r r Regional and Hemispheric Determinants of Language Laterality: Implications for Preoperative fMRI Mohamed L. Seghier,* Ferath Kherif, Goulven Josse, and Cathy J. Price Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London, United Kingdom Abstract: Language is typically a function of the left hemisphere but the right hemisphere is also essential in some healthy individuals and patients. This inter-subject variability necessitates the localization of lan- guage function, at the individual level, prior to neurosurgical intervention. Such assessments are typically made by comparing left and right hemisphere language function to determine ‘‘language lateralization’’ using clinical tests or fMRI. Here, we show that language function needs to be assessed at the region and hemisphere speciﬁc level, because laterality measures can be misleading. Using fMRI data from 82 healthy participants, we investigated the degree to which activation for a semantic word matching task was lateral- ized in 50 different brain regions and across the entire cortex. This revealed two novel ﬁndings. First, the degree to which language is lateralized across brain regions and between subjects was primarily driven by differences in right hemisphere activation rather than differences in left hemisphere activation. Second, we found that healthy subjects who have relatively high left lateralization in the angular gyrus also have rela- tively low left lateralization in the ventral precentral gyrus. These ﬁndings illustrate spatial heterogeneity in language lateralization that is lost when global laterality measures are considered. It is likely that the com- plex spatial variability we observed in healthy controls is more exaggerated in patients with brain damage. We therefore highlight the importance of investigating within hemisphere regional variations in fMRI acti- vation, prior to neuro-surgical intervention, to determine how each hemisphere and each region contributes to language processing. Hum Brain Mapp 32:1602–1614, 2011. VC 2010 Wiley-Liss, Inc. Key words: functional MRI; language; laterality index; laterality maps; inter-hemispheric dissociation; left and right hemisphere activity; semantic processing r Human Brain Mapping 32:1602–1614 (2011) r r r Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/online open#OnlineOpen_Terms Additional Supporting Information may be found in the online version of this article. Contract grant sponsor: The Welcome Trust; Contract grant spon- sor: The James S. MacDonnell Foundation (conducted as part of the Brain Network Recovery Group initiative). *Correspondence to: Mohamed L. Seghier, Wellcome Department of Imaging Neuroscience, Institute of Neurology, 12 Queen Square, London WC1N 3BG, United Kingdom. E-mail: m.seghier@ﬁl.ion.ucl.ac.uk Received for publication 11 March 2010; Revised 15 June 2010; Accepted 24 June 2010 DOI: 10.1002/hbm.21130 Published online 2 September 2010 in Wiley Online Library (wileyonlinelibrary.com). VC 2010 Wiley-Liss, Inc. INTRODUCTION In this article, we investigate how the relative involve- ment of the left and right hemisphere in language process- ing varies with the individual and the anatomical region. Our questions have implications for both theoretical and clinical perspectives of language function. From a theoreti- cal perspective, the key observations are that (a) language is more impaired after lesions to the left than right hemi- sphere; (b) language processing activates the left more than the right hemisphere in functional neuroimaging experiments; but (c) the degree to which language is left lateralized varies greatly, along a continuum, with some individuals showing bilateral or right hemisphere laterali- zation [Knecht et al., 2000; Springer et al., 1999]. From the clinical perspective, inter-subject variability in language lateralization has important implications for predicting how neurosurgical intervention will impact upon language