an overview and working hypothesis - hebrew university...

Brain (2000), 123, 2373–2399

R E V I E W A R T I C L E

The neurological basis of developmental dyslexiaAn overview and working hypothesis

Michel Habib

Cognitive Neurology Laboratory, Department of Neurology, Correspondence to: Dr Michel Habib, Centre de recherche,CHU Timone, 13385 Marseille, France Institut Universitaire de Geriatrie, 4565 Ch. Queen Mary,

Montreal (QUE), Canada H3W 1W5E-mail: [email protected]

SummaryFive to ten per cent of school-age children fail to learn toread in spite of normal intelligence, adequate environmentand educational opportunities. Thus defined,developmental dyslexia (hereafter referred to as dyslexia)is usually considered of constitutional origin, but its actualmechanisms are still mysterious and currently remainthe subject of intense research endeavour in variousneuroscientific areas and along several theoreticalframeworks. This article reviews evidence accumulatedto date that favours a dysfunction of neural systemsknown to participate in the normal acquisition andachievement of reading and other related cognitivefunctions. Historically, the first arguments for a neuro-logical basis of dyslexia came from neuropathologicalstudies of brains from dyslexic individuals. These earlystudies, although open to criticism, for the first time drewattention towards a possible abnormality in specific stagesof prenatal maturation of the cerebral cortex andsuggested a role of atypical development of brainasymmetries. This has prompted a large amount ofsubsequent work using in vivo imaging methods in thesame vein. These latter studies, however, have yieldedless clear-cut results than expected, but have globallyconfirmed some subtle differences in brain anatomy whose

Keywords: dyslexia; brain imaging; phonology; temporal processing; reading

Abbreviations: BA � Brodmann area; CVC � consonant–vowel–consonant; ERP � event related potential;fMRI � functional MRI; LLI � language learning impairment; MMN � mismatch negativity

IntroductionDuring the past few years, dyslexia has been the focus ofconsiderable interest from researchers in different scientificareas, for both theoretical and practical reasons. First, publicawareness that this condition, which affects ~10% of thepopulation (or up to 20% depending on a more or less

© Oxford University Press 2000

exact significance is still under investigation. Neuro-psychological studies have provided considerable evidencethat the main mechanism leading to these children’slearning difficulties is phonological in nature, namely abasic defect in segmenting and manipulating the phonemeconstituents of speech. A case has also been made forimpairment in brain visual mechanisms of reading as apossible contributing factor. This approach has led to animportant conceptual advance with the suggestion of aspecific involvement of one subsystem of vision pathways(the so-called magnosystem hypothesis). Both phono-logical and visual hypotheses have received valuablecontribution from modern functional imaging techniques.Results of recent PET and functional MRI studies arereported here in some detail. Finally, one attractiveinterpretation of available evidence points to dyslexia asa multi-system deficit possibly based on a fundamentalincapacity of the brain in performing tasks requiringprocessing of brief stimuli in rapid temporal succession.It is proposed that this so-called ‘temporal processingimpairment’ theory of dyslexia could also account for atleast some of the perceptual, motor and cognitivesymptoms very often associated with the learning disorder,a coincidence that has remained unexplained so far.

conservative definition), has a neurobiological basis, gaverise to the hope of rational and effective therapy, whichstimulated research in quite different areas such asneurophysiology, neuropathology, neuropsychology, linguis-tics and the educational sciences. As a consequence, dyslexia

2374 M. Habib

has become a fertile ground for transdisciplinary studies anda model for elucidating biological, educational and socio-cultural factors of brain/cognition interactions anddevelopment. Finally, the recent explosion of brain imagingmethods has found a unique experimental setting for studyingthe brain mechanisms of reading in general and those ofimpaired reading in particular.

The notion that dyslexia may have a neurological originwas initially and independently mentioned at the turn ofthe last century by the Scottish ophthalmologist JamesHinshelwood and the British physician Pringle Morgan whoboth emphasized the similarity of certain symptoms indyslexic children or teenagers with the neurological syndromeof ‘visual word blindness’ (Hinshelwood, 1895; Morgan,1896). Indeed, as first reported by the French neurologistJules Dejerine, damage to the left inferior parieto-occipitalregion (in adults) results in a specific, more or less severe,impairment in reading and writing, suggesting that this region,namely the left angular gyrus, may play a special role inprocessing the ‘optic images of letters’ (Dejerine, 1891).These early authors thus reasoned that impaired reading andwriting in their young dyslexic patients could be due todefective development of the same parietal region which wasdamaged in adult alexic patients (Hinshelwood, 1917).

However, these speculations remained unconfirmed untilthe first description of the brain of a dyslexic boy who diedfrom brain haemorrhage due to a vascular malformation(Drake, 1968). Besides evidence of difficulties learning toread, this patient also had a family history of migraine andlearning disorders and this was especially the case in hisonly brother. Pathological examination showed a series ofbrain malformations principally in the cortical gyri of theleft inferior parietal region, including ectopias in the outer(molecular) cortical layer. As will be developed below, thispattern of cortical abnormalities, suggesting defective brainmaturation, is central to the description given in more recentstudies and to pathophysiological hypotheses which havebeen proposed since then.

Another line of neurological speculation has followed theinitial observations that dyslexic children have poor orinadequate brain lateralization, especially for language. It iscustomary to cite the American neurologist Samuel Orton(Orton, 1925, 1937) as the ‘founding father’ of the nowfamous atypical lateralization theory of dyslexia. In particular,one idea proposed by Orton and later appropriated byGeschwind, was that the lateralization of language functionsto the left hemisphere was delayed in dyslexics, so that thelanguage prerequisites for learning to read could not developnormally. (For instance, the high incidence of left-handersand the mirror-writing phenomenon were taken as evidencefor abnormal lateralization in these children.) This theoryhas been at the origin of a large number of experimentalstudies, especially those using lateralized brain stimulationsuch as dichotic listening (see, for instance, Obrzut, 1988;Harel and Nachson, 1997). With his colleague AlbertGalaburda, the late Norman Geschwind was, undeniably, the

originator of a current of thought (and thereby of the vastresearch effort which followed) turning brain asymmetry ingeneral, and cortical asymmetry in dyslexia in particular, intoone of the key issues in neurological science for the secondhalf of the twentieth century (see, for instance, Geschwindand Behan, 1982; Geschwind and Galaburda, 1985, 1987).

In the present paper, I will overview the main argumentsand experimental data obtained to date in favour of aneurological basis of developmental dyslexia. In this attempt,I shall first successively provide a brief description of thedyslexic syndrome, a sketch of the main aetiological factorsand a description of the dyslexic brain. The major part ofthe presentation will then be devoted to the main theoriescurrently proposed to account for the mechanism of readingimpairment. Throughout this review, special emphasis willbe placed on morphological and functional in vivoinvestigations of the dyslexic brain. Finally, I will propose atheoretical framework for future studies in this domain.

The definition and clinical spectrum ofdyslexiaDevelopmental dyslexia is defined as a specific and significantimpairment in reading abilities, unexplainable by any kindof deficit in general intelligence, learning opportunity, generalmotivation or sensory acuity (Critchley, 1970; World HealthOrganization, 1993). It is widely recognized, although notuniversally (see Shaywitz et al., 1992), that dyslexia is morefrequent in males (from 2 : 3 to 4 : 5, depending on thestudy), with significant familial occurrence. Children withthis condition often have associated deficits in related domainssuch as oral language acquisition (dysphasia), writing abilities(dysgraphia and misspelling), mathematical abilities(dyscalculia), motor coordination (dyspraxia), posturalstability and dexterity, temporal orientation (‘dyschronia’),visuospatial abilities (developmental right-hemispheresyndrome), and attentional abilities (hyperactivity andattention deficit disorder) (Weintraub and Mesulam, 1983;Rapin and Allen, 1988; Dewey, 1995; Gross-Tsur et al.,1995, 1996; Fawcett et al., 1996). Besides their multiplepossible interrelations and associations, all thesedevelopmental syndromes share in common their relative‘specificity’, i.e. the fact that general intelligence is intact,as reflected in a normal or above normal non-verbal IQ.Depending on the pattern of such associated disorders, verbaland performance IQ may show usual (verbal � performance)or reversed dissociation. Such a dissociation, per se, is agood argument in favour of a ‘developmental lesion’ affectingseparately one or several brain circuits or modules specializedin various aspects of cognitive function. Such comorbidityalso suggests a common origin involving either geneticfactors or prenatal environmental influences, or both (seebelow). It also has important diagnostic as well as prognosissignificance, influencing both evaluation and remediation ofthe reading disorder.

Neurology of dyslexia 2375

One aspect of these associated disorders has receivedparticular attention during the last decades, namely thefrequency of oral language impairment. A considerableproportion of dyslexic children have known not only moreor less severe problems in oral language and speechacquisition, from mere delay to severe dysphasia, but also,as will be developed below, subtle impairment in perceptionand/or articulation of speech, which is currently consideredthe most likely mechanism leading to the reading disorders.Accordingly, one of the most widely recognized oral languageconcomitants of dyslexia is a task known as ‘rapid automatednaming’ where children have to speak aloud as quickly aspossible the names of pictures presented on a sheet recurrentlyin random order (Korhonen, 1995). Finally, it has beensuggested that a clinically covert deficit in articulatoryefficiency may be demonstrated by adequate testing in mostdyslexics (Heilman et al., 1996). However, it is important tokeep in mind that the relationship between oral languagedeficits and dyslexia is far from being straightforward since,although these are not the majority, there are dyslexics forwhom even sophisticated examination fails to disclose orallanguage impairment, and, more often, severe dysphasicswho learn to read without apparent difficulty.

