Abstract
Objective: To identify clinical factors contributing to the lateralization of mesiotemporal memory functions in epilepsy by using memory-activated fMRI.
Methods: Sixty patients aged 16 to 63 years with mesial temporal lobe epilepsy (MTLE) and 20 patients aged 16 to 60 years with extratemporal epilepsy (ETE) due to circumscribed epileptogenic lesions who consecutively underwent presurgical evaluation including continuous video-EEG monitoring and structural MRI examinations were examined. During memory fMRI, the activation condition consisted of retrieval from long-term memory induced by self-paced performance of an imaginative walk through the patient’s hometown. On the basis of a previous study, memory lateralization was defined as typical if larger fMRI activation was in the mesiotemporal structures contralateral to the epileptic focus.
Results: There were 45 patients with MTLE who had typical memory lateralization (75%), whereas only 9 patients (45%) with ETE exhibited typical memory lateralization (p = 0.013). In MTLE patients, bilateral independent epileptiform discharges occurred more often in the atypical group than in patients with typical memory lateralization (p = 0.015).
Conclusions: The fMRI lateralization of mesiotemporal visuospatial memory functions in patients with mesiotemporal lobe epilepsy (MTLE) is asymmetric: The larger activation usually appears contralateral to the side of the epileptogenic region. These findings occur more often in MTLE; in patients with extratemporal epilepsy, such type of asymmetry is not characteristic. In MTLE patients with bilateral independent epileptiform discharges, this type of asymmetry is also less frequent.
Recently, fMRI has been used to visualize activation of the mesiotemporal structures implicated in memory function.1–5⇓⇓⇓⇓ Aiming to replace the invasive Wada Test in predicting postoperative memory loss prior to epilepsy surgery, only preliminary memory fMRI studies have been published, dealing with 10 to 30 patients.1–5⇓⇓⇓⇓
Visuospatial memory learning and retrieval are confined to mesiotemporal structures.6 Our previous study found that activation of the mesiotemporal structures during visuospatial memory retrieval was symmetric in healthy people and asymmetric in temporal lobe epilepsy (TLE): Activation of the mesiotemporal structures ipsilateral to the epileptogenic region was usually diminished.2 This fMRI study uses the same paradigm as in our previous work2 and aims to investigate which clinical data are implicated in the asymmetric distribution of fMRI activity.
Our working hypotheses are that 1) asymmetric participation of mesiotemporal structures in memory fMRI activation is a result of a dysfunction ipsilateral to the epileptogenic region, 2) an extratemporal epileptogenic region does not cause asymmetric memory lateralization of the mesiotemporal structures, and 3) bilateral epileptic activity may also disturb the memory fMRI activation on the side contralateral to the epileptogenic region.
For these reasons, we chose 80 patients with mesiotemporal and extratemporal epilepsy and investigated the following variables that may theoretically be responsible for the inducement of impairment of mesiotemporal memory function. We assumed that longer duration of epilepsy and frequent seizures or spikes impair ipsilateral memory functions. According to our working hypothesis, generalized seizures, bilateral interictal epileptiform discharges (IEDs), and nonlateralized seizure activity may theoretically also contribute to memory function disturbances of mesiotemporal structures contralateral to the epileptogenic region.
Methods.
Subjects.
We included 60 patients with mesial TLE (MTLE) and 20 patients with extratemporal epilepsy (ETE) due to circumscribed epileptogenic lesions (all older than 16 years), who consecutively underwent our adult presurgical evaluation program including continuous video-EEG monitoring and who had structural and memory-activated fMRI examinations between January 2001 and July 2002 at the Bethel Epilepsy Center. Patients from our previous fMRI study2 were not included. General data and clinical history (onset and duration of epilepsy, presence of generalized tonic-clonic seizures, seizure frequency) were derived from medical records registered at admission to our in-patient department before beginning video-EEG monitoring.
Structural MRI investigations.
