 1998) and it has been proposed further that similar processes could take place in the posttraining sleep of humans (Smith, 1996). Recent neuroimaging data (Maquet et al., 2000) support this hypothesis that memory traces are processed during sleep in humans. Our results suggest a hierarchical and chronological processing involving the parahippocampal gyri during the immediate retrieval and involving the hippocampus during the 24-h-delayed retrieval. Memory Retrieval in Patients with Medial Temporal Lobe Epilepsy During 24-h-delayed retrieval, the pattern of activations in patients differed from that in controls mainly in two ways: first, they did not show mesiotemporal activation; second, they exhibited a dramatic decrease in all neocortical activations. Loss of Mesiotemporal Activation Left MTLE patients exhibited no parahippocampal or right hippocampal activations during the 24-h-delayed retrieval. This finding is in agreement with the fact that decreased parahippocampal activations had already been detected in both control subjects and LTLE patients during the immediate retrieval. However, one could have expected the persistence of a right hippocampal activation in patients with left temporal lobe epilepsy. But, this at first sight unexpected finding may be explained by the epileptic process. Functional connections exist between both hippocampal formations in humans (Nieuwenhuys et al., 1988). In medial temporal lobe epilepsy, intracranial electroencephalographic data show that the seizure discharge spreads to the contralateral medial temporal lobe structures before involving other brain areas (Gotman, 1987; Spencer et al., 1987). The propagation of the seizure spread to the contralateral hippocampus may take two anatomical ways: an anterior pathway via the orbitofrontal cortex as suggested by Lieb et al. (1991) or a posterior pathway via the dorsal hippocampal commissure or the brain stem (Lieb et al., 1987). It may be thus hypothesized that the seizure activity arising from the left hippocampus spreads to the right hippocampus and interferes with its normal function. The loss of right hippocampal activation may be interpreted as the result of the left medial temporal lobe epileptic activity, leading to a memory dysfunction.
Neocortical Activations The most surprising fact was the dramatic decrease of brain activation during the 24-h-delayed retrieval condition in epileptic patients. The complex distributed network that was activated in control subjects was reduced to a single peak of activation located in the left lingual gyrus in LTLE patients. Furthermore, the patients were also unable to stabilize the abnormal memory retrieval network which was activated during immediate retrieval since the aberrant left dorsolateral frontal cortex activation was reduced to only two peaks of activation during the 24-h-delayed retrieval. This inability to reactivate the normal and abnormal memory retrieval networks may explain the extremely poor performances of the patients at 24 h compared to controls and may be related to the epilepsy and to the hippocampal pathology. Another explanation is that the patients failed to do the task and that their poor performances reflect this failure. Anyway, in these patients with left temporal lobe epilepsy, we may suggest that the left hippocampal sclerosis combined to the right hippocampal dysfunction leads to a more global loss of the neocortical activations sustaining the memory retrieval processing. All these data suggest that medial temporal lobe structures may play a role in stabilizing and recoding overnight the neocortical networks involved in episodic verbal memory and are keys to retrieving stored information. REFERENCES Adam, C., Clemenceau, S., Semah, F., Hasboun, D., Samson, S., Aboujaoude, N., et al. 1996. Variability of presentation in medial temporal lobe epilepsy: A study of 30 operated cases. Acta Neurol. Scand. 94: 1–11. Andreasen, N. C., O’Leary, D. S., Arndt, S., Cizadlo, T., Hurtig, R., Rezai, K., et al. 1995. Short-term and long-term verbal memory: A positron emission tomography study. Proc. Natl. Acad. Sci. USA 92: 5111–5115. Brodmann, K. 1909. Vergleichende Lokalisationslehre der Grosshirnrinde in Ihren Prinzipien Dargestellt auf Grund des Zellenbaues. Barth, Leipzig. Dupont, S., Van de Moortele, P. F., Samson, S., Hasboun, D., Poline, J. B., Adam, C., et al. 2000. Episodic memory in left temporal lobe epilepsy: A functional MRI study. Brain 123: 1722–1732. Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. B., Frith, C. D., and Frackowiak, R. S. J. 1995. Statistical parametric mapping in functional imaging: A general linear approach. Hum. Brain Mapp. 2: 189 –210. Gotman, J. 1987. Interhemispheric interactions in seizures of focal onset: Data from human intracranial recordings. Electroencephalogr. Clin. Neurophysiol. 67: 120 –133. Hennevin, E., Hars, B., Maho, C., and Bloch, V. 1995. Processing of learned information in paradoxical sleep: Relevance for memory. Behav. Brain Res. 69: 125–135. Henson, R. N., Shallice, T., and Dolan, R. J. 1999. Right prefrontal cortex and episodic memory retrieval: A functional MRI test of the monitoring hypothesis. Brain 122: 1367–1381.