The reading disorder itself may either appear as primary,thus manifesting at the time when the child learns to read,or as the ultimate and often most worrying feature of analready diagnosed learning disorder. In the large majority ofcases, and irrespective of the age of diagnosis, children whofail to achieve normal reading performances make the sametype of errors: visual confusions between morphologicallysimilar letters, especially those having a symmetricalcounterpart (such as b and d), difficulty in acquiring a global‘logographic’ strategy which would allow them to recognizecommon words presented briefly, and difficulty ingeneralizing previously learned grapheme to phoneme rules(especially for complex letter clusters). This latter aspectappears as the core dysfunction in dyslexia, since graphemeto phoneme conversion is a critical stage in learning to read(Frith, 1995). This stage is compromised by the two mainaspects of neurological dysfunction evidenced in dyslexicchildren, which affect visual perceptual and phonologicalprocesses (see below). Besides cases of obvious dysgraphiadue to associated motor and/or coordination–dexterityimpairment, the written production of dyslexic children isalso stereotyped: phonemic errors in the transcription fromoral to written form of letters and syllables, defective spatialarrangement of letters, inversions, omissions and substitutionsof letters and/or syllables, aberrant segmentation of words,and weak grammatical development, which all combine tobring about a fuzzy, sometimes incomprehensible production.

Due to the multitude of possible combinations of thesebasic dysfunctions, a rational remedial approach usuallyinvolves specific and specialized teaching best provided byone or more competent professionals (speech therapists,occupational therapists, neuropsychologists and/orspecialized educators, depending on the organizational

context specific to each country). Finally, after several monthsor (more often) years of remedial effort, not withoutunavoidable psychological consequences of this special andlongstanding treatment, reading becomes possible, althoughoften clumsy and effortful, sometimes with persisting errors,especially with irregular or exceptional words (surfacedyslexia), as well as in the area of comprehension. But thecommon outcome in adolescence and adulthood is a moreor less profound spelling impairment (Treiman, 1985), whichwill persist as the permanent hallmark of the developmentaldisorder (and stands as a valuable indicator for retrospectivediagnosis of dyslexia in adults). One of the most fruitfulcontributions of these last years to the analysis and rationaltherapy of dyslexia has been provided by the neuro-psychological approach, through its systematic endeavour to‘dissect’ the mechanisms of reading impairment in a givensubject in order to develop adequate remedial protocols. Oneimportant step has been to individualize the phonologicaland surface types of developmental dyslexia (Castles andColtheart, 1993), by analogy to classical subtypes of acquireddyslexia, which are classified according to the rate of errorsin reading non-words, which is tightly dependent on a non-lexical phonological procedure, and exception words, whichrelies on a lexical, visuo-orthographic procedure. However,the distinction between surface and phonological forms ofdyslexia has not replaced the old empirical terminology ofdysphonetic versus dyseidetic types (Boder, 1973), whichremains widely used. (It must be noted here that mostdyslexics of the Boder’s dyseidetic type probably have aquite special reading disorder where attentional and spatialdifficulties interfere with the process of learning to read,rather than constituting a definite, specific incapacity forreading.) It must be noticed, in this regard, that the surface/phonological distinction is only descriptive and devoid ofany aetiological assumption as to the underlying brainmechanisms, whereas the dysphonetic/dyseidetic distinctionclearly refers to two opposed mechanisms, one related to aspeech discrimination deficit, the other to visual perceptionimpairment (see below).

Aetiological considerationsThe basic postulate of current research in this field is thatdyslexia and related disorders are fundamentally linked to aconstitutional characteristic of the brain. Evidence for agenetic origin of dyslexia has been increasingly accumulatingduring the last few years and will not be reviewed here. Thereader is referred to more specific writings by Pennington(Pennington, 1991, 1997, 1999), Schulte-Korne andcolleagues (Schulte-Korne et al., 1996), Smith and colleagues(Smith et al., 1998), and Flint (Flint, 1999), and to recentdiscoveries regarding the involvement of specificchromosomes (Fagerheim et al., 1999; Fisher et al., 1999;Gayan et al., 1999). It suffices to say for our present purposethat dyslexia is very probably of genetic origin, since itoccurs most often in families. However, genetic transmission

2376 M. Habib

is probably complex and non-exclusive. In particular, it isconceivable that different forms of dyslexia may occur withinthe same family, whereas different genes have been implicatedin different aspects of the reading disorders. For instance,it has been suggested that chromosome 15 is related toperformance on a single word reading task, whilechromosome 6 involvement would be related to aphonological awareness task (Grigorenko et al., 1997; see,however, Fisher et al., 1999, for an opposite view). Probablymore relevant are data obtained recently by Castles andcolleagues in a twin sample (Castles et al., 1999). Theseauthors compared subjects’ scores on exception word readingand non-word reading tasks to build surface and phonologicaldyslexic subgroups taken at each end of this distribution.Reading deficits were found to be significantly heritable inboth subgroups. However, the genetic contribution was muchgreater in the phonological dyslexics than in the surfacedyslexics, suggesting a significant environmental influencefor the latter subgroup. The nature of such an environmentalinfluence is still totally speculative, but an attractivehypothesis has pointed to the possible intervention of theprenatal environment (Geschwind and Behan, 1982; see alsoBryden et al., 1994).

Indeed, from a neurological point of view, the largeprevalence of oral or written language deficits among theselearning disordered children suggests a special vulnerabilityof the left hemisphere cortical systems subserving variousaspects of language-related abilities to these aetiologicalfactors (Geschwind and Galaburda, 1985). Hormonal factors,such as foetal testosterone levels during late pregnancy, mayplay a crucial role, and this is possibly reflected in the largemale predominance in most of these conditions. However,empirical evidence is lacking for such a hormonal role in theaetiology of dyslexia (Tonnessen, 1997). Another aspectsuggested by the Geschwind–Behan–Galaburda theory isrelated to the putative role of immune factors, based onpartial evidence that dyslexia may occur more often infamilies suffering from various immune diseases (Penningtonet al., 1987; Hugdahl et al., 1990; Crawford et al., 1994). Inspite of contradictory evidence (Gilger et al., 1998), there iscurrently a consensus towards the conception of a complexlink between several traits including non-righthandedness,immune diseases, sex hormones and verbal learning disorders,but the nature of this link, although probably genetic, remainstotally speculative (Hugdahl, 1994). Some arguments,however, are derived from animal studies, especially rodentmodels in which a genetic basis to autoimmune disease hasbeen found in association with cortical anomalies and learningdifficulties (Galaburda, 1994). It is noteworthy that one locusimplicated in chromosome 6 studies (Cardon et al., 1994) ispart of the HLA (human leucocyte antigen) complex, knownto participate in the immune system control. Finally, itmust be observed that these possibly aetiologically relevantassociations are not specific to dyslexia, but probably alsoconcern other conditions, such as hyperactivity disorder inwhich, for instance, male predominance is even larger and

the immune link probably also present, with genetic studiespointing to the HLA system (Odell et al., 1997).

The dyslexic’s brainThe seminal anatomical studies of the BostonschoolUndoubtedly, the most significant contribution of these lastfew decades to the neurology of dyslexia was the descriptionby Galaburda and colleagues of the brains of one (Galaburdaand Kemper, 1979), then four (Galaburda et al., 1985) brainsof male dyslexic subjects. Later on, the same group reportedthe analysis of three additional female brains (Humphreyset al., 1990). To summarize these studies, two mainobservations were made. First, at the microscopic level, ameticulous analysis of serial coronal slices of the post-mortem specimens, compared with a similar analysis of non-dyslexic brains (Kaufmann and Galaburda, 1989) disclosedspecific cortical malformations including ectopias (smallneuronal congregations in an abnormal superficial layerlocation), mainly distributed across both frontal regions andin the left language areas; dysplasia (loss of characteristicarchitectural organization of the cortical neurons, mainlysubjacent to the site of ectopias); and more rarely, vascularmicro-malformations. In some instances, these corticalmalformations took the appearance of a microgyrus (ormicropolygyrus), an aspect also found in the subsequentanalysis by Cohen and colleagues of the brain of a dysphasicchild (Cohen et al., 1989) (It must be noted that, even thoughthe child whose brain was studied by Cohen and colleagueswas unequivocally suffering important delays in oral languageacquisition, in several of the dyslexics reported by Galaburdaet al. (1985), oral language was also reported as beingdelayed.) No ectopias were found in the study by Cohen andcolleagues, but the microgyrus, as reported by Galaburdaand Kemper (Galaburda and Kemper, 1979), was located inthe left temporal cortex. The main lesson drawn from thesemicroscopic observations is that all the brains studied differedfrom control brains in a way that suggested abnormal corticaldevelopment. Since neuronal migration is thought to takeplace during the sixth gestational month, the mechanismleading to these cortical lesions was presumed to occur beforeor during this period of the foetal brain development. Finally,in addition to these neuronal abnormalities, the female brainsshowed glial scars in the border zones between the arterialterritories, suggesting a vascular mechanism, supposedly ofimmune origin (Humphreys et al., 1990).