MRI scanning was performed on a 1.5 T Siemens Magnetom Symphony (Erlangen, Germany) equipped with ultra gradients, a standard head coil, and vacuum cushions to reduce patient movement. The MR investigation for epilepsy consisted of coronal and axial fluid-attenuated inversion recovery (FLAIR) data sets (repetition time [TR] = 9,000 milliseconds, echo time [TE] = 110 milliseconds, inversion time = 2,500 milliseconds, slice thickness = 5 mm, field of view [FOV] = 201 × 230, matrix = 220 × 256), coronal proton density and T2-weighted images (TR = 3,075 milliseconds, TE = 14/85 milliseconds, slice thickness = 5 mm, FOV = 201 × 230, matrix = 210 × 256), axial T2-weighted images (TR = 5,401 milliseconds, TE = 90 milliseconds, slice thickness = 5 mm, FOV = 230 × 230, matrix = 270 × 512), and T1-weighted coronal three-dimensional sequence (MPRAGE; TR = 11.1 milliseconds, TE = 4.3 milliseconds, slice thickness = 1.5 mm, FOV = 201 × 230 mm, matrix = 224 × 256).
FMRI acquisition.
Scout T1-weighted images were obtained in every subject prior to fMRI to position the T2*-weighted images with slice orientations coronal and perpendicular to the long axis of the hippocampus.2 For fMRI, 16 contiguous coronal T2*-weighted images covering the temporal lobe with a slice thickness of 4 mm were obtained using a standard echo planar imaging (EPI) sequence (TR = 1,600 milliseconds, TE = 50 milliseconds, FOV = 192 mm, matrix = 64 × 64). Two hundred scans were acquired over a 10-minute period, covering a blocked design of alternating 30 seconds of activation vs 30 seconds of reference condition.
Activation paradigm.
The activation condition during the memory fMRI consisted of covert retrieval from long-term memory induced by the self-paced performance of Roland’s Hometown Walking Task, an imaginative walk through the patient’s hometown.2,7⇓ The paradigm consisted of 10 activation blocks and 10 baseline blocks. Each block was introduced by spoken commands using built-in communication devices. The duration of each block was 30 seconds. During each block, 10 sets of 16 coronal T2*-weighted MR slices were obtained. During the activation block, retrieval from long-term memory without language was induced. For each subject, an individual hometown walk encompassing 10 destinations was prepared. The walk started either at home or at a well-known central point (e.g., main station). The subjects were asked to select a familiar landmark as the destination. This landmark served as the starting point for the next part of the walk to the next destination. After preparation of 10 pairs of starting points and destinations, the complete route was presented to the subject to ensure the consistency and comprehension of the words denoting the route. Subjects were asked to mentally navigate through the 10 different routes and to imagine as many details as possible while navigating. Subjects were instructed to imaginatively look around the destination before beginning the baseline condition. After 30 seconds, each route was interrupted by a baseline task. The baseline condition consisted of covertly counting odd numbers. For more details, see our previous work.2
Image analysis.
For fMRI, on-line image processing was performed using software provided with the commercially available scanner that is used routinely for fMRI language lateralization8 and has recently been compared with standard off-line postprocessing software (SPM 99; Mathworks, Newton, MA).9 The T2*-weighted images were corrected for subject movement using an algorithm for realignment in k-space. Images were smoothed using a Gaussian filter (width 2.0) to prepare statistical comparisons on a voxel-by-voxel basis. Voxel-by-voxel z tests were performed for each subject, identifying average signal intensity increases as measured during the activation phases compared with the average signal intensity acquired during reference conditions. The statistical threshold chosen was z > 4. Statistical maps showing activated voxels were projected onto EPI images of the same patient, thus using images for display purposes with geometric distortions similar to the fMRI data. To perform group data analysis, two investigators blinded to clinical data counted the voxels in a predefined region of interest over both mesiotemporal areas. Counting used the crus fornix as the posterior starting point and continued anteriorly until no activated voxels were found. Activated voxels were defined as those voxels that had neighboring activated voxels. More methodologic details are presented in our previous work.2
Noninvasive continuous video-EEG monitoring.