DELAYED MEMORY RETRIEVAL IN TEMPORAL LOBE EPILEPSY Lieb, J. P., Dasheiff, R. M., and Engel, J., Jr. 1991. Role of frontal lobes in the propagation of mesial temporal lobe seizures. Epilepsia 32: 822– 837. Lieb, R., Babb, T. L., Engel, J., Jr., and Darcey, T. 1987. Propagation pathways of interhemispheric seizure discharges in humans versus animal hippocampal epilepsy. In Fundamental Mechanisms of Human Brain Function: Opportunities for Direct Investigation in Association with the Surgical Treatment of Epilepsy (J. Engel, Jr., G. A. Ojemann, and H. O. Lu¨ders, Eds.), pp. 165–170. Raven Press, New York. Maquet, P., Laureys, S., Peigneux, P., Fuchs, S., Petiau, C., Phillips, C., et al. 2000. Experience-dependent changes in cerebral activation during human REM sleep. Nat. Neurosci. 8: 831– 836. Nieuwenhuys, R., Voogd, J., and Van Huijzen, C. 1988. The Human Central Nervous System, 3rd rev. ed. Springer-Verlag, New York/ Berlin/Heidelberg. Schacter, D. L., Buckner, R. L., Koutstaal, W., Dale, A. M., and Rosen, B. R. 1997. Late onset of anterior prefrontal activity during retrieval of veridical and illusory memories: A single trial fMRI study. NeuroImage 6: 259 –269.
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Skaggs, W. E., and McNaughton, B. L. 1996. Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science 271: 1870 –1873. Skaggs, W. E., and McNaughton, B. L. 1998. Spatial firing properties of hippocampal CA1 populations in an environment containing two visually identical regions. J. Neurosci. 18: 8455– 8466. Smith, C. 1996. Sleep states, memory processes and synaptic plasticity. Behav. Brain. Res. 78: 49 –56. Spencer, S., Williamson, P., Spencer, D., and Mattson, R. 1987. Human hippocampal seizure spread studied by depth and subdural recording: The hippocampal commissure. Epilepsia 28: 479 – 489. Squire, L. R., Ojemann, J. G., Miezin, F. M., Petersen, S. E., Videen, T. O., and Raichle, M. E. 1992. Activation of the hippocampus in normal humans: A functional anatomical study of memory. Proc. Natl. Acad. Sci. USA 89: 1837–1841. Talairach, J., and Tournoux, P. 1988. Co-planar Stereotactic Atlas of the Human Brain 3-Dimensional Proportional System: An Approach to Cerebral Imaging. Thieme, New York.
Delayed Verbal Memory Retrieval: A Functional MRI Study in Epileptic Patients with Structural Lesions of the Left Medial Temporal Lobe Sophie Dupont,* ,† ,‡ Yves Samson,† ,§ Pierre-Franc¸ois Van de Moortele,† Se´verine Samson,* Jean-Baptiste Poline,† Claude Adam,* ,‡ Ste´phane Lehe´ricy, ¶ Denis Le Bihan,† and Michel Baulac,* ,‡ *Unite´ d’Epileptologie and §Department of Urgences Ce´re´bro-vasculaires, Clinique Neurologique Paul Castaigne, ¶Department of Radiology, and ‡LENA, CNRS UPR640, Hoˆpital de la Pitie´-Salpeˆtrie`re, Paris, France; and †CEA–SHFJ, 91406 Orsay, France Received December 27, 2000
In a previous functional magnetic resonance imaging (fMRI) study, we suggested that in left medial temporal lobe epilepsy (LTLE) poor verbal episodic memory performances were sustained by abnormal neocortical and mesiotemporal activations. In the present study, we attempted to examine the evolution of these abnormal neocortical and mesiotemporal activations over 24 h. We thus observed the fMRI brain regions activated during the 24-h-delayed retrieval of a word list in the same sample of healthy control subjects and LTLE patients. In control subjects, a similar left occipitotemporofrontal network was activated during both immediate and 24-h-delayed retrieval conditions. In addition, the 24-h-delayed retrieval also activated a larger parietal region and the right hippocampus. This distributed neocortical and mesiotemporal network was very poorly activated during the 24-h-delayed retrieval in LTLE patients, suggesting the inability to reactivate areas that are keys to retrieving stored information. © 2001 Academic Press
INTRODUCTION In a previous paper (Dupont et al., 2000), we used functional magnetic resonance imaging (fMRI) to identify neocortical and mesiotemporal regions involved in encoding and immediate retrieval of a word list in control subjects and patients with left medial temporal lobe epilepsy (LTLE). In both encoding and immediate retrieval tasks, control subjects activated a distributed neocortical network mainly involving the left occipitotemporofrontal ventral cortex. Mesiotemporal activations were found only during the immediate retrieval task and were restricted to the parahippocampal gyri, with a predominant rightsided lateralization. No hippocampal activation was detected. In LTLE patients, neocortical and mesiotemporal activations were modified. Neocortical occipitotemporofrontal ventral activation was less marked than in control subjects and we noticed the