Besides these microscopic anomalies, all the dyslexicbrains of the Boston studies, as well as that of the dysphasicchild studied by Cohen and colleagues (Cohen et al., 1989),displayed a macroscopic peculiarity, namely an absence ofthe usual left � right asymmetry of the planum temporale.In fact, this small triangular part of the superior surface ofthe temporal lobe had been reported by earlier anatomists asasymmetrical in the majority of brains, a fact confirmed in


the first such study in the modern area by Geschwind himself(Geschwind and Levistky, 1968; for a review, see Galaburdaand Habib, 1987). Since this asymmetry was believed toparallel the functional linguistic preponderance of the lefthemisphere, and by reference to the above-mentionedevidence of incomplete lateralization in dyslexics, this regionnaturally deserved to come under close scrutiny. Theprediction was apparently totally confirmed, since all thebrains studied displayed this particular symmetrical aspect;however, it is not specific since it is present in roughly one-third of routine brains. In other terms, planum symmetryseemed necessary but not sufficient to define the dyslexic’sbrain. Although the developmental mechanisms leading tosuch atypical symmetry still remain a subject of debate (see,for instance, Steinmetz, 1996), these findings, combinedwith the above-mentioned microscopic features, have beengenerally considered good evidence of maturational deviancebeing at the origin of the learning difficulties of dyslexics.

Towards a better understanding of thesignificance of cortical asymmetries: in vivomorphological imaging of the dyslexic brainSeveral more recent attempts have been made at replicatingthese findings, through in vivo examination of largerpopulations of dyslexic individuals using morphological brainMRI. Cortical anatomy can reliably be demonstrated usingMRI which provides a unique opportunity to respond to thetwo main criticisms addressed to results from pathologicalfindings: the limited number of brains analysed and theuncertainty persisting as to the diagnosis and subtype ofdyslexia (Hynd and Semrud-Clikeman, 1989). Hopefully,using the remarkable definition of brain MRI to analysecortical asymmetries in subjects carefully diagnosed andselected should provide clear-cut answers. Several recentstudies have yielded complete reviews of the available data,most of them concluding that the evidence is not fullyconvincing (Beaton, 1997; Morgan and Hynd, 1998;Shapleske et al., 1999). Table 1 summarizes the maincharacteristics and results of these different studies.

Whereas initial studies seemed to confirm pathologicalfindings statistically, with a larger incidence of reversed (orabsent) asymmetry, it is noteworthy that more recent ones(using more refined MRI technology) have failed to confirmsuch a tendency. For instance, the study by Leonard andcolleagues, one of the most sophisticated and reliableavailable, reports an atypical pattern of gyrification in rightand left temporal as well as parietal perisylvian cortices(Leonard et al., 1993). One intriguing finding in this studyis the suggestion that in addition to interhemisphericasymmetry, it would be interesting to consider intra-hemispheric asymmetries, i.e. the relative importance, withineach hemisphere, of the temporal and parietal banks of theposterior sylvian fissure.

Among studies finding significant differences between

dyslexics and controls, that of Larsen and colleagues wasthe first to suggest that atypical symmetry in dyslexia isspecifically linked to phonological impairment (Larsen et al.,1990). They showed that a subgroup of their dyslexics withimpaired performance on a non-word reading task hadsymmetrical planum temporales, whereas those with impairedword recognition did not differ in this respect from controls.

As summarized in Table 1, although there is a globaltendency in the literature to confirm in vivo the initialneuropathological observations of Galaburda et al. (1985),there are notable exceptions when authors fail to find anysignificant bias towards symmetry in dyslexics. This isespecially so in the most recent studies where the surfacearea of the planum temporale was measured directly. Forexample, in a study of eight dyslexics and eight controls (allmale right-handers) with a MRI-based surface reconstructiontechnique, Green and colleagues failed to disclose any groupdifference in asymmetry of the caudal infra-sylvian surface(Green et al., 1999). These inconsistencies may relate tothe selection of subjects, or to the mode of anatomicalmeasurement. Alternatively, purely environmental factorsmay act as confounding variables. For example, it has beendemonstrated that intensive training in the auditory modalitycan modify the degree of asymmetry in the posterior auditoryregion, increasing the size of the left planum (Schlaug et al.,1995a). This finding is in line with neuroplasticity studies inanimals, showing that direct training notably alters the sensoryneural maps at the single cell level (Recanzone et al., 1993).

In a recent study (Habib and Robichon, 1996) of 16dyslexic young adults and 14 controls, all male students fromthe same engineering school (to ensure that both groups hada similar intellectual as well as academic level), we failed todisclose significant differences in planum temporaleasymmetry between the two groups. Instead, we found thata parietal area, situated in front of the planum temporale, onthe other bank of the sylvian fissure, is less asymmetrical indyslexics than in controls, and that the degree of asymmetryof this area is inversely proportional to the individuals’performance on a phonological task. [Interestingly, a recentand controversial paper by Witelson and colleagues has foundtotal absence of asymmetry in this region (parietal operculum)on photographs of the brain of Albert Einstein, who was notonly a mathematical genius, but also a self-admitted dyslexic(Witelson et al., 1999).] This finding suggests that parietalrather than temporal asymmetry may be the most relevantmorphological characteristic of the dyslexic brain. It isnoteworthy, in this context, that recent functional imagingstudies have found dissociations between anatomicalpreponderance of the left planum temporale and functionalasymmetry of the temporal cortex during auditory verbaltasks (Karbe et al., 1995). Moreover, it seems that the planumtemporale itself is not specifically activated by verbal auditorystimuli, since it responds equally to tones and words duringpassive listening tasks and more strongly to tones duringactive listening (Binder et al., 1996; Celsis et al., 1999).

Finally, as the posterior region of the inferior frontal gyrus

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2380 M. Habib

is classically related to language output, the study of itsmorphology in developmental dyslexics appears to beespecially relevant. Paradoxically, such studies are rathersparse. While Galaburda and colleagues have reported at thecytoarchitectonic level the presence of numerous ectopiasand dysplasias bilaterally in the inferior frontal gyrus ofdevelopmental adult dyslexics (Galaburda et al., 1985), othersusing neuroimaging have shown macroscopic symmetry ofthe anterior speech region in dyslexic children (Hynd et al.,1990). However, Jernigan and colleagues found a significantdifference between language-disordered individuals andnormal controls in the inferior frontal regions, with reverseddirection of asymmetry (Jernigan et al., 1991). More recently,Clark and Plante showed a relationship between the sulcalmorphology of the inferior posterior frontal gyrus and a familyhistory of developmental language disorders, suggesting anincreased risk factor for these disabilities when extra sulciare present in this frontal region (without, however, anylateralized effect) (Clark and Plante, 1998).

In our young engineers population, we recently measuredBroca’s area asymmetry (Robichon et al., 2000) and founda more frequent symmetrical pattern in areas 44 and 45 indyslexics, and a correlation between this pattern and subjects’non-word reading performance. This result is consistent withfunctional imaging studies (see below) suggesting a role ofthe left inferior frontal gyrus in speech perception and rapidauditory processing, as well as in phonological aspectsof reading (Fiez et al., 1995; Fiez and Petersen, 1998;Price, 1998).

Finally, it appears from this review of anatomical aspectsof brain asymmetry in dyslexia that far from resolvingquestions opened by the initial pathological observations,in vivo morphometry using the most refined imaging methodshas raised different issues. Tendencies but no strong effectshave been shown and only a few aspects of the complexinterplay of several factors have been revealed, the majorityof which are probably still to be discovered. One potentiallyinteresting avenue could be the use of methods such asdiffusion tensor MRI, which would be able to show thedirectionality of white matter fibres (Klingberg et al., 2000).

The interhemispheric deficit theory of dyslexiaThese considerations may not apply to another brain structure,the corpus callosum, whose involvement in dyslexia andother developmental disorders has been suspected for a longtime. Thus, besides theories pointing to defective brainlateralization, another frequently proposed potentialmechanism is abnormal collaboration and/or communicationbetween the hemispheres. This hypothesis relies on well-documented evidence of impaired interhemispheric transferof sensory or motor information in dyslexics (Gross-Glennand Rothenberg, 1984; Best, 1985; Gladstone et al., 1989;Moore et al., 1995; Markee et al., 1996). A few studies havelooked for a structural concomitant of impaired callosalfunction by measurement of the mid-sagittal surface of the

corpus callosum on MRI scans. Duara and colleagues founda larger total callosal area in female but not male dyslexicsand a larger posterior (splenial) area in male and femaledyslexics, in 21 adult dyslexics compared with controls(Duara et al., 1991). Conversely, Larsen and colleagues failedto demonstrate any difference in callosal measurements, eitherfor total or splenial areas, between 17 dyslexic adolescents and19 controls (Larsen et al., 1992) (for negative evidence, seealso Cowell et al., 1995; Pennington et al., 1999). Hynd andcolleagues compared 16 dyslexic children with 16 age-matched controls and only found significant differences inthe anteriormost region (genu), which was smaller in dyslexics(Hynd et al., 1995). Finally, Rumsey and colleagues founda larger posterior third of the callosum, that included theisthmus and splenium, in 21 dyslexic men than in 19 controls(Rumsey et al., 1996).

In our own study of 16 dyslexic men (Robichon andHabib, 1998), we found that (i) our dyslexics’ corpus callosumdisplayed a more rounded and an evenly thicker callosalshape and (ii) only right-handed dyslexics had a larger mid-callosal surface, especially in the isthmus. These findings areglobally consistent with the fact that more symmetrical brainsmay possess more overall (right plus left) brain tissue intemporoparietal regions connected through the posterior partof the callosum. Moreover, they raise the important issue ofwhether more callosal connections reflect lesser corticalasymmetry, or have a special significance per se, for instancein terms of interhemispheric inhibition or collaboration. Froma neurodevelopmental point of view, differences in callosalsize may reflect hormonal influences during critical periodsof development of interhemispheric connections. It has beenshown that the size of the mid-posterior part of the callosumis proportional to salivary testosterone concentrations (Moffatet al., 1997). Finally, a changed callosal size in dyslexia mayalso result from intensive remedial therapy, since it has beenshown that intensive training may affect callosal morphology(Schlaug et al., 1995b).

