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Neurobiology of dyslexia:a reinterpretation of the dataFranck Ramus

1,2

1 Laboratoire de Sciences Cognitives et Psycholinguistique (EHESS/CNRS/ENS), 46 rue dUlm, 75230 Paris Cedex 5, France2 Institute of Cognitive Neuroscience, University College London, 17 Queen Square, London WC1N 3AR, UK

Theories of developmental dyslexia differ on how to bestinterpret the great variety of symptoms (linguistic,sensory and motor) observed in dyslexic individuals.One approach views dyslexia as a specic phonologicaldecit, which sometimes co-occurs with a more generalsensorimotor syndrome. This article on the neurobiol-ogy of dyslexia shows that neurobiological data areindeed consistent with this view, explaining both how aspecic phonological decit might arise, and why asensorimotor syndrome should be signicantly associ-ated with it. This new conceptualisation of the aetiologyof dyslexia could generalize to other neurodevelopmen-tal disorders, and might further explain heterogeneitywithin each disorder and comorbidity betweendisorders.

Developmental dyslexia is a mild hereditary neurologicaldisorder that manifests as a persistent difculty inlearning to read in children with otherwise normalintellectual functioning and educational opportunities.Researchers typically attempt to characterize dyslexia at

the genetic, neurobiological and cognitive levels of description, and to uncover causal pathways between thedifferent levels.

One notable aspect of dyslexia that puzzles theoristsand causes much confusion is the variety of symptomsthat are consistently associated with it: problems withreading, of course, but also problems with phonology (themental representation and processing of speech sounds),sensory difculties in the visual, auditory and tactiledomains, problems with balance and motor control, andmore [1,2] . Another puzzle is that dyslexia is frequentlycomorbid with other neurodevelopmental disorders, suchas specic language impairment (SLI), attention decit

hyperactivity disorder (ADHD) or dyspraxia [3,4] .This plurality of symptoms has led to two broad

approaches to dyslexia. One has been to concentrate onone particular cognitive symptom thought to reect themost direct causal explanation: for instance, in thephonological theory of dyslexia [5] (Figure 1 a), a specicdecit in the representation and processing of speechsounds is thought to cause difculty in learning andhandling the relationship between letters and speechsounds (graphemephoneme correspondences). Withinthis approach, the other symptoms of dyslexia are

considered as simple comorbid markers, without causalrelationship with the reading disability.

Conversely, the alternative theoretical approach gives aprimary explanatory role to the sensory and/or motorsymptoms. This approach has led to the formulation of theories of dyslexia tracing the causes of reading disabilityback to auditory (temporal) processing decits (via thephonological decit) [6,7] , visual (magnocellular) dysfunc-tion [8,9] and/or motor (cerebellar) dysfunction [10,11] .The culminating point of this approach has been theunication of its different variants under the generalmagnocellular theory ( Figure 1 b), in which a generalizeddysfunction of cells in the magnocellular pathway affectsall sensory modalities and prolongs itself in the posteriorparietal cortex and the cerebellum [1]. Uniquely, thistheory accounts for reading disability both throughauditoryphonological and visualspatial decits, andencompasses all known cognitive, sensory and motormanifestations of dyslexia.

However, as I have argued elsewhere [2,12] , themagnocellular theory only partly succeeds in explaining

the whole dataset. In particular, it fails to explain why theprevalence of sensorimotor dysfunction is so much lowerthan that of the phonological decit in the dyslexicpopulation. Even within the subset of dyslexics affectedby sensory and/or motor disorders, the causal relationshipwith the reading impairment is far from clear [2,13] . Onthe basis of a comprehensive review of the literature,I have previously advocated that dyslexia is, in mostindividuals, explained by a specic phonological decit;furthermore, a general sensorimotor syndrome occursmore often in the dyslexic than in the general population,but does not by itself play a signicant causal role in theaetiology of the reading impairment [2] . This paperreviews the neurobiology of dyslexia and argues that theavailable data do indeed support this view, by explainingboth how a specic phonological decit might arise andwhy a sensorimotor syndrome should be signicantlyassociated with it.