All patients underwent continuous video-EEG monitoring lasting 1 to 7 days as part of their presurgical evaluation. At least 1 night of sleep and 1 (sleepless) day were required. However, the sleep and awake states were not investigated separately in this study. Thirty-two- to 64-channel EEG recordings were used. Electrodes were placed according to the 10–10 System; the number of electrodes and their placement varied individually corresponding to the suspected epileptogenic region and side. The interictal EEG samples were automatically recorded and stored on computer. In this study, the first 2 minutes of each computer-recorded hour was reviewed and evaluated by visual inspections. Ictal EEG data were recorded in files separate from the interictal files. Only definitive IED (spikes or sharp waves) were evaluated; background abnormalities or pathologic slow waves were not considered in this study. Bilateral IEDs were defined if at least one interictal discharge appeared independently over each of the temporal lobes.
Statistical methods.
For statistical analysis, Mann-Whitney, χ2, and Fisher exact tests were carried out. For multivariate analysis, we performed a stepwise logistic regression for all variables.
Categorization of patients according to lateralization of memory.
On the basis of our previous study, we defined the memory lateralization as typical if the larger memory activation was in the mesiotemporal structures contralateral to the epileptic focus. In that study, we were able to categorize the patients according to the activated voxel distribution within the right vs left mesiotemporal regions using the following discriminant function2: Ci = −0.522 + 0.088Xi, left − 0.085Xi, right, where X = number of activated voxels. In that study, we found that Ci < 0 was typical of left-sided epilepsy and Ci > 0 right-sided epilepsy.2 Thus, for further evaluation, we divided the patients into two groups: 1) patients with typical memory lateralization (patients with right-sided epileptic focus in whom Ci > 0 and patients with left-sided epileptic focus in whom Ci < 0); and 2) patients with atypical memory lateralization (patients with right-sided epileptic focus in whom Ci ≤ 0 and patients with left-sided epileptic focus in whom Ci ≥ 0). Additionally, we calculated an individual asymmetry index (AI) for the mesiotemporal memory activation as used in earlier works studying cognitive fMRI10: AI = (activated voxels on left − activated voxels on right)/all activated voxels.
If the AI was greater than 0.2 in left-sided patients or less than −0.2 in right-sided MTLE, we categorized these cases as lateralized memory representation ipsilateral to the epileptogenic region. The ±0.2 threshold for the definition of a lateralized fMRI activation during cognitive tasks was based on a language-activated fMRI study.10
Results.
Sixty patients (27 men) with MTLE were aged 16 to 63 years (mean 35 ± 12 years). Structural MRI showed hippocampal sclerosis in 44, benign tumors in 14 patients, focal cortical dysplasia in 1, and cavernoma in another patient, localized in the mesiotemporal region. There were 32 patients with left-sided and 28 patients with right-sided epilepsy.
Twenty patients (12 men) with ETE were aged 16 to 60 years (mean 30.9 ± 12 years). Fourteen patients had frontal lobe epilepsy and six parieto-occipital lobe epilepsy. There were five patients with malformations of cortical development, five patients with benign tumors, three patients with posttraumatic lesions, three patients with cavernoma, and four patients with other structural abnormalities on MRI. There were 13 patients with left-sided and 7 patients with right-sided epilepsy.
Of 60 patients with MTLE, there were 45 who had typical fMRI memory lateralization (75%), whereas only 9 patients (45%) with ETE had typical memory lateralization (figure 1). The difference between ETE and MTLE patients was significant (p = 0.013). For further analysis of factors contributing to typical memory lateralization, we included only the MTLE patients (table).