Dyslexia: in search of the neurofunctionaldefect(s)Beyond the neuroanatomical aspects reviewed in the previoussection, active research is currently in progress from differentperspectives in order to elucidate how the dyslexic brainfunctions or malfunctions. It must be emphasized here thatconsiderable caution is required when attempting to drawany explanatory model of dyslexia from the results reportedbelow, since most of them only reflect statistical tendenciesand never represent a systematic rule. As a consequence, allthe theories proposed to date suffer from notable exceptions,where a given effect is sometimes only present in a minority ofsubjects, obviously limiting the impact of such observations.Moreover, finding a relationship between two measuredvariables does not mean that they are causally tied, sothat any theory based on such observations must remain


hypothetical, explaining, at best, only one part of the reality.Another methodological consideration concerns thepopulation studied in some of the works cited in this section.It is possible that researchers advocating different theorieshave based their observations on more or less differentpopulations, so that their conclusions may differ. This is thecase for ophthalmological departments which may artificiallyisolate a selection-biased population with an unusuallyimportant visual contribution to dyslexia; this may also bethe case for professionals or institutions receiving youngerchildren, with a disproportionate incidence of oral languagedeficits. In this regard, arguments drawn from data obtainedin so-called language learning impaired (LLI) or specificlanguage impaired (SLI) children, although probablyincluding typically dyslexic individuals, have been criticizedas being only loosely representative of the dyslexicpopulation. However, in the present review, we will alsoconsider results obtained in such populations as they possiblyprovide valuable information on the neurobiological bases oflanguage learning problems in general, and dyslexia inparticular.

Neuroscientific research has explored three main pathwaysduring the past decade: the phonological processing theory,the visual theory and the temporal processing theory. In thepresent section, I will review arguments in favour of each ofthe three theories in the light of results from studies involvingbrain functional investigations in dyslexics.

The central role of phonological disorders indevelopmental dyslexiaOne of the most robust discoveries in the domain of cognitivemechanisms leading to dyslexia is the repeated demonstrationthat the core deficit responsible for impaired learning to readis phonological in nature and has to do with oral languagerather than visual perception. The deficit is in the ability tomanipulate in an abstract form the sound constituents of orallanguage, so-called phonological awareness (or meta-phonology). Whereas most children are able to perform tasksrequiring segmenting words in smaller units (syllables andpartly phonemes) well before reading age, dyslexic childrenare still unable to do so even after several months of readingand writing (Liberman, 1973; Bradley and Bryant, 1983).Lundberg and colleagues (Lundberg et al., 1988) showedimproved reading abilities in children previously trained insuch exercises and these observations are the basis of thewidespread use of oral language exercises for therehabilitation of reading and spelling disorders. An importantconcept of the phonological processing theory is that thereis a deficit at the level of phoneme representation itself. Forinstance, several researchers have found that dyslexics arepoorer than age-matched controls (and also than controlsmatched for reading age) at tasks that require processing ofsubtle differences between phonemes that are acousticallysimilar to each other. This is best exemplified in tasks of

categorical perception when children have to categorize as‘ba’ or ‘da’ an artificial acoustic continuum between the twosyllables. A number of studies (Godfrey et al., 1981; Werkerand Tees, 1987; Reed, 1989) have shown a deficit in thistask in a proportion of dyslexics that is variable acrossdifferent studies. The deficit is generally found for itemssituated close to the intercategorical boundary, especiallyarticulatory oppositions (/ba/–/da/; /da/–/ga/), or less oftenvoice-onset oppositions such as /ba/–/pa/ (Manis et al., 1997).The latter authors showed such deficits are found specificallyin a subgroup of dyslexic children with a phonologicalawareness deficit (as assessed in a task in which subjectshad to pick out a phoneme within a non-word said aloudby the examiner). Manis and colleagues concluded thatinadequate representations of phonemic units resulting fromsuch perceptual deficits could prevent dyslexic children fromusing and normally manipulating phonological information,thus impairing their ability to acquire phonologicalprerequisites to learning to read (Manis et al., 1997). As willbe developed below, phonemic processing impairment indyslexia may even stem from a more elementary generalauditory problem with the detection of stimuli with certaintemporal properties. A defect in sensitivity to auditoryfrequency modulation has been shown in dyslexia and foundto be related to the rate of errors in a non-word reading task(Witton et al., 1998), a result not replicated in another study(Bishop et al., 1999). Recently, Helenius and colleagues haveshown that the illusion of ‘stream segregation’, normallyobtained when two pure tones are repeated rapidly inalternation, is present in adult dyslexics even at much slowerrates (Helenius et al., 1999). This can be taken as anequivalent to the phenomenon of sensory persistence reportedbelow for the visual modality.

Demonstration of a visual processing deficit: the‘magnosystem’ theoryBesides the multitude of deficits demonstrated in phonologicaland orthographic aspects of reading, researchers have soughtpart of the mechanism of reading disorders within the domainof visual perception, using tools primarily designed forinvestigations of visual function. Several lines of evidenceargue in favour of this strategy.

First, clinical studies have long reported that most dyslexicsmake errors that follow visual rather than strictly phoneticlaws, e.g. confusions between symmetrical (b/d) or visuallyclose (m/n) letters, and that at least some of them may derivefrom purely perceptual impairments. Although such errors arepresent in most children with otherwise typical phonologicalproblems, they can also occur predominantly or evenexclusively in some, a situation often referred to asvisuoattentional dyslexia (Valdois et al., 1995). Accordingly,the characterization of a ‘dyseidetic’ subgroup of dyslexics(Boder, 1973) supposed a visual deficit at the origin of thedisorder with preferential use of a phonetic strategy when

2382 M. Habib

reading. A reverse dissociation was proposed for‘dysphonetic’ dyslexics.

Up to 75% of dyslexic children may be affected byophthalmological problems that disturb binocular vision,ocular tracking or motion perception, to the point thatophthalmological remedial methods have even been proposedas treatment in the past. However, each of these problemscan be interpreted as a consequence rather than a cause ofreading impairment if one considers that these various abilitiesdevelop in normal readers partly under the influence ofreading itself.

Such an explanation does not hold, however, for moreelementary perceptual abnormalities repeatedly reported indyslexic children. Globally, visual perceptual studies haveshown that dyslexic children process visual information moreslowly than normal readers. For instance, there are studiesthat show longer visual persistence at low spatial frequencies(Lovegrove et al., 1980a, b), or a slower flicker fusion rate(Martin and Lovegrove, 1987). However, the bestdemonstration of a low-level visual deficit in dyslexics isthat of altered contrast sensitivity. Dyslexics may need10-fold lower spatial frequencies to perceive the same contrastas non-dyslexic children. This contrast sensitivity deficit mayaffect 75% of dyslexics, especially those with evidence ofan associated phonological deficit (Lovegrove et al., 1980a, b,1982, 1990; Eden et al., 1996b; Cornelissen et al., 1998).Contrast sensitivity deficit (but not abnormal visualpersistence) could even be specific to a dysphonetic subgroupof dyslexics, being absent in dyslexics classified as dyseideticor mixed (Slaghuis and Ryan, 1999). Moreover, visualdetection of motion, another function usually ascribed to themagnosystem, has been found correlated to performance ofa lexical decision task (Cornelissen et al., 1998), a findinginterpreted as reflecting variations in lettering positionencoding.

Several researchers have suggested that deficits observedin psychophysical experiments may be accounted for byreference to the distinction between sustained and transientvisual channels (for a review, see Stein and Walsh, 1997)[More precisely, during reading, the activity in the transientchannel (magnosystem) would be inhibited at each ocularsaccade by activity in the sustained channel (parvosystem).If such inhibition does not occur, visual processing of a givenletter within a word would be compromised by abnormalpersistence of the preceding letter(s).] Since these channelscan be distinguished by their preferred spatial frequencies,their temporal properties and their contrast sensitivity, it hasbeen suggested that the impairment observed in dyslexicsboth in contrast sensitivity and visual persistence may resultfrom disturbance in the transient system, which mediatesperception of global form, movement and temporal resolution.As a confirmation of this hypothesis, Livingstone andcolleagues have provided electrophysiological and neuro-anatomical evidence of an alteration of the magnocellularcomponent of the visual pathway (M-system), and shownthe absence of specific electrical responses to high spatial

frequency and low contrast visual targets in dyslexic childrenwho responded normally to targets with greater contrast andlower spatial frequency (Livingstone et al., 1991). In thesame article, they report that the dyslexic brains previouslyshown by Galaburda and colleagues (Galaburd et al., 1985)to display cortical changes, also display subtle abnormalitiesin the neuronal organization of the lateral geniculate nucleus(the thalamic relay of the retinocortical pathway). Consistentwith the M-system theory, only neurons of the magnocellularpart of the nucleus were abnormally atrophied, whereasthe parvocellular part of the nucleus was intact. Theseneuropathological findings, however, have never beenreplicated, a deficiency that represents an obvious limitationto any line of argument based on such neuropathologicalevidence. More recently, Jenner and colleagues failed to finda specific involvement of the magnocellular component ofthe primary visual cortex, but reported an absence in dyslexicsof the asymmetry in neuronal size found in normals, namelymore large cells in the left occipital lobe (Jenner et al., 1999).