emergence of a new dramatic activation of the dorsolateral frontal cortex. Parahippocampal activation was decreased bilaterally. In this study, however, as in most retrieval studies performed during PET or fMRI experiments (Henson et al., 1999; Schacter et al., 1997; Squire et al., 1992), word retrieval was only assessed a few minutes after the encoding processing. To our knowledge, a single neuroimaging study (Andreasen et al., 1995) examined both immediate and 1-week recall of an overlearned word list in healthy normal volunteers. They found that similar regions were activated in both immediate and delayed retrieval conditions: large right frontal areas, biparietal areas, and the left cerebellum. In the present study, we planned to confirm these results in control subjects by examining the evolution of the normal cerebral networks sustaining episodic memory after a 24-h time delay. We also wanted to determine whether a similar consolidation of the cerebral activations would occur in LTLE patients. Therefore, we scanned all the subjects (control subjects and epileptic patients) with the same blocked fMRI recognition paradigm after a 24-h-delayed period including a full night of sleep. MATERIAL AND METHODS Subjects The study population included 7 patients (4 women and 3 men; median age 37 years; range 18 –53 years) with medial temporal lobe epilepsy who were undergoing presurgical evaluation for anterior temporal lobectomy at the Pitie´-Salpeˆtrie`re Epilepsy Unit. They were matched with a control group, consisting of 10 healthy volunteers (8 women and 2 men; median age 24 years; range 23–31 years). All subjects gave informed written consent in accordance with the Declaration of Helsinki, and the Local Ethics Committee approved the study. Six patients underwent presurgical evaluation (Adam et al., 1996) in-
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cluding medical, neurological, and neuropsychological examinations, video-EEG monitoring, brain MRI, FDG–PET examinations, and an intracarotid amytal test. The 7th patient underwent the same investigation, with the exception of the neuropsychological examination and the intracarotid amytal test. The inclusion criteria for our study were the following: right-handed lateralization, surface EEG recordings consistent with left-sided medial temporal lobe seizure onset, left hippocampal sclerosis diagnosed on volumetric MRI without any other structural abnormalities, and/or left temporal lobe hypometabolism on interictal FDG–PET. All patients were otherwise healthy. fMRI Procedures
Session 1 (Day 0) This block fMRI recognition paradigm has already been described in a previous paper (Dupont et al., 2000). Briefly, subjects were visually instructed to recall silently a supraspan of 17 abstract words that they had learned 20 min before. At the end of the session, subjects were tested to establish the efficiency of the retrieval of the verbal information and were asked to recall out loud the words that they had previously learned. For the first session (encoding, immediate retrieval), it was clearly explained to the subjects before and during the experiment that they had to learn and recall the words. At the end of the first session, we told the subjects that the second session would be totally different in order to avoid rehearsal of the word list between the interval.
Imaging parameters and acquisition procedures were identical to those described in a previous paper (Dupont et al., 2000). Blood oxygenation-level-dependant fMRI data were acquired on a 3-T Bruker system equipped with a prototype fast-gradient system and the standard quadrature head coil. Subjects were placed in a supine position in the MRI scanner. Their heads were immobilized with cushions to reduce motion artifact. The stimuli were projected onto a mirror located at the end of the scanner bore. Subjects were equipped with prism glasses that allowed them to see the projection in central vision without image distortion. For each subject, conventional structural images were first collected to provide detailed anatomic information. Following the acquisition of these sagittal and axial inversion recovery turbo-flash T1-weighted localizer images, gradient-echo echoplanar fMRI was performed in 22 contiguous 5-mm axial slices (repetition time 6 s, 64 ⫻ 80 matrix, 22-cm 2 field of view) covering the whole brain. The entire session, including both structural and functional sequences, lasted 45 min the first day and 50 min the following day.
fMRI data were analyzed on SPARC workstations (Sun Microsystems, Mountain View, CA). Statistical analysis was performed in MATLAB (Mathworks, Natick, MA) using a statistical parametric mapping software package (SPM96) (Friston et al., 1995).
Memory Task Procedures
Statistical Analysis
Memory tasks included verbal episodic memory retrieval tasks. The aim of the present experiment was to create two retrieval conditions that differed in relation to immediate retrieval or 24-h-delayed retrieval. Two sessions were performed on consecutive days. A sequential task-activation paradigm was employed, alternating between an experimental condition and a baseline condition. The baseline condition was the same for all the experiments and consisted of the fixation of the letter A. Scanning was performed over a 324-s block. Each block included five control and four experimental conditions beginning with the control condition. The study words were exposed for 2 s at four times alternating with the baseline condition.
