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Purpose: Verbal memory decline is a frequent complication of left anterior temporal lobectomy (L-ATL). The goal of this study was to determine whether preoperative language mapping using functional magnetic resonance imaging (fMRI) is useful for predicting which patients are likely to experience verbal memory decline after L-ATL.
Methods: Sixty L-ATL patients underwent preoperative language mapping with fMRI, preoperative intracarotid amobarbital (Wada) testing for language and memory lateralization, and pre- and postoperative neuropsychological testing. Demographic, historical, neuropsychological, and imaging variables were examined for their ability to predict pre- to postoperative memory change.
Results: Verbal memory decline occurred in over 30% of patients. Good preoperative performance, late age at onset of epilepsy, left dominance on fMRI, and left dominance on the Wada test were each predictive of memory decline. Preoperative performance and age at onset together accounted for roughly 50% of the variance in memory outcome (p < 0.001), and fMRI explained an additional 10% of this variance (p ≤ 0.003). Neither Wada memory asymmetry nor Wada language asymmetry added additional predictive power beyond these noninvasive measures.
Discussion: Preoperative fMRI is useful for identifying patients at high risk for verbal memory decline prior to L-ATL surgery. Lateralization of language is correlated with lateralization of verbal memory, whereas Wada memory testing is either insufficiently reliable or insufficiently material-specific to accurately localize verbal memory processes.
Brain surgery is an effective treatment for individuals who suffer from medically intractable epilepsy (Wiebe et al., 2001; Tellez-Zenteno et al., 2005). One common surgical procedure for epilepsy is anterior temporal lobectomy (ATL), which produces long-term cure rates of approximately 60–80% (McIntosh et al., 2001; Tellez-Zenteno et al., 2005). Common complications of ATL include upper quadrant visual field defects (Hughes et al., 1999; Barton et al., 2005), impairments on naming and other language tasks (Hermann et al., 1994; Langfitt & Rausch, 1996; Bell et al., 2000b; Sabsevitz et al., 2003), and declarative memory deficits. ATL typically involves removal of much of the anterior medial temporal lobe (MTL), including portions of the hippocampus and parahippocampus, which are known to be critical for encoding and retrieval of long-term episodic memories (Squire, 1992). Verbal memory decline after left ATL (L-ATL) is a consistent finding in group studies (Chelune et al., 1991; Hermann et al., 1995; Kneebone et al., 1995; Loring et al., 1995b; Helmstaedter & Elger, 1996; Martin et al., 1998; Chiaravalloti & Glosser, 2001; Sabsevitz et al., 2001; Lee et al., 2002; Stroup et al., 2003; Baxendale et al., 2006; Lineweaver et al., 2006) and is much more frequent than nonverbal memory decline after right ATL (R-ATL) (Lee et al., 2002). Studies using longitudinal neuropsychological methods that sensitively measure memory encoding processes show that significant verbal memory decline occurs in 30–60% of patients who undergo L-ATL (Chelune et al., 1993; Martin et al., 1998; Sabsevitz et al., 2001; Stroup et al., 2003; Gleissner et al., 2004; Baxendale et al., 2006; Lineweaver et al., 2006). One principal goal of the preoperative evaluation in ATL candidates is, therefore, to estimate the risk of verbal memory decline.