To summarize, the considerable research effort currentlydevoted to visual theories of dyslexia may seemdisproportionate, since almost all in the field agree thatphonological impairment is the crucial phenomenon. Indeed,if the pathognomonic dysfunction in visual dyslexia is inthe rapid recognition of written words (Lovett, 1987;Siegel, 1993), current theories of reading emphasize thedevelopment of word decoding skills, which in turn relyheavily on basic language skills, particularly phonologicalskills (Bentin, 1992; Rack et al., 1993; Siegel, 1993).Actually, the magnosystem theory, again triggered byresults coming from neuropathological studies (Livingstoneet al., 1991; Galaburda and Livingstone, 1993), is eminentlyfragile even if negative results are still scarce (see, forinstance, Johannes et al., 1996; Spinelli, 1997; Barnardet al., 1998; Jenner et al., 1999). In particular, recentattempts at correlating a psychophysical deficit in therealm of presumably M-dependent visual functions withbehavioural performance is not always convincing,especially since the neuropsychological profile of thepatients is ill-defined (Talcott et al., 1998). Finally, arecent review of the available literature on contrastsensitivity (Skottun, 2000) concludes that there is morenegative than positive evidence for the existence of adeficit in contrast sensitivity in dyslexia.

Probably the more attractive feature of the M-deficittheory is that it can be extended to other sensory channels,since there is some evidence that the magno/parvodistinction also exists anatomically and functionally forother sensory modalities. Thus, Galaburda and colleagueshave shown that, just as the M-pathway may be specificallyaffected in the dyslexics’ lateral geniculate, the same maybe true for the medial geniculate, situated on the auditorypathway (Galaburda et al., 1994). In this view, dyslexiawould be a ‘pathology of the magnosystems’, which couldaccount for phonological as well as visual impairment.


The ‘temporal (rate)-processing’ theory ofdyslexiaAnother very attractive hypothesis, which possibly mayreconcile the phonological and visual deficit accounts,postulates that the different levels of impairment reportedabove all stem from a unique basic deficit, involvingprocessing by the brain of the rate and temporal features ofvarious kinds of stimuli. In other terms, these children’sbrains would be fundamentally unable to process rapidlychanging or rapidly successive stimuli either in the auditoryor the visual modality. Tallal and Piercy have thusdemonstrated that children with LLI are poor at processingstimuli that incorporate brief, rapidly changing components,especially when these changes occur in the tens ofmilliseconds time range that characterizes the acoustics ofongoing speech (Tallal and Piercy, 1973).

As a consequence, the hypothesis posits that thesechildren’s language problems result from their inability toperceive the rapid acoustic elements included in humanspeech, namely, the formant transitions whose duration is asshort as a few tens of milliseconds. Moreover, this rateprocessing constraint would be both non-specific to language,since it also concerns non-verbal sounds, and non-modalitydependent, since it has also been demonstrated using visualand sensory-motor tasks (Tallal et al., 1985).

However, most available evidence comes from auditoryexperiments. In particular, Tallal and Piercy found thatchildren with LLI were impaired in discriminating syllables/ba/ versus /da/ that naturally incorporate 40 ms durationformant transitions (Tallal and Piercy, 1974). However, thesesame children were unimpaired in discriminating thesesyllables when formant transitions were artificially expandedfrom 40 to 85 ms (Tallal and Piercy, 1975).

Tallal and colleagues were able to correctly classify 98%of children as normal or language-impaired on the basisof six variables involving rapid perceptual and productionabilities (Tallal et al., 1985). Many dyslexics, with or withoutobvious oral language involvement, also manifest rateprocessing problems (e.g. Tallal, 1980; Wolff, 1993; Tallalet al., 1995; Stein and Walsh, 1997). Farmer and Klein havereviewed five studies, including 10 different experimentsinvolving temporal order judgement in dyslexia, five in thevisual modality and five in the auditory modality (Farmerand Klein, 1995). In all studies significant group differenceswere found, except for one auditory condition (vowels, whichacoustically do not incorporate rapid changes) and in onevisual experiment (symbols). The same authors also reviewedsix studies involving discrimination of stimulus sequences. Innine out of 15 conditions tested, dyslexics were significantlypoorer than controls.

During the last few years, the temporal processing theoryof dyslexia has been rather severely contested, especially onthe basis of the apparent initial confusion between suchdifferent concepts as time duration and sequential processing.Thus, Mody and colleagues (Mody et al., 1997) designed

several studies in order to test the validity of the initialfindings of Tallal and Piercy (Tallal and Piercy, 1975). Theycompared poor and good readers on a similar task usingeither classical /ba/–/da/ pairs or other pairs presumed to bephonetically more contrasting (/da/–/sa/ and /ba/–/sha/). Onlyon the former and not on the latter two pairs did dyslexicsperform less well than controls, leading the authors to theconclusion that it is the phonetic distance not the temporalorder difficulty which is reflected in the dyslexic’s poorperformance in temporal order judgement tasks.

However, as pointed out by Denenberg, the study by Modyand colleagues suffers from the fact that the statistical powerrequired to challenge previously established evidence maynot be reached in this study (Denenberg, 1999). Moreover,the selection of their ‘poor reader’ group may be misleading,as is the case for several other studies in the literature.

In order to test the validity of a link between temporalprocessing and phonological deficit, Nittrouer carried outseveral tasks including a non-verbal sequencing task adaptedfrom that of Tallal and colleagues (Tallal et al., 1980) and a‘stop closure detection’ task using a discrimination betweenthe words /say/ and /stay/ (Nittrouer, 1999). None of thesetasks was found significantly impaired in otherwise severelyphonologically affected children.

Other studies have tried to test the temporal processinghypothesis by using artificially modified auditory stimuli. Intheir study of 15 dyslexic boys and 15 non-dyslexic controlstaken from the same school (mean age 15 years 2 months),McAnally and colleagues tested the influence of artificiallystretching or compressing synthesized consonant–vowel–consonant (CVC) stimuli on the performance of these childrenat discriminating between 11 different CVC syllables(McAnally et al., 1997). Although dyslexics tended to performpoorly compared with controls, this deficit was found to beindependent of the time characteristics of the stimuli. Theseauthors conclude that ‘limited exposure of children withdyslexia to time-stretched synthetic CVC syllables did notimprove their ability to identify the stimuli correctly’. Thisresult obviously questions the validity of significant resultsobtained by Tallal and colleagues (Tallal et al., 1996) andMerzenich and colleagues (Merzenich et al., 1996) with atemporally based remedial method, results which have beenpartly replicated more recently by our group (Habib et al.,1999) [See, however, the work by Bradlow and colleagues(Bradlow et al., 1999) discussed in the headed MMN section.]Moreover, we recently obtained preliminary resultssuggesting that artificially slowing each element of aconsonant cluster may improve dyslexic children’s ability todiscriminate and reproduce the sequence of the twoconsonants (De Martino et al., 2000). Work is still in progressto try and elucidate these apparent inconsistencies.

Other dimensions of the temporal theoryNeurological accounts of dyslexia usually ascribe at leastsome of the symptoms observed to a left-hemisphere

2384 M. Habib

dysfunction. That the left hemisphere is a good candidate forsubserving the role of rapid processing of brief stimuli isalso widely admitted (for the most recent evidence, see Belinet al., 1998; Liegeois-Chauvel et al., 1999). Adult aphasicswith acquired left-hemisphere damage are also impaired onrate processing tasks, and the degree of impairment iscorrelated with the extent of the language impairment (Tallaland Newcombe, 1978). In addition, older adults who oftenreport difficulty understanding speech despite normal hearing,exhibit a temporal sequencing decrement (Trainor and Trehub,1989). There is, thus, converging evidence to suspect thatthe left hemisphere is specifically pre-wired to support thefunction of processing transient sensory events, especiallywhen these events become meaningful through their temporo-spectral characteristics. Therefore, the notion that dyslexiamay in fact be a ‘dyschronia’ (Llinas, 1993) has emergedduring the last few years. One group of such studies hasconcerned the competence of dyslexic children in fine motorskills. The first evidence in this area has come from earlystudies by Stambak, showing that dyslexic children performsignificantly worse than normal in tasks where they have toreproduce a rhythmic tapping sequence (Stambak, 1951).More recently, Nicolson and Fawcett have repeatedly shownthat dyslexic children differ significantly even from reading-age controls in tasks involving automation of motor skill,motor reaction times, speed of naming and even in pure bodymotor balance (Fawcett and Nicolson, 1992, 1994; Nicolsonand Fawcett, 1993, 1994). Although initially emphasizing apossibly specific automation defect in dyslexia, these authorscurrently favour the thesis of a cerebellar involvement,especially in view of evidence of time estimation deficits indyslexics, a function thought to depend on the activity of thecerebellum (Nicolson et al., 1995; Fawcett et al., 1996). Thisposition has been reinforced by recent results which Nicolsonand colleagues (Nicolson et al., 1999) and others (Rae et al.,1998) have obtained with functional imaging, both studiesshowing abnormal metabolism in the right cerebellum indyslexics.

Finally, in clinical practice, there are numerouscircumstances where dyslexic children seem to have troublewith various aspects of temporal processing, well beyond thesole sensory motor level. For instance, it is very usual tofind severe delays in time duration awareness, sequentialnaming problems for concepts pertaining to time (such asthe days of a week), errors in time relocation of memories, andvagueness of temporal distance or remoteness appreciation. Itis not rare to see a parent of a dyslexic child, who was formerlydyslexic, admitting his or her own persisting problemsoccasionally emerging when confronted by situations wheretime constraints have to be handled. Hence, the termdyschronia could apply to dyslexia from more than one pointof view. Whether or not these different levels of ‘temporalfeatures’ impairment are dependent on the same mechanismis not yet known, but represents a reasonable and testablehypothesis.