Data from anatomical studiesPost-mortem examination and brain imaging studies havedocumented many differences between dyslexic andcontrol brains, for example in the left perisylvian cortex,the underlying white matter, the thalamus, the corpuscallosum, and the cerebellum (see Refs [14,15] forreviews). In most cases, the functional signicance of

Corresponding author: Franck Ramus ([email protected]). Available online 14 October 2004

Opinion TRENDS in Neurosciences Vol.27 No.12 December 2004

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TRENDS in Neurosciences

Poorreading

Poorgrapheme phonememapping

Thalamicdisruption

MGN and LGN

Motorimpairment

Visualimpairment

Cerebellardisruption

Auditoryimpairment

Left hemisphereperisylviananomalies

Hormonalconditions

Genetic riskfactor for cortical

anomalies

Geneticmodulation of

anomalylocation

Genetic riskfactor

Environmentalrisk factor

Posterior parietalcortex disruption

Poorphonologicalawareness

Poor verbalshort-termmemory

Slowlexical

retrieval

Poordigit span

Slowautomatic

naming

Poorspoonerisms

Poorcoherent motion

detectionClumsinessPoor frequency

discrimination

Poorreading

Poorgrapheme phonememapping

Left hemisphereperisylviananomalies

Genetic riskfactor

Phonologicaldeficit

Poordigit span

Slowautomaticnaming

Poorspoonerisms

B e h a v i o u r

C o g n i t i o n

B i o l o g y

B e h a v

i o u r

C o g n i t i o n

B i o l o g y

Magnocellulardisruption

MGN and LGN

Motorimpairment

Visualimpairment

Cerebellardisruption

Auditoryimpairment

Genetic riskfactor

Posterior parietalcortex disruption

Poorcoherentmotion

detection

ClumsinessPoor frequencydiscrimination

(a) The phonological theory (b) The magnocellular theory

(c) The proposed model

Figure 1. Three causal models of the aetiology of developmental dyslexia. Ovals represent traits at the biological, cognitive and behavioural levels of description; arrowsrepresent causal relationships between traits. Only a subset of all possible behavioural manifestations is represented. (a) Traits and relationships postulated by thephonological theory. (b) Traits and relationships postulated by the magnocellular theory. (c) The proposed model. Solid lines are used for core traits of developmentaldyslexia,dashed lines for associated traits that are not necessarilypresent in each affected individual. Cases of comorbiditywith other developmental disorders (e.g. speciclanguage impairment) are not represented. Abbreviations: LGN, lateral geniculate nucleus; MGN, medial geniculate nucleus.

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these brain differences has not been elucidated. It is noteven clear which of those differences are specicallyrelevant to dyslexia, given comorbidity issues. Never-theless, the functional signicance of two types of brainanomaly has been studied in greater detail.

Anomalies of cell migration (molecular layer ecto-pias and focal microgyri) have been observed byGalaburda and colleagues in the perisylvian cortex of dyslexic brains [1618] , predominantly in the left hemi-sphere, and with a much greater prevalence than incontrol brains [19] . Ectopias consist of 50100 neurons(and glia) that, in the course of neural migration, havemissed their target in the cortex and have escaped into themolecular layer through a breach in the external gliallimiting membrane, accompanied by mild disorganizationof the subjacent cortical layers ( Figure 2 ). Microgyri aremore severe disturbances where organization of all layersof the cortex is severely affected. Cytoarchitectonicanomalies have also been observed in the thalamus of dyslexics: in the lateral geniculate nucleus (LGN), themagnocellular layers were more disorganized and con-

tained smaller cell bodies [9] . Similarly, there was adisproportionate number of small neurons in left medialgeniculate nucleus (MGN) of dyslexics [20] .

It is natural to hypothesize that anomalies in themagnocellular layers of the LGN are the cause of visualdecits, and that anomalies in the MGN are the cause of auditory decits. Similarly, it is easy to see corticalanomalies in left perisylvian areas as the underlyingcause of phonological, and perhaps other, cognitivedifculties.

In this anatomical evidence, one can therefore seedirect neurological support for auditory and magnocellu-lar theories of dyslexia. The implicit causal (bottom-up)

scenario is that anomalies in the thalamus engenderectopias and microgyri in certain cortical areas to whichthe thalamus is connected. At the cognitive level, thiswould translate into the auditory decit causing aphonological decit, and into the basic visual decitcausing visualspatial attentional problems, as prescribed

by the magnocellular theory. However, this scenario mightwell be incorrect [21] . Indeed, Galaburda and colleagueshave found that, at least in animal models, the causaldirection seems to be the opposite (top-down) that is, thecortical anomalies engender the thalamic anomalies.