Functional memory asymmetry during the intracarotid amobarbital, or Wada, test is predictive of verbal memory decline from L-ATL, in that patients who show memory functions lateralized to the side of surgery are more likely to decline (Kneebone et al., 1995; Loring et al., 1995b; Bell et al., 2000a; Chiaravalloti & Glosser, 2001; Sabsevitz et al., 2001). Other studies have not found this test to be strongly predictive, however (Chelune & Najm, 2000; Stroup et al., 2003; Lacruz et al., 2004; Kirsch et al., 2005; Lineweaver et al., 2006), and many authors have raised concerns about its specificity and test–retest reliability (Novelly & Williamson, 1989; Loring et al., 1990; Lee et al., 1995; Kubu et al., 2000; Simkins-Bullock, 2000; Martin & Grote, 2002; Loddenkemper et al., 2007). Other presurgical tests of MTL functional or anatomical asymmetry are also modestly predictive of memory outcome, including structural MRI of the hippocampus (Trenerry et al., 1993; Chelune & Najm, 2000; Wendel et al., 2001; Stroup et al., 2003; Cohen-Gadol et al., 2004; Lineweaver et al., 2006) and interictal positron emission tomography (Griffith et al., 2000). Preoperative neuropsychological testing also has predictive value, in that patients with good memory abilities prior to surgery are more likely to decline than patients with poor preoperative memory (Chelune et al., 1991; Hermann et al., 1995; Helmstaedter & Elger, 1996; Jokeit et al., 1997; Davies et al., 1998; Stroup et al., 2003; Gleissner et al., 2004; Baxendale et al., 2006; Lineweaver et al., 2006; Baxendale et al., 2007).
Our aim in the present study was to determine the value of preoperative functional magnetic resonance imaging (fMRI) for predicting verbal memory decline from L-ATL. A previously published fMRI study demonstrated promising results in a small patient sample (Richardson et al., 2006). This prior study and two that examined nonverbal memory decline (Rabin et al., 2004; Janszky et al., 2005) focused on activation in the hippocampus and surrounding MTL. Given the relative difficulty of measuring robust activation signals in the hippocampus with fMRI, we explored the possibility that a language lateralization test might provide information concerning verbal memory lateralization. The fMRI protocol we used provides a language lateralization measure that is strongly correlated with Wada language asymmetry (WLA) (Binder et al., 1996) and predicts language outcome after L-ATL (Sabsevitz et al., 2003). Here we assess the ability of this test to predict verbal memory decline after L-ATL, and we compare its predictive power to other standard tests used for this purpose, including the Wada memory test.
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Anterior temporal lobe resection is a very effective treatment for medically intractable temporal lobe epilepsy, yet this benefit must be weighed against the risk of cognitive decline, particularly in patients undergoing left ATL. Consistent with many prior studies (Chelune et al., 1993; Martin et al., 1998; Sabsevitz et al., 2001; Stroup et al., 2003; Gleissner et al., 2004; Baxendale et al., 2006; Lineweaver et al., 2006), we found a high incidence of verbal memory decline after left ATL. Depending on the specific measure used, 33–55% of L-ATL patients declined on a verbal learning test (SRT) relative to a R-ATL control group. How clinically significant are such deficits? No patient in our series experienced the severe ‘global amnesia’ described in rare patients with bilateral MTL lesions (Scoville & Milner, 1957; Guerreiro et al., 2001; Di Gennaro et al., 2006), who are unable to form any new episodic memories. Moreover, it is unclear whether amnesia of this severity ever occurs after unilateral temporal lobe resection (Novelly & Williamson, 1989; Loring et al., 1990; Baxendale, 1998; Kubu et al., 2000; Simkins-Bullock, 2000; Kapur & Prevett, 2003). Instead, patients undergoing L-ATL often show a relative decline from their baseline on standardized psychometric tests. In some cases these declines are proportionally quite large, as in the 33% of patients in our series who declined more than 17 points on the CLTR measure of the SRT. Relative to the average preoperative score of 30 on this test, a 17-point decline represents more than a 50% decrement in performance. Prior studies suggest that patients are aware of such memory deficits, and that these deficits adversely affect quality of life and employability (Perrine et al., 1995; Helmstaedter et al., 2003; Stroup et al., 2003; Lineweaver et al., 2004; Langfitt et al., 2007). A few patients in our series had declines of 40 or more points on the CLTR and LTS measures from the SRT (Fig. 1). Such deficits may be comparable in severity to those of rare patients described in the literature as having “amnesia” after unilateral temporal lobectomy (Loring et al., 1994a; Kapur & Prevett, 2003).
