r Seghier et al. r mixed lateralizations (e.g., [Kamada et al., 2006; Kurthen et al., 1992; Lee et al., 2008; Risse et al., 1997]) in patients who showed strong lateralization for expressive language function to one hemisphere and the opposite lateralization for receptive language ability. The negative covariance in regional laterality that we observed across subjects may reﬂect the use of different task strategies that are supported by different regions (e.g., [Reinke et al., 2008; Seghier et al., 2008b; Seghier and Price, 2009; Sugiura et al., 2007]. For example, our post hoc tests indicated that left angular gyrus activation was strongly associated with amodal semantic processing (activated for semantic matching on both words and pictures) but left ventral precentral activation was more activated for words than pictures (see Fig. 3C) consistent with a role in trans- lating orthography to phonology [Fiez et al., 2006]. Irre- spective of the exact cause of this regional dissociation in laterality, damage to one region is likely to increase activa- tion and lateralization in the other region, during the semantic word matching task. Therefore, the negative cor- relation we observed between lateralization in different regions of the same semantic word matching network clearly has implications for interpreting laterality changes following brain damage (e.g., [Crosson et al., 2009; Hertz- Pannier et al., 2002; Klingman and Sussman, 1983; Saur et al., 2006; Thomas et al., 1997]). Regional Activation Versus Laterality Given the difﬁculties interpreting LI at the individual subject level (irrespective of how LI is assessed), we suggest that the contribution of many right and left hemisphere regions should be considered independently. This high- lights the potential contribution of fMRI for presurgical investigations (e.g., [Petrella et al., 2006; Pouratian et al., 2002]). It also emphasizes that, if global or regional laterali- zation indices are assessed, the relative contributions of the left and right hemispheres need to be considered so that the contribution of the right hemisphere is not ignored. A further advantage of using regionally speciﬁc activa- tions, within hemisphere, for presurgical planning is that this approach circumvents the challenges associated with the computation of regionally speciﬁc LI. Speciﬁcally, the problem with assessing LI in multiple regions is that voxel based analyses of fMRI data are complex and therefore widespread heterogeneity needs to be reduced to a few manageable variables that minimize the number of regions tested [Chlebus et al., 2007; Deblaere et al., 2004; Hund- Georgiadis et al., 2002; Seghier, 2008; Spreer et al., 2002]. In this context, Seghier [2008] suggested that, to avoid mis- interpretation (and the generalization) of a single global LI per subject, a minimum of three regional LI values should be assessed per subject, including LI from an anterior region (frontal), a posterior region (temporal), as well as across the whole hemisphere. More recently, Guillen et al. [2009] parcellated the brain into 48 anatomical regions and calculated an LI for each region [Guillen et al., 2009]. They also suggested combining LI measures (e.g., one frontal and one temporal) in a 2D projection plane that displays the laterality of each subject in a more intuitive manner (see similar discussion in [Seghier et al., 2004]). Furthermore, assessing laterality in patients presents fur- ther complications due to the impact of the damage upon structure and vasculature. Previous reports have shown that even lateralities at the regional level might be mislead- ing when the regions of interest are at the vicinity of the damage (e.g., Ulmer et al., 2004; Wellmer et al., 2009]. The optimal procedure for computing regional LIs would obvi- ously depend on the nature and the location of the damage (for more details see Wellmer et al., 2009]. At the voxel level, Liegeois et al. [2004] have recommended that high deﬁnition laterality measures should not be used in patients, as the matching between homologues structures of both hemispheres can be hindered by the spatial deforma- tions that are caused by lesions (e.g., mass effect). In this particularly challenging context, there are some general principles that can help to optimize LM in patients if neces- sary, although we are arguing here that such complicated methodological procedures could be avoided if the relative contribution of each hemisphere is preserved (see below). First, improved normalization is the key for accurate LM, using for instance the uniﬁed normalization-segmentation algorithm [Ashburner and Friston, 2005] that has previously been shown to be robust in brain-damaged subjects [Crin- ion et al., 2007]. Second, using procedures that can explicitly model lesions as an additional class would minimize tissue misclassiﬁcation during segmentation [Seghier et al., 2008c] and thus would improve brain normalization. Third, excluding lesioned voxels (with abnormal signal) and their homologue voxels in the other hemisphere, by explicit masking procedures, would avoid mixing voxels with abnormal/atypical signal. Fourth, at the group level, it is more judicious to limit second-level analyses on LM to patients with comparable lesions (those showing maximum lesion overlap). Irrespective of the exact procedure, our point here is that these challenges are avoided if presurgical planning focuses on region speciﬁc activations within hemi- sphere at the site of the intended surgery. Beyond Laterality in the Clinical Setting All current methods for assessing laterality in fMRI act as reductionist tools that aim to homogenize (simplify) the complexity of fMRI maps. Despite all the well-known limi- tations in assessing LI in fMRI [Chlebus et al., 2007; Jansen et al., 2006b; Seghier, 2008], there is still a growing interest in optimizing such laterality measures in clinics (e.g., [Suarez et al., 2009; Wang et al., 2009]). This over-reliance on LI in the clinical setting is a direct consequence of the history of the development of this ﬁeld that aimed to con- vince clinicians about the validity and reliability of fMRI. This validation era, inaugurated by two seminal papers r 1610 r