For each subject, we performed a stereotaxic reorientation of the images along the bicommissural line. Images were then coregistered and resliced to correct movement and further spatially transformed to standard stereotaxic coordinates to correct for anatomical variance across subjects. The standard reference space used in SPM96 is based on the Talairach and Tournoux stereotaxic atlas (Talairach and Tournoux, 1988). The resulting images were convolved with a three-dimensional Gaussian filter to suppress noise. The data were then analyzed statistically on a voxelby-voxel basis using a two temporal basis functions model. We first performed an individual analysis for each subject and then a multisubject analysis using
Postsleep Session (Day 1) The following day, after a full night of sleep, subjects were visually instructed to recall silently the list of words that they had learned the previous day (24-hdelayed retrieval). Subjects were told that they had to recall the list that they had learned the previous day just 2 s before the functional scanning began. At the end of the session, subjects were again tested to establish the efficiency of the 24-h-delayed retrieval and were therefore asked to recall out loud the words that they had previously learned. We also checked at this time that the patients did not have seizures between the two experiments. Image Analysis
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We also conducted a two-way ANOVA (group ⫻ immediate and delayed retrievals) using retrievals as repeated measures. The results confirmed that there was a significant difference between the patients group and the control group (F ratio ⫽ 14.76; P ⫽ 0.0016) and also evidenced a significant difference between immediate and delayed retrieval (F ratio ⫽ 4.84; P ⫽ 0,0438) in the whole group (patients ⫹ controls). No interaction was found. Within-Group Comparisons of Hemodynamic Response
FIG. 1. Memory test longitudinal performances in controls and patients.
a similar method. Since our aim was to investigate the global changes in neocortical activations in relation to the hippocampal damage, we focused our study on the group analysis. For this multisubject analysis, a given voxel was considered to be significantly activated if, on comparison with a reference task, there was an increase in the hemodynamic response function at P ⬍ 0.0001 (P ⬍ 0.01 corrected for multiple comparison). These values correspond to Z scores of 3.72 and above in this study. A region was considered to be activated if a spatially contiguous set of voxels were all independently significant at a level of P ⬍ 0.003. RESULTS Memory Test Performance As expected, the retrieval performances of the control subjects were broadly similar over 24 h. Control subjects recalled 9.9 ⫾ 4.3 words (mean ⫾ SD) (median 11 words, range 2–16 words) during the 24-h-delayed retrieval and 10.3 ⫾ 4.4 words (median 11 words, range 2–16 words) during the immediate retrieval experimental condition.. The difference between the two retrievals in the two separate groups was not statistically significant. LTLE patients’ retrieval performances tended to decrease after the 24-h-delayed period but the difference did not reach significance (2.4 ⫾ 3.6 words during the 24-h-delayed retrieval (median 1 word, range 0 –10 words) versus 3.1 ⫾ 2.5 words recalled during the immediate retrieval (median 2 words, range 1– 8 words)) (see Fig 1). As expected, LTLE patients’ performances were significantly worse than those of control subjects during both immediate and 24-h-delayed retrieval (P ⬍ 0.0007 and P ⬍ 0.0014, respectively).
