This study provides further clarification regarding Wada/fMRI concordance in a large sample that included a substantial number of patients with atypical language dominance. The data show that these two methods of determining language dominance have a relatively high level of concordance. An average of the previous comparison studies shown in Figure 2, weighted by sample size, indicates an overall discordance rate of 15%, which is comparable to our rate of 14%. A few prior studies reported 0% discordance, although with one exception (Binder et al., 1996), all of these studies had 8 or fewer participants (Desmond et al., 1995; Bahn et al., 1997; Hertz-Pannier et al., 1997; Baciu et al., 2001; Liegeois et al., 2002). On the other hand, several studies reported discordance rates of 25% or more. These variable results are paralleled by substantial variability in methodology. Numerous fMRI language tasks have been used, including covert fluency (Bahn et al., 1997; Hertz-Pannier et al., 1997; Worthington et al., 1997; Yetkin et al., 1998; Benson et al., 1999; Lehericy et al., 2000; Liegeois et al., 2002; Rutten et al., 2002; Adcock et al., 2003; Sabbah et al., 2003; Woermann et al., 2003; Deblaere et al., 2004; Gaillard et al., 2004; Arora et al., 2009), abstract versus concrete word identification (Desmond et al., 1995), rhyming (Baciu et al., 2001), syntactic or semantic judgments (Carpentier et al., 2001; Arora et al., 2009), sentence repetition (Lehericy et al., 2000), sentence comprehension (Rutten et al., 2002; Arora et al., 2009), story listening (Lehericy et al., 2000), semantic decision (Binder et al., 1996; Spreer et al., 2001; Benke et al., 2006; Szaflarski et al., 2008), and naming (Rutten et al., 2002; Gaillard et al., 2004). These language tasks have been contrasted with a wide variety of different control tasks or, in some cases, “passive” or “resting” baseline conditions. In addition, nonstandardized Wada administrations, varied fMRI regions of interest (e.g., whole brain, frontal, temporal), variable methods of quantifying or categorizing asymmetry, and variable definitions of discordance (e.g., visual rating, varied cut scores) all likely contribute to the variability in discordance rates reported across studies.
A novel aspect of the current study is that it is based on a semantic decision fMRI contrast that was validated previously to be predictive of cognitive outcomes. Language lateralization measured with this fMRI method is predictive of both naming (Sabsevitz et al., 2003) and verbal memory (Binder et al., 2008a) change after left anterior temporal lobectomy surgery. In both studies, fMRI was also more strongly predictive of outcomes than Wada language or memory asymmetry. This fMRI contrast has also been compared directly to similar measures using “passive” and “resting” baseline conditions and shown to produce both more consistent left lateralization and a greater volume of activation in healthy control subjects (Binder et al., 2008b). The use of tasks with overt responses allows the level of engagement in the tasks to be continuously monitored and encouraged through verbal feedback when necessary. Therefore, this fMRI paradigm offers numerous advantages that make it optimal for comparison against the Wada test.
Predictors of discordance
We observed the highest rates of discordance in patients who had bilateral language representation on fMRI (57%), followed by the group that had bilateral language on Wada testing (40%). Bilateral language representation has been associated with discordance in two previous studies (Benke et al., 2006; Arora et al., 2009). Of the 69 discordant cases reported in previous studies (Fig. 2), 28 had bilateral language representation on fMRI and 26 had bilateral language representation on Wada testing, suggesting further that discordance rates are high when either test indicates bilateral language representation. In addition, the current multiple regression analysis identified fMRI LI as the strongest predictor of the difference between Wada and fMRI LIs. Although we acknowledge that there may be an element of circularity in the analysis, the results are clinically informative, indicating that the lower the fMRI LI (i.e., the more rightward shift of the fMRI LI), the larger the difference between Wada and fMRI LIs. One likely explanation for this relationship is that fMRI is more sensitive than the Wada test to right hemisphere language processing. In some patients with partial right hemisphere language representation, for example, the right hemisphere component may be inadequate to sustain even minimal performance when the left hemisphere component is anesthetized, making the patient appear to be entirely left-lateralized on the Wada test. Left hemisphere anesthetization during the Wada could also interfere with right hemisphere processing through a diaschisis effect (Andrews, 1991).
Somewhat surprisingly, there were no systematic relationships between measures of test quality and LI discordance. Some of these quality factors (such as head motion and excessive sedation) almost certainly affect the results in individual cases, but cases with extreme movement were removed because the data were considered invalid. In the remaining sample, these effects were apparently either too infrequent or too small to consistently skew the test results in a particular direction.
It is difficult to draw conclusions about the four “extreme” cases of discordance in which fMRI showed right hemisphere dominance and Wada testing indicated left hemisphere dominance. All four patients had a right hemisphere seizure focus and were right-handed. Therefore, one would expect the left hemisphere to be the language dominant hemisphere as indicated by Wada testing. The mechanism for this pattern of extreme discordance is unclear, although for one case, very low levels of activation were noted across both hemispheres. Another possible mechanism to explain some cases of extreme discordance is the rare finding of interhemispheric dissociation of language functions, which is estimated to occur in 3% of epilepsy patients (Kurthen et al., 1992). One of the four extreme cases showed strongly right lateralized activation in the angular gyrus and left lateralized activation in the temporal lobe. This is consistent with other rare cases of interhemispheric dissociation of language functions that have been reported in individuals with discordant Wada and fMRI results (Lee et al., 2008). In such cases, the anterior language functions shift to the side opposite the seizure focus, whereas posterior language functions remain ipsilateral to the seizure focus (Kurthen et al., 1992).
As with all comparisons of fMRI and Wada language testing, the limitations of this study include a relatively small number of discordant cases and a somewhat arbitrary definition of LI discordance. The small sample size limits power to detect consistent group differences or individual or methodologic predictors of discordance. However, this is by far the largest sample of patients with Wada and fMRI language testing reported to date, and also the largest sample of discordant cases. Regarding the definition of LI discordance, a plethora of different methods have been suggested for comparing Wada and fMRI results, and different methods for calculating language lateralization have been used, including qualitative categorization methods and a variety of quantitative methods. We used a categorical criterion combined with difference scores between the LIs to operationally define discordance. We attempted to account for the unique differences inherent in each method by examining previously published language lateralization estimates from neurologically normal and epilepsy samples, and choosing cut scores that would yield similar numbers of patients in each language dominance group when assessed with Wada and fMRI. An additional caveat is that a small percentage of individuals (about 4% on each test) who had clearly invalid Wada or fMRI evaluations due to excessive sedation, excessive movement, or inability to perform the fMRI tasks were excluded from the study. These and other measures of test quality are critical for determining the validity of the tests and are likely to cause discordant results if not monitored.
Finally, it should be emphasized that both Wada and fMRI methods vary considerably across centers, and discordance rates may depend on a variety of methodologic factors, including the fMRI tasks used (both language and control conditions), Wada testing and scoring methods, and methods for computing lateralization. Therefore, the results reported here reflect a specific combination of Wada and fMRI methods and may not generalize to studies using very different methods.