Contribution of electrophysiological studies tothe understanding of the neurology of dyslexiaRecent years have seen a growing use of electrophysiologicaltechniques in research on the neurobiological mechanismsunderlying language-learning disorders. As speech processingand reading are complex cognitive skills, entailing severallevels of brain organization, these processes can be difficultto differentiate with behavioural measures. Event-relatedpotentials (ERPs) provide sensitive neurophysiologicalmeasures of the timing and cortical utilization of differentstages of cognitive processing, and thus are well suited forinvestigations of the levels of cognitive processing requiredfor reading. ERPs have been shown to be valuable in thestudy of normal cognitive development, as well as in theinvestigation of cognitive disturbances in childhood (e.g.Martineau et al., 1992; Stauder et al., 1993; Taylor, 1995).Most studies were devoted to ‘classical’ electrophysiologicalevents such as mismatch negativity (MMN), P300 and N400(for a review of peculiarities of ERPs in childhood, see Taylor,1995). However, some works also described abnormalities ofearlier events such as N1, P2 or N2 in dyslexic or LLIchildren, but these will not be reviewed here.

MMNThe MMN is an ERP characterized by a negative deflectionwith a frontocentral distribution, that peaks between 100 and250 ms after stimulus onset. The MMN is thought to begenerated in the supratemporal auditory cortex and is elicitedin situations where any physically deviant auditory stimulusoccurs randomly and infrequently in a series of homogeneous,or standard, stimuli (Naatanen et al., 1978). It can be elicitedindependent of attention and by very small acoustic changes.The MMN therefore reflects an automatic ‘change-detectionresponse’ (Kraus et al., 1995) and may be used to investigate,at a pre-attentive level, whether the auditory system hasdistinguished between two stimuli.

Using the MMN evoked response, Kraus and her colleagueshave obtained evidence suggesting auditory deficits in certainchildren with learning problems (Kraus et al., 1996). Usingspeech stimuli from two continua (/da/ to /ga/ and /ba/ to/wa/), these authors found that learning-impaired childrenwere poorer in speech discrimination than were normalcontrols, and that impaired discrimination was correlatedwith diminished MMNs. In other words, children who werepoor at discriminating certain speech contrasts also showedreduced or absent MMNs. The MMN is a correlate ofauditory processing at pre-attentive levels, so these findingssuggest discrimination deficits in some learning-impairedchildren originate in the auditory pathways before consciousperception. Several studies using a similar paradigm haveconsistently shown reduced MMN in learning disorderedchildren (for review, see Leppanen and Lyytinen, 1997). Forinstance, Schulte-Korne and colleagues presented 12-year-old dyslexics and controls with either language stimuli (85%


standard /da/, 15% deviant /ba/) or pure tones (standard 1000Hz, deviant 1050 Hz) (Schulte-Korne et al., 1998). TheMMN response differed between the two groups only for thelanguage stimuli. These results point to a specific deficit ofpre-attentive mechanisms for language processes as a possiblesource of these children’s difficulties learning to read. In theperspective of testing the temporal processing hypothesis,Bradlow and colleagues have measured the MMN responseto an auditory contrast /da/–/ga/ and found diminishedresponses in dyslexic children compared with controls(Bradlow et al., 1999); yet, when the transition duration ofthe stimuli was lengthened to 80 ms the dyslexics’ responsebecame closer to that of controls. Interestingly, this effectwas not present when only the behavioural performance onthe same stimuli was recorded, suggesting that the temporaldeficit may be too subtle to appear clinically while clearlymanifesting through electrophysiological investigation.

Recently, Kujala and colleagues have used the MMNresponse to test the hypothesis of a basic auditory dysfunctionin eight adult dyslexics compared with eight controls (Kujalaet al., 2000). They contrasted two stimulus conditions, oneso-called ‘tone-patterned’ where four 500 Hz tones weredisplayed in such a way that the third one was either closeto the fourth (standard pattern) or closer to the secondtone (deviant pattern). In the other condition (‘tone-pair’condition), the stimuli were made of only two tones separatedby either 150 (standard) or 50 (deviant) ms. Only in thetone-patterned condition did dyslexics differ from controls,in such a way that the too-early (deviant) tone failed to elicita MMN in dyslexics, whereas the two groups did not differin the tone-pair condition. The authors’ conclusion was thatdyslexic adults have problems in discriminating temporalsound features only when they are ‘surrounded by otherstimuli, such as phonemes in words’.

Finally, one potentially useful application of this methodhas been proposed by Leppanen and Lyytinen who comparedthe MMN in 6-month-old infants with and without familialrisk of learning disorder (Leppanen and Lyytinen, 1997).Children genetically at risk displayed reduced MMNamplitudes in the left electrodes only, suggesting a predictivevalue of this pattern for the later occurrence of dyslexia.

P300In another group of electrophysiological studies ofdevelopmental language impairments, the amplitude and/orlatency of the P300 component has been compared. TheP300 is elicited in ‘odd-ball’ tasks where subjects must attendto a train of frequently occurring stimuli and respond at thepresentation of a different, infrequent deviant stimulus. Thisevent is related to conscious processing and evaluation ofstimuli as well as memory updating. Several studies havereported a smaller or later P300 in developmental dyslexics(Taylor and Keenan, 1990) and in children with attention-deficit disorder (Holcomb et al., 1985), suggesting inefficientprocessing of task-relevant stimuli. Duncan and colleagues

found P300 abnormalities among adults with childhooddyslexia only in those also suffering from attention-deficitdisorder (Duncan et al., 1994). Since attention deficits arepresent in many dyslexics, it is difficult to determine therespective contribution of the two disorders to the ERPabnormalities (Taylor, 1995).

N400An anomalous N400 has been observed in many studies ofdevelopmental language disorders (Stelmack et al., 1988;Neville et al., 1993). The results, however, are inconsistentmaking interpretation difficult. Stelmack and colleagues, forexample, found a reduced N400 in dyslexics, which theauthors interpreted as a ‘failure to engage long-term semanticmemory’ (Stelmack et al., 1988). Other investigators (Nevilleet al., 1993), on the other hand, found an enhanced N400in language-impaired children. More recent observations(M. Besson, personal communication) suggest that the N400,classically obtained when brain activity is recorded whilenormal subjects read incongruous sentences (‘the motherholds the child in her nostrils’) but not with recordings duringreading of sentences with congruous endings (‘. . . in herarms’), is elicited in dyslexics on congruous endings as well.This would mean that semantic integration could be deficientor more effortful in dyslexics, or, alternatively, that whenreading dyslexics use semantic strategies not used bynormal readers.

The contribution of brain functional imagingto the neurology of dyslexiaTable 2 summarizes 13 studies published to date in whichimages of the functioning brain from a group of dyslexicsand a group of matched non-dyslexic controls have beencompared. It must be noted, first, that most of these studieshave involved adults with a past diagnosis of learning disordermainly affecting reading abilities, so that it is highly difficultto retrospectively ascertain the type and intensity of thedisorder. Secondly, these studies did not take into accountthe diversity of clinical forms of dyslexia and thus areexposed to the possible pitfall of putting together cases withdifferent pathophysiological mechanisms. The variety ofimaging methods, from magnetoencephalography tofunctional MRI (fMRI), as well as multiple techniques andexperimental designs even across studies using one method,render fragile any attempt to draw firm conclusions from thisoverview. However, some important information has beenalready obtained.

Brain activation during phonological tasks indyslexicsThe first study to use PET and 15O-labelled water in dyslexicswas that of Rumsey and colleagues (Rumsey et al., 1992).

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2388 M. Habib

Tab

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(1)

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98dy

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MT

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However, this study (as well as two more from the samegroup, see Table 2), used a region of interest method foranalysis which limits the scope of the results since it isalways possible to overlook a peak of activation situatedoutside chosen regions with this method. Moreover, sincethe choice of regions of interest is dictated by preconceivedideas, the outcome of such studies is inevitably weakenedby a risk of tautology. However, the results were importantand have served as a basis for subsequent studies.

Fourteen adult dyslexics and 14 control subjects performeda rhyming task in which they had to press a button eachtime two words, within a pair presented binaurally throughheadphones, were judged to rhyme. Rhyming tasks areclassically thought to explore some aspects of phonologicalawareness. To achieve such a task, subjects must concentrateon the sound form of the word endings, keep them in short-term memory and compare them according to phonologicalsimilarity. Such a task is especially difficult to perform foradult dyslexics who usually compensate by trying to resort tovisual-orthographic mechanisms. For instance, non-rhymingpairs such as ‘shoe’/‘toe’, that are orthographically similar,and others such as ‘head’/‘said’ which rhyme but areorthographically dissimilar are particularly puzzling for manydyslexics, showing high error rate in this task. In the studyby Rumsey and colleagues, the task is made intentionallyeasy by avoiding such conflicting pairs (Rumsey et al., 1992).The main result is that dyslexics fail to activate a ‘lefttemporoparietal region’ activated in controls performing thetask. Moreover, an interaction between group and conditionfor the left inferior and right anterior frontal regions wassuggested in that dyslexics showed a trend to relativedeactivation in these regions, whereas controls showed anon-significant increase in activity. Finally, dyslexics showedan activation compared with controls in a right-middletemporal region. From these results, the authors concludethat the main dysfunctional region in dyslexia is situated inthe temporal cortex of the left hemisphere, and that thisdefect is related to their core phonological deficit.

