Epilepsy surgery candidates provide a unique opportunity to examine the effects of a chronic focal abnormality on the cerebral organization of language. It is well documented that patients with early left hemisphere lesions, particularly non-right-handed patients, have a higher incidence of atypical (right or bilateral) representation of language functions. Atypical language representation is estimated to occur in 5% to 53% of right-handed epilepsy patients [1
], while the incidence of atypical language representation in the healthy right-handed population is approximately 4–6% [3
]. Prior reports of Wada language testing in large patient cohorts have noted rare cases with qualitatively different language abilities in the left and right hemispheres. Following the traditional distinction between “expressive” and “receptive” language abilities, most of these patients have been described as having interhemispheric dissociation between speech production and comprehension abilities [2
]. The most common pattern involves arrest of speech output on a variety of tasks (e.g., counting, naming, reading aloud, and repetition) with relatively preserved ability to follow commands after injection of one hemisphere, and the opposite pattern on injection of the other hemisphere. We observed this pattern in only 4 of 490 patients, consistent with two prior reports showing a combined incidence of 6 in over 644 cases [2
]. Although relatively rare, these patients provide an opportunity to understand factors that influence language reorganization in chronic brain disease.
Our patients showed several notable features that may offer preliminary clues to the presumed reorganization in language functions that occurred. First, all had had seizures for more than 20 years prior to Wada testing (average duration of 28 years). Although epilepsy of long duration is common among patients in surgical programs (the average duration in our entire sample is approximately 20 years), the fact that interhemispheric dissociation of speech production and comprehension networks was not observed in patients with shorter duration epilepsy suggests that it may be more likely in patients with longstanding epilepsy. Second, three of the four patients had seizures begin relatively late in development (ages 9, 14 and 25), suggesting that interhemispheric separation of production and comprehension processes may be more likely to occur after language lateralization has been established in earlier years. Third, the three patients whose language comprehension was represented in the left hemisphere (S1, S2, and S4) were all right-handed and had seizure foci in the left hemisphere. Evidently, the presence of seizures in the temporal lobe resulted in a rightward shift of speech production processes, while language comprehension processes remained in the left hemisphere. In contrast, S3 showed right dominance for language comprehension, was left-handed (with a left-handed father), and had a right hemisphere seizure focus. We speculate that S3 was originally right-dominant for language and, analogous to the other three patients, experienced a shift of speech production processes to the hemisphere opposite from the seizure focus. Thus, interhemispheric dissociation of language functions in all four patients was likely due to a shift of speech production capacities to the hemisphere contralateral to the seizure focus. In contrast, language comprehension processes appear not to have shifted to the hemisphere opposite from the seizure focus, despite many years of recurring seizures.
We can only speculate on possible reasons why speech production capabilities in our patients showed greater capacity for interhemispheric reorganization than comprehension processes. One possibility is that the articulatory skills indexed by speech production tasks emphasize motor, sensory, and motor planning processes that have a relatively symmetric representation in the normal brain [34
]. Thus, the non-dominant hemisphere may possess an innate ability to support speech production after chronic damage to the dominant hemisphere [4
]. Another likely factor is the relatively more distributed anatomical representation of brain regions involved in comprehension, which include large regions of the dominant temporal, parietal, and frontal cortex [44
], compared to the more focal representation for speech articulation mechanisms in sensorimotor, premotor, and inferior prefrontal cortex [36
]. As a result of this difference, language comprehension processes may be better able to reorganize intra
hemispherically, whereas damage to the dominant hemisphere articulatory system is, at least in some patients, more easily compensated by a shift of control to the opposite hemisphere. Janszky et al. [47
] showed that higher interictal spike frequency is associated with a shift (left to right) of word production ability in temporal lobe epilepsy patients. Votes et al. [43
] presented a patient who showed increased fMRI activation in the right inferior frontal gyrus on verbal fluency tasks following a left hemispherectomy. While all our cases suggest shifting of speech production, one of Kurthen et al.’s [12
] cases indicates shifting of language comprehension, but not speech production. This patient had a left temporo-parietal seizure focus without evidence of frontal damage and left parieto-occipital hypoperfusion on interictal SPECT. Wada testing suggested better comprehension ability in the right and expressive speech in the left hemisphere. This patient underwent left anterior two-thirds temporal lobectomy and showed intact language abilities three months after surgery on neuropsychological assessment. Although Kurthen et al. [12
] acknowledge that determination of language dissociation in this patient was complicated by persistent perseveration during Wada testing, this case raises the possibility of the shifting of language comprehension by focal epileptic activities in temporoparietal areas.
Interhemispheric dissociation of language capabilities could explain some cases of discordance between Wada and fMRI language lateralization. Using a Wada lateralization index calculated over all language subtests, the Wada and fMRI results were markedly discordant in two of our four patients and moderately discordant in another. Concordance was also poor using a Wada index based on speech production tasks, but was much better overall when using only the comprehension components of the Wada. These results are consistent with a previous report showing that this fMRI protocol gives different lateralization results than a Wada test based only on side of speech arrest [48
]. These patterns can be explained by the fact that the fMRI task contrast used here emphasizes speech perception and lexical-semantic retrieval processes and is not designed to activate speech articulation systems.
According to the traditional neuroanatomical view of language, which localizes speech production to Broca’s area in the frontal lobe and speech comprehension to Wernicke’s area in the temporal lobe, different patterns of lateralization in the frontal and temporal lobes would be predicted in patients with interhemispheric dissociation of these functions. Specifically, fMRI activation in the temporal lobe and other posterior heteromodal regions is predicted to be associated with the hemisphere serving language comprehension in the Wada test. Similarly, frontal lobe activation is expected to correlate with the hemisphere of speech production based on Wada testing. In contrast to these predictions, we observed no differences in lateralization of activation in frontal and temporoparietal ROIs, both of which were similar to the whole hemisphere lateralization pattern. The fMRI task contrast used in the present study activates not only temporal and parietal regions but also frontal regions supporting language comprehension [49
]. This result is consistent with a large body of neuroimaging evidence indicating involvement of the prefrontal cortex in a variety of language processes, including lexical-semantic retrieval and selection [44
]. Because the frontal lobe supports a variety of linguistic processes, it is overly simplistic to equate the frontal lobe with speech production. In our patients, the motor control processes necessary for speech production appear to have shifted to the hemisphere contralateral to the seizure focus, while other frontal lobe language processes did not shift away from the seizure focus.
Given its rare occurrence, dissociation of language functions could not explain all cases of discordant Wada and fMRI tests, but it provides a potential explanation for some of these cases. Multiple language tasks assessing comprehension as well as speech articulation might, in combination, yield more concordant results between the Wada test and fMRI mapping. Several groups of researchers have advocated such a “language panel” approach and reported that agreement between the Wada test and fMRI increased when multiple language tasks were incorporated in the fMRI studies [22
]. On the other hand, this improvement in concordance may have occurred simply because the combination of several fMRI data sets enhances statistical power and reliability in areas where overlapping activation occurs across tasks [25
]. Other studies have shown that some tasks are better than others for the purpose of determining language lateralization. For example, listening to sentences, single-word reading, and object naming tasks, when compared to resting or passive baseline states, produced lateralization results that were not well correlated with Wada lateralization [17
]. Thus, simply combining a number of tasks may be ineffective if these tasks and their controls are not suitably designed to target language processes of interest. In addition to the multiple task approach, multiple neuroimaging modalities, including activation and deactivation methods such as magnetoencephalography and transcranial magnetic stimulation, might be necessary to optimize the localization of component language functions.