Tables 1 and 2 indicate the coordinates of the areas of significant activation (P ⬍ 0.0001, corrected for multiple comparison) during immediate and 24-h-delayed retrievals for both hemispheres in control subjects and LTLE patients. A peak of activation consists of voxels that survived a voxel-wise multiple-comparison correction of P ⬍ 0.001 (Z ⬎ 3.72) using a two basis function model. For each comparison, we tested the following thresholds: height threshold P ⬍ 0.05, P ⬍ 0.01, P ⬍ 0.0001; and extent threshold P ⫽ 0.000, P ⫽ 0.000, P ⫽ 0.013 (P corrected ⬍ 0.05) and found similar results. Control Subjects Activation Minus Baseline Hippocampal and parahippocampal activations. As shown in Table 2, a robust hippocampal activation (coordinates 24, ⫺39, 3; Z ⫽ 7.12) was detected in the posterior part of the right hippocampus (see Fig. 2). A left parahippocampal activation was also seen during the 24-h-delayed retrieval. This activation was located within 6 mm of one of the two peaks of activation detected during the immediate retrieval. Similarly, right parahippocampal activation very close to those found during the immediate retrieval was observed during the 24-h-delayed retrieval. But there again, a single peak was detected during the 24-h-delayed retrieval while four peaks were detected during the immediate retrieval. Neocortical activations. Figure 3 shows the SPM cortical activation maps during the two retrieval tasks for the 10 healthy volunteers. The network of neocortical regions activated during the 24-h-delayed retrieval shared similarity with the one activated during the immediate retrieval, including the following regions: the left occipital cortex, the lingual gyrus, the left lateral parietal cortex (Brodmann’s areas 7 and 40), the left superior temporal gyrus (Brodmann’s area 22), and the ventrolateral frontal cortex (Brodmann’s areas 44 and 45) bilaterally. However, there were notable differences. There was a dramatic decrease in the occipitotemporofrontal activations in terms of number of activation peaks and Z scores (see Table 1): only two peaks of activation were seen during the 24-h-delayed
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TABLE 1 Activation Foci in Normal Control Subjects and Epileptic Patients during Immediate and 24-h-Delayed Retrieval Tests (Stereotaxic Coordinates Are Expressed in mm) (Left Hemisphere) Controls Immediate retrieval Region Occipital cx Primary occipital cortex Occipitotemporal cx (BA 37/41/42) Fusiform gyrus Lingual gyrus Parietal cx (BA 40/7)
Superior temporal cx (BA 22)
Frontal cx Ventrolateral frontal cortex (BA 44/45)
LTLE patients 24-h-delayed retrieval
Immediate retrieval
24-h-delayed retrieval
x
y
z
Z value
x
y
z
Z value
x
y
z
Z value
⫺18 ⫺18 ⫺42 ⫺51 ⫺45 ⫺30
⫺78 ⫺66 ⫺60 ⫺27 ⫺24 ⫺54
15 21 6 15 3 0
5.28 4.74 4.77 4.83 5.1 7.18
⫺18
⫺78
18
6.58
⫺12
⫺66
15
6.61
4.87 7.01
⫺57
6
7.77
⫺12 ⫺51 ⫺42 ⫺39 ⫺33 ⫺33 30 ⫺30
⫺57 ⫺36 ⫺36 ⫺36 ⫺51 ⫺60 ⫺33 ⫺45
⫺54 ⫺54
3 3
⫺12
⫺30 ⫺21 3 27 36 45 48 48 48 42
7.46 4.29 4.40 6.24 7.34 7.61 5.03 6.68
⫺36 ⫺45
⫺45 ⫺66
42 24
5.02 7.18
⫺45
5.57
⫺33
⫺63
21
⫺57
9
5.95 ⫺57 ⫺54 ⫺39 ⫺42 ⫺45
15 21 21 36 51
15 3 9 0 12
6.78 5.72 5.16 4.55 5.07
⫺57 ⫺51 ⫺48 ⫺48 ⫺39 ⫺48 ⫺42 ⫺51 ⫺45
27 30 33 45 51 18 6 9 33
24 30 21 18 24 30 30 36 36
4.73 5.84 5.32 5.03 3.96 6.69 6.27 4.78 5.50
⫺9 ⫺3 ⫺18
18 6 ⫺45
45 66 3
5.32 7.57 4.81
⫺30 ⫺36
⫺63 ⫺39
48 48
6.23 5.21
⫺66 ⫺63 ⫺57 ⫺45 ⫺54 ⫺42 ⫺42 ⫺48 ⫺45 ⫺42
⫺33 ⫺36 ⫺33 ⫺45 24 18 27 12 21 9
9 18 6 18 6 3 3 21 18 30
6.04 4.66 6.69 8.08 4.8 5.87 6.62 7.11 6.09 5.95
⫺45 ⫺39
21 24
21 12
5.31 7.29
Dorsolateral frontal cortex
Cingulate cortex Anterior (BA 32) Posterior (BA) Medial frontal cx (BA 6/8)
⫺21 ⫺15
Mesiotemporal Parahippocampal gyrus
⫺12 ⫺33
36 30
⫺48 ⫺39
18 15
⫺6 ⫺6
x
y
z
Z value
⫺9
⫺60
6
5.20
⫺51 ⫺42
18 12
36 39
5.70 4.00
⫺12 ⫺3 ⫺3
⫺66 6 15
15 69 60
7.50 5.30 7.30
4.22 4.37
7.56 6.73
⫺15
⫺42
retrieval in the left occipital cortex versus seven during the immediate retrieval, one peak versus five peaks were found in the left superior temporal cortex during respectively 24-h-delayed and immediate retrievals, and finally two peaks versus six peaks were found in the left ventrolateral frontal cortex. Conversely, there was an apparent increase in the spatial extent of the activated left parietal cortex (Brodmann’s areas 7 and 40, seven peaks during the 24-h-delayed retrieval versus two peaks during the immediate retrieval), with the emergence of a new sym-
0
4.74
metrical activation, although less extensive, in the contralateral parietal region. Immediate versus Delayed Retrieval The direct comparison between immediate and delayed retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) confirmed the clear decrease in the 24-h-delayed retrieval activations located in the left temporal and ventrolateral frontal regions (see Fig. 3).