Also consistent with prior studies was the finding of relatively preserved verbal and nonverbal memory function after R-ATL, and preserved nonverbal memory after L-ATL (Lee et al., 2002; Stroup et al., 2003; Lineweaver et al., 2006). The nonverbal memory tests used here assessed single-trial memory for abstract visual figures and learning of spatial patterns. It is possible that other tests might be more sensitive for detecting postoperative deficits in R-ATL patients, such as tests focusing on face or route learning (Bohbot et al., 1998; Chiaravalloti & Glosser, 2001). Nonetheless, the conclusion we draw from these data is that relative loss of verbal episodic memory ability after L-ATL is by far the most prevalent and significant memory deficit associated with ATL surgery, and should, therefore, be the main focus of attempts to reduce memory decline after ATL.
Our aim in the present study was to determine whether preoperative fMRI predicts verbal memory decline. An equally important question is whether fMRI adds any predictive value over and above that available from other tests, particularly noninvasive measures like preoperative test performance and medical history data. A third important issue is whether the Wada test contributes predictive value, and whether this relatively invasive test provides additional information over and above the noninvasive tests.
The most powerful predictor of verbal memory decline in our L-ATL sample was preoperative memory performance, which accounted for roughly 30–40% of the variance in outcome, depending on the specific outcome measure. Consistent with many prior studies (Chelune et al., 1991; Hermann et al., 1995; Helmstaedter & Elger, 1996; Jokeit et al., 1997; Davies et al., 1998; Stroup et al., 2003; Gleissner et al., 2004; Baxendale et al., 2006; Lineweaver et al., 2006; Baxendale et al., 2007), patients with higher preoperative test scores tended to show larger declines. One possible explanation for this phenomenon is that the better preoperative performers have more function to lose, i.e., the poor performers show less decline due to a psychometric “floor effect.” While this may be part of the story, the data also suggest an inherent biological dependence of verbal memory on the left hemisphere. If it was possible for verbal memory to shift fully to the right temporal lobe in patients with long-standing left temporal epilepsy, such patients would show good preoperative verbal memory and would be unaffected by left ATL. Evidence indicates, however, that more severe left MTL pathology is associated with worse preoperative verbal memory (Sass et al., 1990; Rausch & Babb, 1993; Saling et al., 1993; Helmstaedter & Elger, 1996; Hermann et al., 1997), indicating that rightward shift of verbal memory in patients with left temporal lobe epilepsy, though protective, is associated with a lower level of baseline function. Preoperative performance can thus be considered an indirect indicator of pathological status of the left MTL. Patients with better preoperative performance typically have milder left MTL pathology, have maintained more of their verbal memory function in the left temporal lobe, and are at higher risk from L-ATL (Hermann et al., 1992; Trenerry et al., 1993; Sass et al., 1994; Seidenberg et al., 1998; Chelune & Najm, 2000).
Language lateralization measured by fMRI was the second most powerful predictor of verbal memory decline, accounting for an additional 10% of the variance in outcome on the SRT tests. Moreover, fMRI added significant predictive power beyond that provided by preoperative test scores and demographic variables like age at epilepsy onset. These other noninvasive measures and fMRI together accounted for 48–61% of the variance in specific outcome measures. This combination of tests also showed good accuracy for predicting categorical decline in individual patients, with sensitivity ranging from 70–90% and specificity ranging from 73–100%. Although these models predicted outcomes fairly well, there remain at least two potential sources for residual unexplained variance. First, although the ATL surgeries were relatively standardized, there was likely some variation in the posterior extent of resection, which may have affected outcomes. Whether extent of resection modifies memory outcome is controversial (Milner, 1970; Ojemann & Dodrill, 1985; Katz et al., 1989; Wolf et al., 1993; Wyler et al., 1995; Graydon et al., 2001) and should be explored in future studies using quantitative pre- and postoperative structural MRI in a multivariate model. A second source of variance is imperfect test–retest reliability. One normative study of the SRT, for example, showed a test–retest correlation of only 0.66 for the CLTR measure (Ruff et al., 1989). Though this result is not directly applicable to our study because the range of normal variation is likely to be small relative to the variation in change scores we studied, it nevertheless serves as a reminder that all psychometric tests are inherently imperfect measurements susceptible to uncontrolled, nonstationary factors.