More insights from animal modelsIn rats, one can surgically induce ectopias and microgyriby poking a hole in the external glial limiting membrane of the developing cortex during late neocortical neuronalmigration. There are also strains of mutant mice thatspontaneously develop similar malformations. Investi-gation of these animal models has led to several importantndings.

First, newborn rats with microgyri in the frontal,parietal or occipital cortex subsequently developanomalies in the MGN: they have more small and fewerlarge neurons than rats receiving sham lesions, a disrup-tion similar to that found in the MGN of dyslexics [22,23] .This suggests that the direction of causation is indeed top-

down, from the cortex to sensory relays in the thalamus.Furthermore, rats with this type of abnormal MGNperformed less well in an auditory discrimination task[2224] , which conrms that the observed disruption inthe MGN has an impact on auditory capacities. Similarauditory disorders are found in mice with ectopias [25] ,suggesting that this top-down scenario might also occurwhen cortical malformations have a genetic origin.Extrapolated to dyslexia, these ndings suggest that theneural basis of the phonological decit could be primary,whereas the neural basis for sensory impairments wouldbe secondary.

Another interesting aspect uncovered in these studiesis that only male rats and mice with microgyri or ectopiaswere initially found to have impaired auditory function[26,27] . Female rats showed normal auditory performanceand did not show a similar anatomical disruption of theMGN, even though they presented with microgyri assevere as those in males [22] . It was then found that thissex difference had a hormonal basis; indeed, female ratsthat were androgenized by injection of testosterone duringgestation showed MGN disruption and impaired auditoryfunction in the same way as males [28] . This thereforesuggests that the neural basis for the phonological decitcan occur either with or without the secondary sensoryimpairments, depending on whether certain hormonalconditions are met.

Finally, the cortical anomalies themselves seem to havean impact on cognitive function: mice and rats withspontaneous or induced ectopias and microgyri exhibit a variety of learning decits [2932] , including problemswith working memory [3335] . Furthermore, the locationof the cortical disruption inuences the specic type of learning decit exhibited by the animal [36,37] , but notthe likelihood of further thalamic disruption and sensoryimpairment [25] . This suggests that the location of corticalabnormalities will be crucial to the nature of the cognitivedecits observed in dyslexia, whereas sensory impair-ments can be expected to arise regardless of the corticallocus and specic type of cognitive decit.

Figure 2. A molecular layer ectopia in a dyslexic subject. Neurons and glia haveescaped into the molecular layer of the cortex,through a breach in the external gliallimiting membrane, to form an ectopia (between the two arrows). Scale bar,250 mm. Micrograph kindly provided by Glenn D. Rosen.




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Scaling up to dyslexia Although the data already reviewed here are not suf-ciently constraining to specify a single neurobiologicalmodel of dyslexia, they seem most compatible with onebased on the following hypotheses ( Figure 1 c):

Genetically driven focal cortical abnormalities suchas ectopias and microgyri, in specic areas of leftperisylvian cortex involved in phonological represen-tations and processing, are the primary cause of dyslexia(Figure 3 ). This is consistent with: (i) anatomical studies of dyslexic brains showing loci of cortical abnormalities; (ii)functional brain imaging studies showing that the verysame areas are involved in phonological processing, andshow abnormal activation in dyslexics; (iii) mouse modelswith ectopias, as already discussed; and (iv) recentndings that the dyslexia susceptibility gene DYX1C1 isinvolved in neural migration, and that the deletion foundin a dyslexic family disrupts its function (Y. Wang et al.,unpublished).

Under certain hormonal conditions (which might ormight not reduce to elevated levels of ftal testosterone),the disruption propagates to the thalamus, provokingadditional (and optional) sensory impairments. This is

consistent with rat and mouse models and the fact thatsensory disorders are present in some, but not all, dyslexicindividuals. Whether this thalamic disruption is speci-cally magnocellular is a subject of debate [1,9,38] and isnot particularly crucial to the present model. Similarly,Stein and Walsh propose that the magnocellular disrup-tion further extends to the posterior parietal cortex andthe cerebellum [1]. If true, this might well explain the visuospatial and motor symptoms observed in certaindyslexics.

In summary, not only do cognitive studies suggest thatdyslexia is a specic phonological decit associated withan optional sensorimotor syndrome, but also the neuro-biological data seem perfectly compatible with this viewand able to explain how this might be.