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TABLE 2 Activation Foci in Normal Control Subjects and Epileptic Patients during Immediate and 24-h-Delayed Retrieval Tests (Stereotaxic Coordinates Are Expressed in mm) (Right Hemisphere) Controls Immediate retrieval Region Occipital cortex Primary occipital cortex Occipitotemporal cx (BA 37/41/42) Fusiform gyrus Lingual gyrus
x
y
6 15
⫺60 ⫺60
z
3 0
24-h-delayed retrieval
Z value
54 39
18 27
15 9
x
y
z
Z value
7.58 4.52
Parietal cortex (BA 40/7) Superior temporal cortex (BA 22) Frontal cortex Ventrolateral frontal cortex (BA 44/45) Dorsolateral frontal cx (BA 9/10/46)
LTLE patients
6.01 7.72
42 36 36
⫺39 ⫺39 ⫺24
36 45 6
5.12 5.98 7.14
51 39
24 27
6 9
5.96 7.59
Posterior cingulum (BA 23/30/31) Medial cortex (BA 6/8) Mesiotemporal cortex Parahippocampal gyrus
12 27 21 24
Hippocampus
⫺42 ⫺45 ⫺42 ⫺54
3 ⫺3 3 3
5.81 7.72 6.66 7.31
15
⫺42
3
7.36
24
⫺39
3
7.12
Immediate retrieval
24-h-delayed retrieval
x
y
z
Z value
3
⫺60
6
5.80
36 45 48 9 24 3 6
24 21 0 ⫺60 ⫺60 30 18
36 42 39 6 15 51 48
4.58 6.63 6.10 7.84 7.38 5.44 6.86
21 27
⫺45 ⫺54
3 3
6.34 6.49
x
y
z
Z value
Note. Areas are named after Brodmann (Brodmann, 1909), coordinates are according to the atlas of Talairach and Tournoux (Talairach and Tournoux, 1988). Immediate retrieval data have been previously reported (Dupont et al., 2000).
Delayed versus Immediate Retrieval The direct comparison between delayed and immediate retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) clearly confirmed the increase of the parietal activation depicted during the delayed retrieval condition. LTLE Patients Activation Minus Baseline The most striking finding was the reduction of the number of overall cerebral peaks of activation (7 peaks of activation in LTLE patients versus 20 peaks of activation in control subjects). Hippocampal and parahippocampal activations. No activation was detected (see Fig. 2). Neocortical activations. Figure 4 shows the SPM cortical activation maps during the two retrieval tasks for the seven MTLE patients. The single peak of activation that was similar to those found in control subjects was located in the left lingual gyrus. All the other areas detected in LTLE patients during the
24-h-delayed retrieval were not activated in control subjects. These areas included the left dorsolateral frontal cortex, the left medial frontal cortex (supplementary motor area), the right lingual gyrus, and the left posterior cingulate cortex. A broadly similar left dorsolateral and medial frontal activation was detected during the immediate retrieval in LTLE patients but the activation located within the dorsolateral cortex was much more extensive during the immediate retrieval condition (nine peaks of activation) than during the 24-h-delayed retrieval (two peaks of activation). Immediate versus Delayed Retrieval The direct comparison between immediate and delayed retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) confirmed that the network of left neocortical regions activated during the immediate retrieval condition was significantly more activated during the immediate retrieval than during the delayed retrieval.
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FIG. 2. Mesiotemporal activations during the immediate and 24-h-delayed retrieval task in a control subject and a patient with left medial temporal lobe epilepsy showing (A) a consistent bilateral parahippocampal activation in control subjects during immediate retrieval, (B) a right parahippocampal activation in LTLE patients during immediate retrieval, (C) a right posterior hippocampal activation located in the hippocampus tail in control subjects during delayed retrieval, and (D) the absence of hippocampal or parahippocampal activations in LTLE patients during delayed retrieval.
Delayed versus Immediate Retrieval The direct comparison between delayed and immediate retrieval (P ⬍ 0.01, P corrected ⬍ 0.01) clearly confirmed the dramatic decrease of the neocortical, hippocampal, and parahippocampal activations depicted during the delayed retrieval condition. DISCUSSION This study provides two major findings: first the evidence of a 24-h-delayed memory retrieval sustained by complex distributed neocortical and mesiotemporal networks in normal controls subjects and second the evidence of an alteration of these mesiotemporal and neocortical networks during episodic memory in left medial temporal lobe epilepsy. Memory Retrieval in Normal Subjects The 24-h-delayed retrieval condition was characterized by the reactivation of brain areas that had already been activated during the immediate retrieval condition and by the modification of the medial temporal lobe activations with the emergence of a new activation encompassing the right posterior hippocampus and a dramatic decrease of the parahippocampal activations.