The first 15O PET study of dyslexics using whole-brainscanning and voxel-based analysis is that of Paulesu andcolleagues (Paulesu et al., 1996). These authors used thesame experimental paradigm as in a previous study (Paulesuet al., 1993) comparing a rhyming and a memory condition.When subjects have to remember six letters successivelyflashed on a screen (‘memory’ condition), they try topronounce them subvocally, in order to put them in theauditory phonological store postulated in classical models ofworking memory (Baddeley, 1986). In another (‘rhyming’)condition, previously used by Sergent and colleagues (Sergentet al., 1992), subjects pronounce letters mentally, but uniquelythis task has no memory requirement and consists of adecision whether the name of a letter rhymes with a targetletter ‘b’ (‘b’ rhymes with ‘c’, not with ‘h’). In normalindividuals, both conditions activate a large perisylvian area,including Broca’s and Wernicke’s areas, whereas parietaloperculum activation is specific to the memory condition.

Paulesu and colleagues found a specific pattern ofactivation in their five dyslexics, compared with five controls(Paulesu et al., 1996). In the memory task, dyslexics showedblood flow increases only in the posterior part (inferiorparietal cortex) of the large perisylvian area activated incontrols, whereas in the rhyming task, these patients onlyactivated its anterior part (Broca’s area). The common findingwith both tasks was the absence of activation of insularcortex. This led the authors to an interpretation of dyslexicdeficits in terms of disconnection between anterior andposterior zones of the language area. Since such impairedactivation of the insular cortex has not been replicated byother functional imaging studies of dyslexics, this hypothesisawaits further evidence. Likewise, most studies published todate have shown increased rather than reduced activity closeto Broca’s area during phonological tasks in dyslexics.However, the finding of reduced left superior temporalactivation is consistent with other more recent studies (seebelow). Finally, the disconnection hypothesis has gainedadditional credence following a recent study (Horwitz et al.,1998) showing that some areas, especially the angular gyrus,fail to co-activate in dyslexics.

Brain functional anatomy of reading in dyslexiaThree important functional imaging studies of reading indyslexics have been reported in the last few years, one usingthe PET method with 15O radiotracer, the second one usingfMRI, and the third (historically the first), withmagnetoencephalography.

Comparing 17 right-handed dyslexics and 14 controls,Rumsey and colleagues performed a PET study which,unlike their previous studies, used a voxel-based whole-brainimaging technique (Rumsey et al., 1997b). The main objectiveof their study was to try to contrast orthographic andphonologic processes in reading. This was done using twodifferent paradigms, one named ‘pronunciation’, whereparticipants had to read aloud pseudowords (presumablyrelying on phonological processing) and irregular words(calling for orthographic processing). The other group oftasks, called ‘decision making tasks’, consisted of havingparticipants read two words or non-words with either aphonological instruction (decide which one of two non-wordssounds like a real word) or an orthographic one (decidewhich of two homophone forms of a same word is correctlyspelled). Besides differences in the global volume ofactivation between the two groups (more brain tissue activatedin dyslexics), the only significant changes observed indyslexics were reduced activations and unusual deactivationsin left posterior temporal/inferior parietal areas, in the‘pronunciation’ paradigm. The authors comment on theabsence of any difference between the locations of brainactivation with the word and non-word versions of the tasks,which could result, they suggest, from a common mechanismfor both kinds of reading errors in dyslexia. Finally, inanother report of the same experiment (Rumsey et al., 1999),

2390 M. Habib

these authors show that activation in only one region, theleft angular gyrus, was correlated with reading skill, and thatthe direction of this correlation was opposite in controls(positive) and dyslexics (negative correlation). They concludefrom this result that the left angular gyrus is ‘the mostprobable site of a functional lesion in dyslexia’.

With fMRI, using imaging parameters that were not optimal(9-mm thick slices, 17 regions of interest ‘that previousresearch had implicated in reading and language’), Shaywitzand colleagues proposed to 29 dyslexics and 32 controls acomplete series of tasks tapping various levels of processingin reading: a line orientation judgement task, presumablyexploring low-level perceptual mechanisms; a letter-casejudgement, presumed to reflect orthographic mechanisms; asingle letter rhyme and a non-word rhyme task, exploringthe phonological level of processing; and a semantic categoryjudgement task (Shaywitz et al., 1998). The main resultwas that in normals there was relative overactivation withphonological tasks (in comparison with orthographic ones)in posterior regions [posterior temporal, Brodmann area (BA)21; supramarginal and angular gyri, BA 39 and 40; andinferior lateral temporal region, BA 37], and a reversed pattern(greater anterior than posterior activation when contrastingphonological and orthographic processing) in dyslexics. Theauthors propose a general explanation for posteriorhypoactivation in dyslexics, that it is ‘due to actual disruptionin a system in charge of phonological processes’, whereasBroca’s area hyperactivation reflects ‘increased effort requiredof dyslexics in carrying out phonological analysis’.

Finally, probably the most informative study on brainfunctioning during reading tasks in dyslexics is that ofSalmelin and colleagues (Salmelin et al., 1996). These authorsused the method of magnetoencephalography to compare sixdyslexics and eight controls on various reading tasksinvolving Finnish words and non-words presented for 300ms every 3 s. Since this method provides only an approximatelocation for the presumed sources of recorded signal, onemust remain cautious about information on the actual brainregions involved. However, the remarkable temporalresolution of the method makes it a valuable complement toother imaging methods, which can only provide informationabout processes occurring within a period of time of severalseconds. Whereas normal controls activated a left inferiortemporo-occipital region 180 ms after the presentation ofwords, dyslexics totally failed to activate this same region.Moreover, a left inferior frontal area activated within 400 msin four out of six dyslexics, but in none of the controls.

This result is of great importance because it clarifies dataobtained by other methods whose interpretation had remainedobscure. For instance, the inferior temporo-occipitalactivation is reminiscent of activation of BA 37 found inseveral studies. Since it appears as early as 180 ms after thepresentation of a word, it is likely to represent early visualprocessing or immediate phonological processing occurringbefore any conscious recognition has occurred. That dyslexicsdo not activate this process suggests either an inability to

achieve these early operations of global word-form perceptionor inefficient immediate phonological extraction. On the otherhand, abnormal activity in Broca’s area could result fromcompensatory silent articulation of a misperceived visualword form. These results thus provide information about thetime course of reading in two areas already suspected to bedysfunctional in dyslexia, allowing a more completediscussion of their role.

A recent study by Brunswick and colleagues using 15O-PET to investigate explicit and implicit reading in dyslexicadults and normal readers came to similar conclusions(Brunswick et al., 1999). In both reading conditions, dyslexicsactivated two regions to a lesser degree than controls: leftbasal temporal lobe (area 37) and left frontal operculum. Inthe explicit reading condition, they overactivated a left pre-motor region situated 20 mm lateral to the area of reducedactivation. This finding confirms that Broca’s area is one ofthe most important brain regions at the origin of the learningimpairment in dyslexics, but that this important role isprobably not unique, since different cortical zones withinthis anatomical region display different patterns of functionalactivation. Involvement of Broca’s area is reminiscent of theabove-mentioned evidence of motor-articulatory deficit indyslexia (Heilman et al., 1996).

Using the same inclusion criteria as in Brunswick’s study,we recently conducted a parallel study in French-speakingdyslexics and matched controls (J. F. Demonet et al.,unpublished results). The only region to show greateractivation in controls than in dyslexics on reading tasks wasprecisely the left inferior temporal region, exactly at thejunction between lateral and mesial aspects of the temporallobe. It is noteworthy that this region is ideally located toserve as an interface between areas associated with processingvisual features of written words (especially the more mesialextrastriate cortex), other temporo-occipital regions involvedin complex visual processing (including the motion areawhich is in close vicinity), and more dorsal language areasin the middle and superior temporal gyri, possibly subservinggrapheme-to-phoneme transformation. One plausible rolewhich could be attributed to this crucial region could be thatof mediating the visual entry into the linguistic system,combining orthographic, lexical and phonological informationabout words. Unpublished observations show that this regionalso activates with stimuli given in the auditory modalitywhen subjects have to perform an orthographic computationon the heard words. Such data are also compatible with thisformulation. Finally, the same region has been found activatedwith Japanese kanji characters, suggesting that its role isprobably more orthographic than phonologic (Uchida et al.,1999).

fMRI study of motion perception in dyslexiaBy reference to theories based on psychophysical andelectrophysiological evidence of a deficit in the magnocellularcomponent of the visual pathways, Eden and colleagues


designed an fMRI experiment contrasting two visualconditions that differentially activate the magnosystem andthe parvosystem (Eden et al., 1996a). The experimentalcondition (M-stimulus) consisted of a moving dot task, whereparticipants had to look passively at an array of dots movingon a computer screen. In the reference task (P-stimulus),they had to look at a stationary pattern. The first conditionis supposed to activate the magnosystem preferentially,especially the human area V5 (MT) which has been shownin earlier experiments to be in the posterior part of theinferior temporal sulcus. As expected, normal controlsactivated this area bilaterally with the M-stimulus, but notwith the P-stimulus, whereas dyslexics failed to activatethis region even in the moving-dot condition. The authors’conclusion is that their data provide a direct demonstrationof a magnocellular deficit in dyslexia, which could be onemanifestation of a basic disorder in the processing of temporalproperties of stimuli (Eden et al., 1996b).