The fMRI LI were less effective predictors of change scores on the WMS-R/III LM tests. In our sample of patients, these tests were less sensitive in detecting verbal memory decline compared to the SRT. For example, the proportion of patients showing decline on the WMS tests (18–27%) was substantially lower than on the SRT tests. The mean percent decline in raw scores on the WMS tests (i.e., change score/preop score) was roughly 20–30%, compared to 30–45% declines on the SRT measures. This difference could be due to an inherently greater effect of L-ATL resections on learning processes (SRT) compared to single-trial encoding processes (WMS), as suggested by several authors (Rausch & Babb, 1993; Saling et al., 1993). In addition, the multiple trials used in the SRT procedure might simply provide a larger sample size and thus more statistically reliable observations (Lee et al., 2002). If the WMS changes are smaller or less reliable, they would be more difficult to predict, which could explain the lower correlations between these outcomes and the fMRI LIs. It is interesting, however, that among the fMRI indexes, the WMS change scores were best predicted by the temporal lobe LI. This pattern suggests that the WMS tests might be more selectively sensitive to processes carried out by the temporal lobe.
In contrast to the noninvasive measures, WMA was only weakly correlated with verbal memory outcome. The Wada memory test was originally developed for the purpose of predicting global amnesia after ATL (Milner et al., 1962). Studies of its ability to predict relative verbal memory decline have been inconsistent, with several suggesting good predictive value (Kneebone et al., 1995; Loring et al., 1995b; Bell et al., 2000a; Chiaravalloti & Glosser, 2001; Sabsevitz et al., 2001) and others showing little or none, particularly when used in combination with noninvasive tests (Chelune & Najm, 2000; Stroup et al., 2003; Lacruz et al., 2004; Kirsch et al., 2005; Lineweaver et al., 2006). Some authors have questioned the general validity and reliability of Wada memory results (Novelly & Williamson, 1989; Loring et al., 1990; Lee et al., 1995; Kubu et al., 2000; Simkins-Bullock, 2000; Martin & Grote, 2002; Loddenkemper et al., 2007). Others have emphasized the sensitivity of the test to stimulus type, relative timing of stimulus presentation, procedures used for recall, and other methodological factors (Loring et al., 1994b; Loring et al., 1995a; Carpenter et al., 1996; Alpherts et al., 2000). A particular concern highlighted in our series is the relatively frequent occurrence of “false negative” Wada results, i.e., patients with memory lateralization to the right hemisphere who nevertheless show significant decline after L-ATL (Fig. 2, Table 5). Several prior reports have also raised concerns regarding such cases (Rausch et al., 1993; Kirsch et al., 2005).
We do not believe the weak predictive power of our Wada memory test can be attributed to procedural flaws. Our test used an object encoding procedure that has been shown to predict verbal memory decline after L-ATL in several small series (Loring et al., 1995b; Sabsevitz et al., 2001). Patients were excluded from the analysis if they showed obtundation or bilateral poor memory performance. As direct evidence for the validity of the test, the L- and R-ATL groups showed markedly different memory asymmetry scores, suggesting that the test was sensitive to asymmetric MTL pathology. Thus, the WMA score was only weakly related to memory decline despite its ability to detect MTL functional asymmetry.
Why is the Wada memory test not a stronger predictor of verbal memory decline? One possibility is that the Wada memory test as usually performed (and as performed here) employs a recognition procedure, whereas the tests used in neuropsychological assessment typically use free recall procedures. The SRT, however, also includes a Recognition subtest very similar to the procedure used for Wada memory evaluation. Significant predictors of change on this subtest included the preoperative score (r =−0.308) and all of the fMRI LIs (e.g., r =−0.408 for the Lateral ROI). In contrast, change on the Recognition subtest was not correlated with WMA (r =−0.110), thus offering no evidence that differences in memory test procedure account for the lack of correlation.