As we noted a memory performance stabilization in the second session, we may hypothesize that these cerebral regions are involved in delayed memory retrieval. These delayed memory retrieval processes seem linked to the reactivation of a left cerebral network that had been previously activated during the immediate retrieval task. Interestingly, the location of the occipitotemporal and ventrolateral frontal regions activated during the immediate and the 24-h-delayed retrievals were very close, with, however, a clear decrease in the 24-h-delayed retrieval activations in terms of number of peaks and Z scores. The dramatic increase of the parietal cortex activation and its bilateralization was much more surprising. The role of the posterior association cortex in memory processes is not well known. Interestingly, the only study that also examined immediate and delayed retrieval conditions (Andreasen et al., 1995) also found a biparietal activation encompassing Brodmann area 40: the left parietal peak of activation was located within 9 mm of one of the nine peaks of activation detected in our study, whereas the right parietal peak of activation was located within 8 mm of one of our two peaks of activation. This may suggest a recoding from the ventral occipitotemporofrontal pathway to the dorsal parietofrontal pathway during the night. An alternative explanation is that control sub-
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FIG. 3. Statistical parametric maps of activation during the immediate and the 24-h-delayed retrieval tasks for control subjects. FIG. 4. Statistical parametric maps of activation during the immediate and the 24-h-delayed retrieval tasks for patients with left medial temporal lobe epilepsy.
jects used different cognitive strategies during the immediate and 24-h-delayed retrievals. We also observed changes in medial temporal lobe activations with a
bilateral decrease of the parahippocampal activations and the emergence of a new right hippocampal activation. Experimental data suggest that sleep states, par-
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ticularly paradoxical sleep or rapid eye movement sleep, could contribute to the effectiveness of memory processing and facilitate memory retrieval in wakefulness (Hennevin et al., 1995). In animal studies, the hippocampal pyramidal cell activity seems specifically correlated with this memory process consolidation (Skaggs and McNaughton, 1996, 1998) and it has been proposed further that similar processes could take place in the posttraining sleep of humans (Smith, 1996). Recent neuroimaging data (Maquet et al., 2000) support this hypothesis that memory traces are processed during sleep in humans. Our results suggest a hierarchical and chronological processing involving the parahippocampal gyri during the immediate retrieval and involving the hippocampus during the 24-h-delayed retrieval. Memory Retrieval in Patients with Medial Temporal Lobe Epilepsy During 24-h-delayed retrieval, the pattern of activations in patients differed from that in controls mainly in two ways: first, they did not show mesiotemporal activation; second, they exhibited a dramatic decrease in all neocortical activations. Loss of Mesiotemporal Activation Left MTLE patients exhibited no parahippocampal or right hippocampal activations during the 24-h-delayed retrieval. This finding is in agreement with the fact that decreased parahippocampal activations had already been detected in both control subjects and LTLE patients during the immediate retrieval. However, one could have expected the persistence of a right hippocampal activation in patients with left temporal lobe epilepsy. But, this at first sight unexpected finding may be explained by the epileptic process. Functional connections exist between both hippocampal formations in humans (Nieuwenhuys et al., 1988). In medial temporal lobe epilepsy, intracranial electroencephalographic data show that the seizure discharge spreads to the contralateral medial temporal lobe structures before involving other brain areas (Gotman, 1987; Spencer et al., 1987). The propagation of the seizure spread to the contralateral hippocampus may take two anatomical ways: an anterior pathway via the orbitofrontal cortex as suggested by Lieb et al. (1991) or a posterior pathway via the dorsal hippocampal commissure or the brain stem (Lieb et al., 1987). It may be thus hypothesized that the seizure activity arising from the left hippocampus spreads to the right hippocampus and interferes with its normal function. The loss of right hippocampal activation may be interpreted as the result of the left medial temporal lobe epileptic activity, leading to a memory dysfunction.
