r Spatial Heterogeneity in Language Lateralization r left hemisphere, this pattern included inferior and middle frontal regions, middle and superior temporal regions, precentral cortex, occipito-temporal cortex, angular gyrus, and supplementary motor area. In the right hemisphere, activation was only signiﬁcant in the cerebellum. The analysis of the voxel based LM identiﬁed the voxels with the most consistently lateralized activation for semantic word matching in our 82 subjects, see Figure 1B. This revealed the typical crossed cerebro-cerebellar language lateralization, with consistent left lateralization in frontal and occipito- temporal regions and right lateralization in the cerebellum. The most consistent effect in LM (i.e., the strongest interaction between task and hemisphere) was observed in the left occi- pito-temporal cortex at [x ¼ 44, y ¼ 52, z ¼ 16; Z ¼ 7.5]. Calculation of the global LI across the whole hemisphere [Nagata et al., 2001] demonstrated that the majority of our subjects (67 of 82 subjects) showed lateralization to the left hemisphere (global LI >0; median LI ¼ 0.26), as shown in Figure 1C. As expected, only handedness showed a signiﬁ- cant effect on global LI values, as right-handed subjects were more left-lateralized than left-handed subjects (t ¼ 3.34, P ¼ 0.001, df ¼ 80). The effect of age on global LI values was not signiﬁcant across all subjects (see Support- ing Information Section 3). The continuous range of LI val- ues, across subjects, was entered as a covariate in the one sample t-test of the original (unﬂipped) images to identify voxels that were either positively (red in Fig. 2), or nega- tively (blue in Fig. 2) correlated with global LI. Our expec- tation was that differences in global LI between subjects would mainly result from variance in left hemisphere acti- vation. Surprisingly, however, we found strong correlations between global LI and right hemisphere activation (see the extensive blue areas distributed over the 3D-rendering of the brain in Fig. 2). Second Level Clustering and Regional Dissociations in Laterality The aim of this analysis was to characterize any regional dissociations in laterality, across subjects performing the same task. Evidence to support this investigation came from observations that voxel based LI was not closely correlated with global LI; see Supporting Information Figure S1. The 50 clusters obtained from the fuzzy clustering are visualized in Figure 3A. A strong negative correlation (r ¼ 0.36, P < 0.001; see scatter plot of Fig. 3B) was observed between lat- erality in clusters centered on the angular gyrus [ 48, 66, 28] and laterality in clusters centered on the ventral precen- tral gyrus [ 58, 2, 16]. Thus, when laterality increased in the angular gyrus (left > right) it decreased in the ventral pre- central gyrus. Critically, this double dissociation across sub- jects was not determined by handedness or any of our other variables (age, gender, stimulus set). Thus there was no evi- dence that these variables were positively correlated with laterality of one region and negatively corrected with later- ality of the other region (or vice-versa). Post Hoc Tests To investigate whether the opposing effects of laterality in the left angular gyrus and left ventral premotor cortex were driven by left or right hemisphere activation, we compared activation in the left and right angular gyrus and left and right ventral precentral gyrus, using data from the original (unﬂipped) images for the contrasts ‘‘semantic word matching versus perceptual matching’’ and ‘‘semantic picture matching versus perceptual match- ing’’ (Fig. 3C). The left angular gyrus was activated by semantic matching on both words and pictures, whereas left ventral precentral activation was only signiﬁcant for semantic word matching (see Fig. 3C). These regions were not consistently activated in the right hemisphere during semantic word matching; but the right angular gyrus was activated by semantic picture matching. DISCUSSION In this article, we have highlighted two important ﬁnd- ings that have implications for the clinical interpretation of language lateralization indices. The ﬁrst ﬁnding is that, across hemisphere, global LI was signiﬁcantly correlated with extensive activation across the right hemisphere (see Fig. 2). Thus, individual variation in the degree to which language is left or right lateralized at the global level was primarily driven by right hemisphere activation, and was not simply a reﬂection of the degree to which the left hemisphere supports language. The second ﬁnding is that healthy subjects who have relatively high left lateralized activation in the angular gyrus also have relatively low left lateralized activation in the ventral precentral gyrus. This demonstrates regional dissociations in language later- alization in a large population of healthy controls and is consistent with previous studies of single subjects or small samples of patients that have demonstrated the reversal of language lateralization in different regions, even when task and stimuli are held constant [Baciu et al., 2003; Jan- sen et al., 2006a; Ries et al., 2004]. The Inﬂuence of the Right Hemisphere on laterality Indices Although many surgeons do use laterality cautiously, a recent international survey across 31 countries [Baxendale et al., 2008] has shown that the majority (86%) of centers treating patients with temporal lobe epilepsy would take into account language laterality, if this information was available. Once language laterality is known, neurosurgical resections are usually less extensive in the language domi- nant side than the nondominant side. Our ﬁndings high- light major limitations in the use of such global lateralization indices for the clinical assessment of r 1607 r