Demb and colleagues have replicated these findings infive adult dyslexics with a similar fMRI method, but withlocalization of the different areas by a more accurate techniquethat uses computational flattening of each brain (Demb et al.,1997, 1998). Speed discrimination thresholds were measuredpsychophysically for each participant to determine asaccurately as possible the efficiency of the magnocellularpathway. Finally, five reading tasks were administered inorder to evaluate the impact of the magnodefect on readingperformance. Stimuli were low luminance level, movinggratings, known to preferentially stimulate M-pathways, asopposed to control stimuli ‘designed to elicit strong responsesfrom multiple pathways’. The results showed that fMRIresponses in both V1 and MT� were less in dyslexics acrossthe full range of contrasts explored, with larger differencesat higher contrasts, especially in V1. Moreover, there wasa strong negative correlation between MT� activity anddiscrimination thresholds, as well as a weaker but significantcorrelation for V1 (in both dyslexics and controls). Finally,a strong correlation was found between MT� activity inthe M-condition and reading speed (in both dyslexics andcontrols).

Taken together, these results obtained in the visual modalityin dyslexics have been suggested as a potential brain markerfor dyslexia (see, however, Vanni et al., 1997 for negativeresults with magnetoencephalography). However, it must benoted that neither Eden and colleagues (Eden et al., 1996a)nor Demb and colleagues (Demb et al., 1998) havecharacterized their dyslexic adults by the neuropsychologicalform of dyslexia. For instance, it would have been interestingto know whether pure phonological dyslexics, with a prevalentgrapheme-to-phoneme conversion deficit, are more or lessimpaired in their ability to activate their visual motion area.On the other hand, it would be important to know whethermagnocellular impairment impinges specifically on thepossibility of using global, whole-word strategies in reading,which could suggest a causal link between the perceptualdeficit and learning disorder. On the contrary, if even purely

phonological dyslexics fail to activate their motion area,this could mean that both visual deficit and phonologicalimpairment stem from a common mechanism, as, for example,suggested by the temporal processing theory.

The temporal processing deficit theory: aworking hypothesis and perspectives forremediationAs mentioned above, although sometimes criticized(Studdert-Kennedy and Mody, 1995; Mody et al., 1997;Nittrouer, 1999), the temporal processing theory remainsone of the most attractive—although largely speculative—explanations available to date that accommodates the clinicaland neuropsychological complexity and diversity of dyslexia,as well as the neurological and physiological data. Moreover,it represents a plausible basis for trying to reconcile dataobtained from the neuropsychological approach, pointing toa phonological deficit, and those demonstrating a visualimpairment. Although the population covered by the term‘dyslexic’ may seem rather heterogeneous (some havingmainly phonological problems, some not, some sufferingfrom motor clumsiness, others being excellent at all kinds ofmotor tasks, some clearly performing poorly on spatial tasks,others managing beyond the average performance of non-dyslexic subjects), it remains tempting and clinically intuitiveto try and explain all these cases, including some fallingoutside the strict definition of dyslexia, through a uniquegeneral framework. The temporal theory potentially offerssuch a useful framework. I will propose here that, beyondthe sole sensory-motor dimension of such evidence, thetemporal processing theory would be extended to other morecognitive characteristics of the dyslexic’s brain functioning.

Difficulties for processing time in its different dimensionsis an amazingly universal characteristic of the dyslexicindividual. Thus, it is plausible that a general difficulty forthe brain (most probably in the left hemisphere) is to integraterapidly changing stimuli. Such a difficulty could account for(i) an impaired perception of transient auditory stimuli, suchas consonants; (ii) a deficit in generation or judgement oftemporal order; and (iii) deficits in multiple stages ofreading that utilize rapid processing, e.g. visuospatial letterarrangement, global word-form perception, integration ofsuccessive relative word positions during oculomotorscanning. In this context, the central feature of phonologicalawareness could appear as a typically sequential activityrequiring at the same time intact phoneme representation,efficient temporal processing of the phonemic constituents andadequate maintaining of information in short-term memory.

Even apparently more complex cognitive functions, suchas awareness of time passing, processing of sequences ofsuccessive events or duration judgement, also probablynecessitate intact temporal coding of information. Therefore,in the absence of a satisfactory explanation for such commonfindings in dyslexics, which can be formulated in terms of

2392 M. Habib

Fig. 1 A postulated mechanism for dyslexia and associated developmental disorders.

impaired or delayed ‘temporal notions’, one can reasonablyhypothesize that they also stem from a developmentaldeficiency in the brain networks devoted to various aspectsof time coding. It is also conceivable that developmentaldyscalculia, which is often associated with severe forms ofdyslexia, may implicate such time processing-dependentcognitive processes: the concept of number (Spelke andDehaene, 1999), including the mental representation ofquantities, may rely heavily on integration of sequentialprocessing into a more abstract form, and thus requireadequate temporal coding of numerical information. Finally,fine motor coordination, as exemplified in bimanual rapidalternation tasks (Wolff et al., 1990b; Wolff, 1993) or morespecifically in graphomotor gestures, probably relies on suchtime-dependent mechanisms and thus on time-coding brainstructures, if they exist. The often associated occurrence ofdysgraphia may therefore be accounted for in this context(although the reason why some even severe dyslexics mayhave normal graphic abilities remains obscure). It is nottrivial to remark that such general motor coordinationimpairment has also been suspected as underlying articulatorydeviance observed in dyslexics’ oral productions (Wolff et al.,1990a). Automation of orthographic rules, whose impairmentis the almost inevitable outcome of all types of dyslexia,may itself require intact sequential processing to first buildan efficient phoneme–grapheme correspondence procedure,and then achieve adequate mastering of the morphosyntacticfeatures of one’s native language, since syntax itself iseminently dependent on temporal integration of successiveevents, although to a variable extent in different languages.Figure 1 illustrates how different elements of the dyslexicsyndrome may tentatively be accounted for by a generaltemporal coding deficit.

From a neurobiological point of view, one may speculatethat the dyslexic brain, perhaps due to abnormal maturational

neuronal migration and assembly and/or connectivity,especially in the left-hemisphere language areas, is normallyunable to hold any kind of functions requiring temporalsimultaneity and/or coordination between even remoteneuronal zones. Synchrony of activity between groups ofneurons is viewed as one of the fundamental features ofelectrical activity of the brain (Llinas, 1993). Furthermore,it is possible that the same general brain property is alsoresponsible for processing all kinds of brain signals whosesignificance relies on their temporal characteristics. Moreover,such temporal coordination of activity in different, evenremote, cortical regions probably requires control from oneor more ‘pacemaker’ structures able to homogenizespontaneous or evoked activity in groups of neurons normallyfunctioning in concert. Anatomically, the cerebellum appearsas one of the best candidates to carry out this task, sincespontaneous rhythmic activity and remote propagation of thisactivity has been clearly demonstrated there (Llinas, 1993;Ivry, 1997). Recent evidence of reduced cerebellar activityin dyslexics performing a motor learning task (Nicolsonet al., 1999) provides an interesting basis for further testingof this hypothesis in normal readers and dyslexics.

Other contributing evidence has also been obtained fromneuroimaging in normal readers. Fiez and colleagues haveshown that activation of Broca’s area is obtained in a similarway when subjects have to listen to consonants and rapidnon-verbal stimuli, but not when they listen to steady-statevowels without rapid acoustic changes (Fiez et al., 1995).Belin and colleagues have used auditory activation with PETto show that non-verbal sounds containing rapid (40 ms) orextended (200 ms) frequency transitions yield differentpatterns of activation in the auditory cortex, bilateralsymmetry for slow-transition stimuli and left unilateralactivity for rapid transitions (Belin et al., 1998). Similarexperiments in dyslexics would certainly provide valuable


information about the temporal processing hypothesis indyslexia and are currently in progress. For example, it isimportant to know whether or not dyslexics recruit differentbrain areas or a different amount of brain tissue dependingon the temporal properties of a speech or non-speech signal.Magnetoencephalography, due to its excellent temporalresolution, may be an ideal tool for this purpose (Nagarajanet al., 1999). Finally, such functional imaging studies indyslexics, that have only been performed for the moment inadults, could be of great value in children, especially asneurobiological markers of therapy efficacy, for example, inrelation to the recently proposed training methods usingacoustically modified speech to improve temporal processingdeficits in dyslexics (Merzenich et al., 1996; Tallal et al.,1996; Habib et al., 1999).

In the context of the hypothesis discussed above, it wouldbe of great interest to seek a relationship between the degreeof temporal processing impairment at the most basic leveland patterns of temporal impairment at a cognitive level, andto evaluate the efficiency of training methods on each ofthese levels. Obviously, however, one important issue forfuture research will be to try and understand why a supposedlycommon basic temporal deficit yields such differentmanifestations and why these manifestations are so variablein their association with the reading impairment.

AcknowledgementsThe author wishes to thank Professor R. S. J. Frackowiakand Dr J. F. Demonet, Dr F. Robichon and Dr K. Giraud fortheir valuable comments on specific paragraphs, Ms FrancoiseJoubaud and Ms Paule Samson for technical and editingsupport, and several colleagues, students, researchers,clinicians or engineers for their participation in researchstudies and/or their sharing ideas and knowledge through alarge number of highly rewarding discussions: A. Galaburda,S. Witelson, P. Tallal, U. Frith, M. Taylor, V. Rey, B. Teston,R. Espesser, to mention but a few. This work was supportedby INSERM P.R.O.G.R.E.S. program, a grant of the FrenchMinistry of Health (P.H.R.C. 97-APHM UF 1848), a researchcontract with C.N.R.S. (P.R.A.) and the ‘Cognitique’programme from the Ministry of National Education. Partsof the brain functional experiments cited were carried outunder Biomed contract BMH4-CT96–0274.

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Received January 24, 2000. Revised June 20, 2000.Second revision July 25, 2000. Accepted July 27, 2000

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