Figure 1. Scatterplot of individual patients with number of activated voxels. Filled squares = patients with right-sided epilepsy; open squares = patients with left-sided epilepsy. The line represents the discriminant function from our earlier work.2 In extratemporal cases (A), the discriminant function line did not discriminate the right- from the left-sided groups. Conversely, in mesiotemporal lobe epilepsy (MTLE) (B), there were more patients with contralateral memory representation (patients with right-sided MTLE are represented on the left side of the discriminant function line and patients with left-sided MTLE on the right side of the line).
Table Comparison of patients with typical vs atypical memory lateralization in patients with MTLE
In MTLE patients, there were no significant differences in the typical vs atypical memory groups regarding age at epilepsy onset, duration of epilepsy, seizure and spike frequencies, or presence of generalized tonic-clonic seizures. Conversely, bilateral independent epileptiform discharges were found more often in the atypical group than in patients with typical memory lateralization. The stepwise logistic regression, which included all the factors presented in the table, confirmed that the presence of bilateral IEDs was associated with an atypical memory lateralization, whereas the other factors were not. The odds ratio (OR) for atypical memory lateralization in patients with bitemporal IEDs was 4.43 (95% CI 1.3 to 15.4). To further confirm our results, we demonstrated that patients who had lateralized memory representation ipsilateral to the epileptogenic region more often had bilateral IEDs (figure 2).
Figure 2. Patients with mesiotemporal lobe epilepsy (MTLE) who had lateralized memory representation ipsilateral to the epileptogenic region (such as asymmetric index was greater than 0.2 in left-sided patients or less than −0.2 in right-sided MTLE) had more often bilateral interictal epileptiform discharges (IEDs) (p = 0.03). Black areas = patients with bitemporal IEDs; white areas = patients with unitemporal IEDs.
Discussion.
Our main findings are as follows: 1) The lateralization of the mesiotemporal visuospatial memory functions in MTLE patients is asymmetric: The larger activation usually appears contralateral to the side of the epileptogenic region, confirming our previous preliminary results2 in a large series of patients; 2) these findings occur more often in MTLE than in ETE; 3) in MTLE patients with bilateral independent epileptiform discharges, such type of asymmetry also occurred significantly less frequently; 4) the lateralization of memory was independent of the age at epilepsy onset, duration of epilepsy, seizure and spike frequencies, generalized seizures, and nonlateralized EEG seizure pattern.
Some methodologic considerations should be addressed regarding the categorization of patients into typical vs atypical groups. In our previous study, we identified a discriminant function2 that allowed us to categorize the side of TLE considering the number of right vs left mesiotemporal activated voxels. However, some patients were miscategorized.2 From this, we expected there to be factors influencing memory lateralization other than the side of seizure onset. Consequently, the current study compared the typically vs atypically categorized patients. We used the discriminant function derived from our previous study in a different patient sample and found that the main factor besides the localization of the lesion was bilateral epileptiform activity.
Memory impairment in focal epilepsy may be a result of underlying pathology and functional disturbance caused by epileptiform activity.11,12⇓ The influence of these two factors on memory impairment is also supported by our findings.
