The pathophysiology of letter-by-letter readingIntroductionMedical history and lesion descriptionBehavioural assessmentGeneral dataReadingBrain imagingProcedureImaging parametersAnalysis of MRI dataResultsOverall reading networkAlphabetic stimuli versus fixationAlphabetic stimuli versus chequerboardsOccipito-temporal activations in the patient and in controlsLetter-by-letter reading: words versus consonant stringsDiscussionPure alexia due to a disconnected VWFA?Role of residual left fusiform activationsThe mechanisms of letter-by-letter readingLetter identification and the right occipito-temporal cortexVerbal working memory and the left perisylvian cortexInterhemispheric connectionsResidual parallel letter perception?AcknowledgementsReferencesNeuropsychologia 42 (2004) 1768–1780The pathophysiology of letter-by-letter readingLaurent Cohena,b,∗, Carole Henrya,b, Stanislas Dehaeneb, Olivier Martinauda,b,Stéphane Lehéricyc, Cathy Lemerb, Sophie FerrieuxaaInstitut de Neurologie, Hˆopital de la Salpˆetrière, 47/83 Bd de l’Hˆopital, 75651 Paris CEDEX 13, FrancebINSERM U562, Service Hospitalier Frédéric Joliot, CEA/DSV, Orsay, FrancecService de Neuroradiologie, Hˆopital de la Salpˆetrière, AP-HP, Paris, FranceReceived 24 March 2004; received in revised form 28 April 2004; accepted 30 April 2004AbstractPure alexia is a frequent and incapacitating consequence of left occipitotemporal lesions. It is thought to result from the disruption or thedisconnectionofthevisualwordformarea(VWFA),aregionreproduciblylocatedwithintheleftoccipito-temporalsulcus,andencodingtheabstract identity of strings of visual letters. Alexic patients often retain effective single letter recognition abilities, and develop an effortfulletter-by-letter reading strategy which is the basis of most rehabilitation techniques. We study a patient who developed letter-by-letterreading following the surgical removal of left occipito-temporal regions. Using anatomical and functional MRI in the patient and innormal controls, we show that alexia resulted from the deafferentation of left fusiform cortex, and we analyze the network of brain regionssubtending letter-by-letter reading. We propose that during letter-by-letter reading (1) letters are identified in the intact right-hemisphericvisual system, with a central role for the region symetrical to the VWFA; (2) letters are serially transferred to the left hemisphere throughthe intact segment of the corpus callosum; (3) word identity is eventually recovered in the left hemisphere through verbal working memoryprocesses involving inferior frontal and supramarginal cortex.© 2004 Elsevier Ltd. All rights reserved.Keywords: Reading; Alexia; fMRI; Fusiform; Language1. IntroductionPure alexia is a frequent and incapacitating consequenceof left occipito-temporal lesions (Binder & Mohr, 1992;Damasio & Damasio, 1983). Affected patients suddenly loseexpert reading abilities that they have acquired through yearsof academic training. At the same time, speech comprehen-sion and production, as well as word spelling, are preserved.The essence of this lost perceptual skill is (1) letter identi-fication invariant for position, size, font, and case; and (2)the fast and parallel identification of arrays of several let-ters (Dehaene et al., 2001; McCandliss, Cohen, & Dehaene,2003). It is not before the age of 10 that children showthe adult reading pattern (Aghababian & Nazir, 2000), i.e.short word reading latencies that are independent of wordlength, at least within a range of about three to seven lettersand in optimal display conditions (Lavidor, Ellis, Shillcock,& Bland, 2001; Weekes, 1997). In severe cases, known asglobal alexia, patients cannot access abstract letter identity∗Corresponding author. Tel.: +33 1 42161849/42161802;fax: +144245247.E-mail address: [email protected] (L. Cohen).(Miozzo & Caramazza, 1998), and are unable to name evensingle letters (Dejerine, 1892). More often, alexic patientskeep effective letter recognition abilities and develop an ef-fortful letter-by-letter reading strategy, which is the basisof most rehabilitation techniques (Greenwald & GonzalezRothi, 1998). Eventually, this procedure may become quiteeffective, although it remains easily detectable in the exces-sive effect of word length on reading latencies (Behrmann,Black, & Bub, 1990).A variety of questions and hypotheses have been putforward concerning letter-by-letter reading (for selectedreferences see Montant & Behrmann, 2000). Does it re-flect the partial preservation of normal premorbid processes(Behrmann, Plaut, & Nelson, 1998), or is it based on novelstrategies (Speedie, Rothi, Heilman, 1982)? Is it basedon residual left-hemispheric (LH) or on compensatoryright-hemispheric (RH) mechanisms (Coslett & Saffran,1998)? Does reveal a general impairment in processing si-multaneous visual objects (Farah & Wallace, 1991) or com-plex displays (Montant & Behrmann, 2000), or is it specificto reading? Such issues may be clarified by refering to asimple model of the visual stages of reading (McCandlisset al., 2003). Letters displayed in one hemifield are first an-0028-3932/$ – see front matter © 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.neuropsychologia.2004.04.018L. Cohen et al./Neuropsychologia 42 (2004) 1768–1780 1769alyzed through a cascade of contralateral retinotopic areas,which compute increasingly abstract representations. Even-tually, a representation of letter identities is created in thevisual word form area (VWFA), reproducibly located withinthe left occipito-temporal sulcus, at about TC –42, –63, –15(Cohen et al., 2003). This representation is invariant forparameters such as size, position, case, font. The transfer ofvisual information from lower-order retinotopic cortices tothe VWFA takes place within the left hemisphere for stim-uli displayed in the right visual field (RVF). For left visualfield (LVF) stimuli, information is conveyed through inter-hemispheric fiber tracts that course in the splenium of thecorpus callosum and over the posterior horns of the lateralventricles (Binder & Mohr, 1992; Molko et al., 2002). TheVWFA then projects to structures involved in phonologicalor lexico-semantic processing.In this framework, pure alexia is thought to result eitherfrom the disruption of the VWFA itself, or from impairedprojections to or from this system. We recently showedthat the critical lesion for pure alexia overlaps accuratelywith the VWFA, as