Neocortical Activations The most surprising fact was the dramatic decrease of brain activation during the 24-h-delayed retrieval condition in epileptic patients. The complex distributed network that was activated in control subjects was reduced to a single peak of activation located in the left lingual gyrus in LTLE patients. Furthermore, the patients were also unable to stabilize the abnormal memory retrieval network which was activated during immediate retrieval since the aberrant left dorsolateral frontal cortex activation was reduced to only two peaks of activation during the 24-h-delayed retrieval. This inability to reactivate the normal and abnormal memory retrieval networks may explain the extremely poor performances of the patients at 24 h compared to controls and may be related to the epilepsy and to the hippocampal pathology. Another explanation is that the patients failed to do the task and that their poor performances reflect this failure. Anyway, in these patients with left temporal lobe epilepsy, we may suggest that the left hippocampal sclerosis combined to the right hippocampal dysfunction leads to a more global loss of the neocortical activations sustaining the memory retrieval processing. All these data suggest that medial temporal lobe structures may play a role in stabilizing and recoding overnight the neocortical networks involved in episodic verbal memory and are keys to retrieving stored information. REFERENCES Adam, C., Clemenceau, S., Semah, F., Hasboun, D., Samson, S., Aboujaoude, N., et al. 1996. Variability of presentation in medial temporal lobe epilepsy: A study of 30 operated cases. Acta Neurol. Scand. 94: 1–11. Andreasen, N. C., O’Leary, D. S., Arndt, S., Cizadlo, T., Hurtig, R., Rezai, K., et al. 1995. Short-term and long-term verbal memory: A positron emission tomography study. Proc. Natl. Acad. Sci. USA 92: 5111–5115. Brodmann, K. 1909. Vergleichende Lokalisationslehre der Grosshirnrinde in Ihren Prinzipien Dargestellt auf Grund des Zellenbaues. Barth, Leipzig. Dupont, S., Van de Moortele, P. F., Samson, S., Hasboun, D., Poline, J. B., Adam, C., et al. 2000. Episodic memory in left temporal lobe epilepsy: A functional MRI study. Brain 123: 1722–1732. Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. B., Frith, C. D., and Frackowiak, R. S. J. 1995. Statistical parametric mapping in functional imaging: A general linear approach. Hum. Brain Mapp. 2: 189 –210. Gotman, J. 1987. Interhemispheric interactions in seizures of focal onset: Data from human intracranial recordings. Electroencephalogr. Clin. Neurophysiol. 67: 120 –133. Hennevin, E., Hars, B., Maho, C., and Bloch, V. 1995. Processing of learned information in paradoxical sleep: Relevance for memory. Behav. Brain Res. 69: 125–135. Henson, R. N., Shallice, T., and Dolan, R. J. 1999. Right prefrontal cortex and episodic memory retrieval: A functional MRI test of the monitoring hypothesis. Brain 122: 1367–1381.
DELAYED MEMORY RETRIEVAL IN TEMPORAL LOBE EPILEPSY Lieb, J. P., Dasheiff, R. M., and Engel, J., Jr. 1991. Role of frontal lobes in the propagation of mesial temporal lobe seizures. Epilepsia 32: 822– 837. Lieb, R., Babb, T. L., Engel, J., Jr., and Darcey, T. 1987. Propagation pathways of interhemispheric seizure discharges in humans versus animal hippocampal epilepsy. In Fundamental Mechanisms of Human Brain Function: Opportunities for Direct Investigation in Association with the Surgical Treatment of Epilepsy (J. Engel, Jr., G. A. Ojemann, and H. O. Lu¨ders, Eds.), pp. 165–170. Raven Press, New York. Maquet, P., Laureys, S., Peigneux, P., Fuchs, S., Petiau, C., Phillips, C., et al. 2000. Experience-dependent changes in cerebral activation during human REM sleep. Nat. Neurosci. 8: 831– 836. Nieuwenhuys, R., Voogd, J., and Van Huijzen, C. 1988. The Human Central Nervous System, 3rd rev. ed. Springer-Verlag, New York/ Berlin/Heidelberg. Schacter, D. L., Buckner, R. L., Koutstaal, W., Dale, A. M., and Rosen, B. R. 1997. Late onset of anterior prefrontal activity during retrieval of veridical and illusory memories: A single trial fMRI study. NeuroImage 6: 259 –269.
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Skaggs, W. E., and McNaughton, B. L. 1996. Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science 271: 1870 –1873. Skaggs, W. E., and McNaughton, B. L. 1998. Spatial firing properties of hippocampal CA1 populations in an environment containing two visually identical regions. J. Neurosci. 18: 8455– 8466. Smith, C. 1996. Sleep states, memory processes and synaptic plasticity. Behav. Brain. Res. 78: 49 –56. Spencer, S., Williamson, P., Spencer, D., and Mattson, R. 1987. Human hippocampal seizure spread studied by depth and subdural recording: The hippocampal commissure. Epilepsia 28: 479 – 489. Squire, L. R., Ojemann, J. G., Miezin, F. M., Petersen, S. E., Videen, T. O., and Raichle, M. E. 1992. Activation of the hippocampus in normal humans: A functional anatomical study of memory. Proc. Natl. Acad. Sci. USA 89: 1837–1841. Talairach, J., and Tournoux, P. 1988. Co-planar Stereotactic Atlas of the Human Brain 3-Dimensional Proportional System: An Approach to Cerebral Imaging. Thieme, New York.