Explaining heterogeneity within dyslexiaOne essential aspect of the proposed model is that itassumes that focal cortical abnormalities disrupt thedevelopment of the particular cognitive function(s) thatwould normally recruit those areas. Of course, there is not

one single area assumed to be involved in phonologicalprocessing that would be disrupted in dyslexia. Rather,the phonological decit of dyslexics is usually described ashaving three main components: poor phonological aware-ness (the ability to access and manipulate speech soundsconsciously), slow lexical retrieval (evidenced in rapidserial naming tasks) and poor verbal short-term memory(as tested by digit span or non-word repetition). Each of these phonological skills in turn involves a whole networkof cortical areas [39] (Figure 3 c). Interestingly, theobserved distribution of ectopias in dyslexic brains closelymatches this network (compare Figure 3 a with Figure 3 c)as well as larger-scale structural anomalies ( Figure 3 b).But note that dyslexic brains vary in terms of both thenumber and the distribution of their ectopias. Thissuggests that there might be several ways to becomedyslexic, depending on which subset of the phonologicalskills network is affected. This is indeed consistent withdata showing that the different components of thephonological decit vary partly independently and provideadditive contributions to the reading disability [40] . Inbrief, variation in the symptoms of the phonological decitmight straightforwardly reect variation in the distri-bution of the underlying cortical abnormalities.

Generalizing to other developmental disordersFrom these premises, one might of course expect focalcortical abnormalities to sometimes arise outside thephonological network. By the same logic, one would thenpredict disruption to the development of the correspond-ing cognitive functions. This could provide a way toexplain neurodevelopmental disorders other than dys-lexia. For instance, ectopias in areas involved in syntax,morphology and/or the lexicon might engender the variousmanifestations of SLI. Similar abnormalities in therelevant areas might also explain developmental dyscal-culia, developmental prosopagnosia, and at least someforms of autism, ADHD or dyspraxia.

It is particularly interesting to note that, as in dyslexia,a certain proportion of individuals affected by the

(a)

(b)

(c)

Figure 3. Neurobiology of developmental dyslexia. (a) Overall distribution of cortical ectopias observed across different dyslexic subjects (kindly provided byGlenn D. Rosen). (b) Brain areas activated in oral language tasks and exhibitingstructural differences between dyslexics and controls. Areas in orange aresupported by one published study, areas in red by more than one. Reproduced,with permission of Sage Publications, Inc., from Ref. [15] . (c) Brain areas activatedduring performance of the main phonological skills impaired in dyslexia:phonological awareness (yellow), rapid serial naming (red) and verbal short-termmemory (blue). Reproduced, with permission, from Ref. [39] .




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disorders just mentioned present with just the same sortof sensorimotor impairments [3,4145] . Animal modelssuggest a straightforward explanation for this: in bothmice and rats, thalamic disruption occurred under theconjunction of high ftal testosterone and ectopias ormicrogyri, whatever the location of these corticalabnormalities.

Therefore, the present model potentially explains notonly the specic cognitive decits characterizing manydevelopmental disorders, but also the fact that thesedisorders are associated with an optional sensorimotorsyndrome: in all disorders, additional hormonal conditionsare the mediating factor to the sensorimotor symptoms.

Explaining comorbidity between disordersFinally, the postulated structurefunction relationshipalso provides an explanation for the typical comorbiditybetween different developmental disorders. Indeed, noth-ing restricts the distribution of cortical abnormalitieswithin a given cognitive domain. If ectopias span, say, boththe phonological and the syntactic systems, then the

outcome would be a case of comorbid dyslexia and SLI. Allother observed comorbidities can be explained accordingly.

Generating new predictionsOne straightforward prediction of the model is that awhole class of domain-specic developmental disorders ischaracterized by similar focal brain anomalies, thedifferences between disorders reducing to differences inlocalization. Unfortunately, post-mortem work has beenextremely limited past the original studies. Brain imagingstudies of dyslexia, SLI and dyscalculia are certainlycompatible with the present prediction [15] but, owing toresolution limitations, they are currently insufcient totest it seriously. Research on the neurobiology of autismand ADHD has shown rather different types of abnorm-alities [46,47] , but this does not exclude the possibilitythat certain cases of these disorders might be explained byfocal anomalies of the same nature as dyslexia in relevantbrain areas.

Because of the steroid hormonal mediation leading tothe thalamic disruption, the model also predicts anincreased prevalence of the sensorimotor syndrome inmales (regardless of the actual sex ratio in dyslexia). Moreprecisely, it predicts that the male:female ratio will beincreased in the subpopulation with a sensorimotorsyndrome, as compared with the subpopulation withoutit (in dyslexia as well as in other developmental disorders).Such predictions could be easily tested by carrying outpost-hoc analyses on already existing datasets includingreliable individual data on sensory and/or motormeasures.