We believe a more viable explanation is that the Wada memory test is not sufficiently material-specific. The objects used in the test can be encoded either verbally, as object names, or nonverbally, as visual percepts. Patients with relatively weak verbal memory might show better memory performance using a nonverbal encoding strategy. If this nonverbal system is lateralized differently from the verbal memory system, the asymmetry of performance on the Wada test might mainly reflect lateralization of the nonverbal system rather than the verbal system (Fig. 6). The verbal memory outcome tests, in contrast, are designed to assess strictly verbal memory functions. These verbal memory outcomes will not be accurately predicted in patients whose WMA reflects mainly nonverbal memory lateralization. Thus the Wada object memory test is a good indicator of overall memory lateralization, and therefore a good indicator of seizure focus lateralization, but may not accurately reflect lateralization of verbal memory processes.
Figure 6. Schematic diagram of a hypothetical model of memory and language representation in temporal lobe epilepsy (TLE). The yellow ovals represent language systems, red rectangles represent verbal episodic memory-encoding systems in the MTL, and blue rectangles represent nonverbal episodic memory-encoding systems in the MTL. (A) Typical state in healthy subjects and patients with late-onset epilepsy. Language and verbal memory processes are strongly left-lateralized, placing the patient at high risk for verbal memory decline. (B) Chronic left TLE without shift. The left MTL is dysfunctional, causing Wada memory lateralization to the right, but verbal memory has not shifted, leaving the patient at high risk for verbal memory decline. (C) Chronic left TLE with shift. Both language and verbal memory functions have shifted partially to the right, lowering the risk for verbal memory decline. Note the relative lack of correspondence, across patient types, between WMA and level of risk.
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Why is language lateralization a stronger predictor of verbal memory decline, both when measured with fMRI and with the Wada test? Compared to WMA, language asymmetry is more closely correlated with lateralization of verbal memory processes (Fig. 6). When language is lateralized to the left side, as in the typical normal state, verbal memory processes are more likely to have remained left-lateralized, and the patient carries a higher risk for verbal memory decline (Fig. 6A, B). Conversely, when language is represented bilaterally or predominantly on the right side, verbal memory is more likely to have shifted to the right, placing the patient at lower risk (Fig. 6C). This model suggests that verbal or nonverbal material specificity of the MTL may be largely a function of the type of information the MTL receives from the ipsilateral neocortex. Only when the right MTL receives verbal information from the right hemisphere does it contribute to supporting verbal memory. As discussed above, however, it also appears that the right MTL may have intrinsic limitations in the verbal domain, in that patients who do not show verbal memory decline, and have presumably shifted some of their language and verbal memory functions to the right hemisphere, also tend to have lower preoperative verbal memory scores. These lower preoperative scores could also be partly explained in some cases by longer seizure duration and a tendency for lower general intellectual function in these patients.
Use of language lateralization to predict memory outcome is counterintuitive and has not, to our knowledge, been examined previously. No prior study to our knowledge has examined whether WLA predicts verbal memory outcome. Indeed, prior studies examining memory outcome have generally treated variation in language representation as a confound that interferes with assessment of other predictors, and most have excluded patients with atypical language dominance. In the only study relevant to this issue, researchers compared a “Montreal” Wada memory procedure similar to the one we used to a “Seattle” Wada procedure (Dodrill & Ojemann, 1997). In the Seattle procedure, short-term recall of objects is tested during anesthesia rather than after anesthesia when language and other functions have returned to normal. Compared to the Montreal procedure, the Seattle procedure was more likely to be abnormal when language was present on the side being tested, suggesting that it partly reflected language processes, particularly those involved in verbal short-term memory. Of note, the Seattle procedure predicted memory outcome (76% accuracy), whereas the Montreal procedure did not (48% accuracy).
