r Spatial Heterogeneity in Language Lateralization r function (e.g., for review see [Bookheimer, 2007; Ganslandt et al., 2009; Stippich et al., 2007; Tharin and Golby, 2007]). For example, if a patient typically uses the right hemi- sphere for language, then neurosurgery in the right hemi- sphere may unexpectedly impair language. As language lateralization varies with the anatomical region (for a review, see [Seghier, 2008], the importance of the left or right hemisphere for language function will depend on which region is affected and tested (e.g., [Berl et al., 2005; Deblaere et al., 2004]). Traditionally, the method used to assess language func- tion prior to neurosurgery is the Wada (intracarotid amo- barbital) test [Wada, 1949]. This procedure suppresses the function of each hemisphere individually which allows the language capabilities of each hemisphere to be assessed. There are several factors that complicate the interpretation of the Wada test (e.g., [Baxendale, 2009; Meador and Lor- ing, 1999]) and this invasive procedure is not risk-free for patients [Loddenkemper et al., 2008]. Its use in the clinical setting is therefore on the decline [Baxendale et al., 2008] and there has been a great deal of interest in replacing the Wada test with functional MRI which is both noninvasive and regionally speciﬁc [Abou-Khalil, 2007; Baxendale, 2009; Bookheimer, 2007; Medina et al., 2007; Rutten and Ramsey, 2010]. Many studies have conducted within subject compari- sons of language lateralization assessed with Wada versus fMRI [Binder et al., 1996; Desmond et al., 1995]. Although the results are consistent in 90% of cases, the residual inconsistencies have led to the conclusion that clinicians cannot rely on fMRI results, particularly when language lateralization is atypical [Arora et al., 2009; Benke et al., 2006; Giussani et al., 2010; Jayakar et al., 2002; Lee et al., 2008; Paolicchi, 2008; Wellmer et al., 2008; Westerveld et al., 1999; Woermann et al., 2003]. For example, in a recent survey across 26 European epilepsy centres (a review of 1,421 Wada procedures), Haag et al. [2008] con- cluded that clinicians currently do not feel that they can rely solely on fMRI results, with the majority of them agreeing on the necessity of performing a Wada test if fMRI revealed atypical laterality [Haag et al., 2008]. Here we argue that both the Wada and fMRI laterality indices, assessed across hemisphere, are misleading in the clinical setting because they do not indicate which regions within a hemisphere are involved in language function. Nor do they account for spatial heterogeneity in language lateralization. Previous reports have already suggested that lateralization measured with fMRI depends on the location and size of the volume of interest (for a critical review see [Josse and Tzourio-Mazoyer, 2004; Seghier, 2008]). There is also evidence that the direction of laterality can reverse within the same individual, even when task and stimuli are held constant. For instance, in a patient with focal epilepsy, lexical activation was right lateralized in frontal cortex and left lateralized in temporal cortex [Baciu et al., 2003]. Conversely, in a presurgical fMRI study of a patient with schizencephaly performing a silent reading task, language was left-lateralized in frontal cortex and right-lateralized in temporal cortex [Ries et al., 2004]. Recently, this dissociation in laterality between frontal and temporal regions has also been demonstrated in one healthy subject during a verbal ﬂuency task [Jansen et al., 2006a] and in another healthy subject during a semantic matching task [Bethmann et al., 2007]. Critically, however, the studies showing regional differences in language later- alization are based on individuals or small samples of patients in a few regions of interest selected on the basis of a priori knowledge. These intriguing observations moti- vate a more extensive investigation of regional differences in laterality at the population level using unsupervised and unconstrained laterality measures with high spatial deﬁnition. The ﬁrst aim of our study was therefore to assess regional differences (dissociations) in language lat- eralization, in a large population of healthy participants, by computing lateralization scores at each voxel across the entire brain [Liegeois et al., 2002]. The need to assess language function in each region indi- vidually rather than across the whole hemisphere highlights a useful contribution for fMRI in presurgical investigations because fMRI can provide a rich source of regionally spe- ciﬁc information. However, a second aim of our study was to demonstrate that fMRI laterality indices are misleading because they do not take into account the relative contribu- tion of each hemisphere. For example, two patients may both activate and need the left hemisphere to the same degree but, depending on the degree of right hemisphere activation, one of these patients may have left lateralized language function and the other may have right lateralized language function. Thus, right lateralization does not indi- cate whether the left hemisphere is necessary or not for lan- guage. It only indicates that activation is relatively higher in the right than left hemisphere. To address this second aim of our study, we compared individuals with stronger versus weaker left lateralization and asked whether those with stronger left lateralization had more left hemisphere activa- tion, less right hemisphere activation or both. In summary, we computed individual laterality measures of activation for semantic matching of words at both the global level (across the whole hemisphere) and regional level in 82 left- and right-handed healthy volunteers. Our aims were to (i) characterize the relative contribution of left and right hemisphere activity to lateralization values, and (ii) identify regional dissociations in laterality in an unsu- pervised manner and with high spatial deﬁnition. MATERIALS AND METHODS Subjects Eighty-two healthy subjects (43 females, 39 males) gave written informed consent to participate in this study. Sub- jects were native English speakers, had normal or r 1603 r