The assessment of memory problems in patients with epilepsy is highly dependent on the tests used.11 Conventional neuropsychological tests used during presurgical evaluation of patients with epilepsy usually measure retention of memory after 30 to 90 minutes.11 During the Wada Test, the interval between encoding and retrieval is even smaller.9 However, the consolidation of memory traces may not be complete after such short periods. Recent studies provide evidence that mesiotemporal lobe structures are critically involved for a period of several hours to weeks in memory consolidation that requires new protein synthesis and gene expression.13 Patients with TLE, even if they have no disturbed retention on conventional neuropsychological tests, showed an apparent deficit on recall 8 weeks after learning (i.e., they had an accelerated forgetting).14 It is reasonable to assume that seizures or interictal spikes are one of the causes for this disturbed long-term consolidation process. However, during conventional neuropsychological testing, usually no seizures occur (if they do, the test is usually interrupted and repeated later). Moreover, the interictal IED activity rate is also low owing to the higher vigilance level during testing.15 Our fMRI paradigm used for activating the mesiotemporal memory areas consists of retrieval from long-term memory induced by the self-paced performance of Roland’s Hometown Walking Task, an imaginative walk through the patient’s hometown.2,7⇓ This task is much closer to the patients’ everyday practical use of their memory than conventional neuropsychological tests and the Wada procedure. The retrieval process required to perform Roland’s Hometown Walking Task uses memory traces consolidated several years before the test situation, which may be much more sensitive to the long-term memory consolidation than the usual neuropsychological tests. We may assume that the brain representation and reorganization of memory functions recruited by this task will be affected by seizures or interictal epileptiform activity. A major shortcoming of this covert task is that it provides no performance measure.
Experimentally evoked repeated seizures induce a long-term spatial memory deficit in rats.16,17⇓ Some data concerning human epilepsy suggest that seizures have short-term and probably also long-term effects on human memory functions.18,19⇓ In a prospective study, we tested patients with intractable TLE by giving them verbal memory tasks every 24 hours during video-EEG monitoring. The retrieval performance was tested 30 minutes and 24 hours after the initial learning phase. Patients who had left-sided seizures between the initial learning phase and the 24-hour retrieval had significantly impaired performance.20
In patients with bilateral epileptiform (ictal or interictal) activity, the Wada Test does not lateralize the epileptogenic region.21 Patients who forget their auras usually have bilateral seizure activity; thus, we can suppose that bilateral epileptiform activity impairs memory production not only ipsilateral but also contralateral to the seizure onset.22
In a recent study using the Wada Test, we found that in patients with focal epilepsy, not only the known factors (i.e., the age at which the brain injury occurred and its localization) but also the epileptic activity itself (interictal discharges and seizure spread) may influence speech organization.23 Other authors found that frequent IEDs resulted in transient cognitive impairment in epilepsy patients, whereas such impairment was not present in those periods when no interictal epileptiform activity appeared during neuropsychological testing.24 Moreover, impairment of spatial task performance was demonstrated during right-sided interictal discharges, whereas during left-sided paroxysm, the verbal cognitive performance was disturbed.24 This suggests that the cognitive impairment caused by interictal spikes is not aspecific but reflects the functional disturbance of the area where the spikes originate.
Bilateral IEDs may represent an extended epileptogenic region because they are more often associated with bilateral seizure onset zone and seizure propagation.25 Earlier, we found that the ratio of spikes on the seizure onset vs the contralateral side is directly related to lateralization of the seizure onset and the contralateral propagation of the preceding seizures.26 Not only the ictal EEG recordings but the clinical seizure semiology27 and ictal SPECT in patients with bilateral spikes also point to a frequent involvement of the hemisphere contralateral to the seizure origin.28,29⇓ Worse surgical outcome of patients with bilateral spikes after temporal lobectomy30 also suggests that the bitemporal interictal discharges represent a widespread functional disturbance.
We found that patients with bilateral independent epileptiform discharges had mesiotemporal memory activation more often nonlateralized or ipsilateral to the epileptogenic region. Because bilateral spikes represent bilateral interictal and, indirectly, ictal activity (bilateral seizure onset or spread to the contralateral hemisphere), we suggest that this bilateral epileptic activity affects the lateralization of fMRI activity in mesiotemporal regions during the performance of a memory task.
Acknowledgments
Supported by grants from the Deutsche Forschungsgemeinschaft (DFG-Eb 111/2-2), Society for Epilepsy Research, Bielefeld, Germany (F.G.W.), and Humboldt Stiftung (J.J.).
The authors thank Terri Shore Ebner, who reviewed the manuscript as a native English speaker.
- Received December 5, 2003.
- Accepted May 11, 2004.
References
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