One previous study assessed prediction of verbal memory outcome with preoperative fMRI. Richardson et al. (Richardson et al., 2006) used an fMRI word-encoding task to predict verbal memory outcome in 12 L-ATL patients. Hippocampal activation on both sides predicted verbal memory decline on a delayed list-recall test (similar to the SRT Delayed Recall measure used in the present study), with left hippocampal activation slightly more predictive (r = 0.72) than right hippocampal activation (r = 0.71). Patients with higher activation levels experienced greater decline after L-ATL surgery. The positive correlation between memory decline and right hippocampal activation was in a direction opposite to that predicted by the ‘functional reserve’ hypothesis, which predicts less decline with greater memory representation in the right MTL. The authors proposed that the right hippocampal activation observed by fMRI might represent a different, “dysfunctional” type of memory processing that “does not provide an adequate postoperative reserve to maintain memory function at the preoperative level” (Richardson et al., 2006). It is probably best to regard these results as preliminary, however, given the limited sample size used. This sample size also precluded the possibility of a multivariate analysis to determine the unique contribution of fMRI relative to other predictors. Compared to this earlier study, the current investigation included a larger number of patients and tested, for the first time, the clinical utility of fMRI in the context of several other variables known to predict memory outcome. Another important difference between the two studies is our use of a large ROI that measures lateralization in a distributed language network, in contrast to the focused hippocampal ROI used by Richardson et al., which presumably isolates processes more specifically related to memory encoding. It could be argued, furthermore, that the fMRI activation tasks used in the two studies are fundamentally different, in that we used a language task whereas Richardson et al. used a memory task. We believe the difference in tasks is nominal more than actual, as semantic decision tasks are well known to result in incidental long-term encoding of the stimulus materials, often referred to as “deep encoding” (Craik & Lockhart, 1972). Such tasks have been used by many researchers to activate the MTL (Henke et al., 1999; Martin, 1999; Heckers et al., 2002; Daselaar et al., 2003), and the fMRI contrast used in the current study, though nominally a language task, produces strong activation in the left hippocampus and surrounding MTL at the group level (Binder et al., 1997; Bellgowan et al., 1998). We chose a large ROI to measure lateralization with this task in the expectation that this approach would provide the most reliable measurements in individual patients. In principle, however, specific identification of verbal memory encoding networks in the MTL could not only enable more accurate prediction of verbal memory outcome but might also provide a means of tailoring resections to reduce memory deficits. Development of robust methods for identifying these networks with fMRI should thus remain a goal of future research.
In conclusion, the present data suggest that verbal memory decline from L-ATL surgery can be predicted with good accuracy using historical, neuropsychological, and fMRI language lateralization data. WLA is shown for the first time to be a better predictor of verbal memory outcome than WMA, though this relatively invasive test does not provide additional predictive capability beyond fMRI and other noninvasive predictors. One question not addressed by the current study is how much more predictive power can be gained from volumetric analysis of the MTL. Quantitative MRI can provide a sensitive index of hippocampal asymmetry that may account for some of the variance in memory outcome after L-ATL (Trenerry et al., 1993; Chelune & Najm, 2000; Lineweaver et al., 2006). We plan to examine this variable in future studies. If the model presented in Fig. 6 is correct, however, it is likely that hippocampal volume asymmetry will be highly correlated with WMA and may not capture variance in outcome due to language representation. fMRI, on the other hand, appears to be a useful tool for providing this additional information.
Fast T*2-weighted imaging capabilities necessary for fMRI are a standard feature on currently marketed clinical MRI systems, and fMRI is now available in some form at most medical centers. Because it is noninvasive, clinical fMRI is likely to be considerably less costly than Wada testing. Implementation of cognitive fMRI protocols such as the one described here requires only installation of relatively low-cost audiovisual stimulation and response monitoring systems, together with expertise in cognitive training and testing provided by a neuropsychologist or cognitive neurologist. Auditory stimuli and presentation scripts used in the current study are available from the authors free of charge.