Another prediction of the model is that if one couldmeasure the relevant hormonal conditions in humanfoetuses, and relate these measures to later outcomemeasures of sensorimotor functions, there would besignicant correlations (more than with measures of each specic cognitive decit). Only major longitudinalstudies including all the relevant measures will be able totest this prediction. In the meantime, one might want tolook for markers of ftal hormonal conditions that persist

throughout development. A possible one is the ratiobetween the lengths of the second and fourth digits(2D:4D ratio), which is inversely correlated to ftaltestosterone levels [48] and signicantly lower in autismthan in the general population [49] . A recent replicationfurther found that the 2D:4D ratio was more specicallycorrelated with the performance of autistic children in visual and motor tasks [50] , which is consistent with themodel (applied to autism), although the evidence is still very preliminary and indirect.

The high heritability of developmental disorders suchas dyslexia and SLI is consistent with the clear geneticorigin of ectopias and related focal anomalies [51,52](Y. Wang et al., unpublished). Furthermore, unless totalcross-heritability between different disorders is shown,the model also predicts that the precise location of corticalanomalies is under genetic control. This is consistent withthe fact that different strains of mutant mice have ectopiasin different locations [29] , but the exact mechanismsinuencing their location are still unknown.

By contrast, ftal hormonal conditions are more likely

to be inuenced by non-genetic factors. The model there-fore predicts a lower heritability of the sensorimotorsyndrome than of specic cognitive decits, which isindeed the case (for auditory and visual versus phonolo-gical decits) [5355] .

It is also notable that all the specic cognitive disordersunder consideration here have a complex genetic aetiol-ogy, involving several regions on different chromosomes[56] . One way to understand this is to speculate that inthese disorders, certain genes are general susceptibilityfactors for focal anomalies such as ectopias, whereas othergenes control the precise location of such anomalies, forinstance by generating molecular gradients interactingwith ectopia susceptibility factors. This broadly predictsthat the genes implicated in all these specic cognitivedisorders will be partly shared (those acting as generalsusceptibility factors), and partly specic to each disorder(those determining specic brain locations). The morespecic predictions are potentially testable using currentmouse models.

Concluding remarksThe model outlined here is compatible with all theavailable cognitive and neurobiological evidence and,uniquely, also offers potential explanations for the associ-ation between specic cognitive developmental disordersand sensorimotor manifestations, heterogeneity withineach disorder, and comorbidity between disorders.

Future research should now aim to uncover the preciselinks between specic genes, brain anomalies and cogni-tive decits. To meet that challenge, research on develop-mental disorders will have to complete a methodologicalrevolution that has only recently begun: the productionand analysis of reliable individual data at all levels of description. Indeed, the present model suggests thatseveral genetic, neurological and cognitive traits areconsistently associated with dyslexia and other disorders,without actually explaining them. This implies that theusual studies focusing on group differences and corre-lations between measures are doomed to confuse core with




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associated decits, and cause with correlation. The futurebelongs to longitudinal studies that will be able to tracecausal pathways throughout development, across genetic,neurological and cognitive measures, and within eachindividual subject.

AcknowledgementsThis work was supported by a Marie Curie fellowship of the European

Community programme Quality of Life (QLGICT 199951305) and aresearch grant from the Fyssen Foundation. I thank Al Galaburda, UtaFrith, John Morton, Alfonso Caramazza and Tim Shallice for discussionand encouragement, and Jeff Lidz and Sarah White for comments on aprevious version of this paper.

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Neurotrophin action on a rapid timescaleYury Kovalchuk, Knut Holthoff and Arthur Konnerth


Molecular motors in neuronal development, intracellular transport and diseasesNobutaka Hirokawa and Reiko Takemura


Binding proteins for mRNA localization and local translation, and their dysfunction in genetic neurological diseaseGary J. Bassell and Soja Kelic


Amyloid-beta precursor protein processing in neurodegenerationValerie Wilquet and Bart De Strooper


Labelling neurons in vivo for morphological and functional studiesPaul Young and Guoping Feng


Post-transcriptional gene silencing in neuronsHenry C. Zeringue and Martha Constantine-Paton




Documents

Ramus 2004 TINS Dyslexia