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How should the nonword ‘jat’ be pro-nounced? Most English speakers wouldagree that it should rhyme with ‘bat’. Yetwhat about the nonword ‘jough’? Shouldit sound like ‘cough’, ‘tough’, ‘dough’ or‘bough’? This example illustrates a majordifficulty of English and other ‘ortho-graphically deep’ languages: mappingsbetween how words are spelled (theirorthography) and how they sound (theirphonology) are only partially consistent.English readers must use the consistencythat is present to support pronunciationof unfamiliar words (such as ‘fint’), butthey also must accurately pronouncewords that violate these same generaliza-tions (for example, ‘pint’). Readers of Ital-ian and other ‘orthographically shallow’languages have an easier task becausemappings between orthography andphonology are highly consistent: a partic-ular letter or letter combination is almostalways associated with the same sound. Inthis issue, Paulesu and colleagues1 usebehavioral measures and functional brainimaging to investigate how the ortho-graphic consistency of one’s native lan-guage affects reading speed and the degreeto which different language-related brainareas are used for reading. The workdemonstrates how brain imaging can beused to address basic research questionsabout mind–brain relationships and howthe results can be applied to questions ofclinical and educational significance.

This study1 was influenced by cogni-tive models of word reading. Previousbehavioral work indicates that skilledreaders of all alphabetic languages auto-matically use multiple procedures totranslate between orthography andphonology, although the precise numberand nature of the procedures is hotlydebated. Common to most models ofreading is some type of sublexical proce-

ciations between orthographic andsemantic (meaning-based) information,and then forming associations betweensemantic and phonological information.Lexical and semantic procedures may helpmaximize reading speed for very commonwords, and they may help constrain theoutput of the sublexical procedure (forinstance, to ensure that ‘pint’ is not pro-nounced so that it rhymes with ‘mint’).Paulesu and colleagues1 theorized that lex-ical and semantic procedures are espe-cially important for English readers,because their sublexical procedure gener-ates multiple alternative pronunciations.(Should ‘fint’ rhyme with ‘mint’ or ‘pint’?)

To test their hypothesis that differencesin the orthographic consistency of Italianversus English may lead subjects to place adifferent emphasis on sublexical versuslexical and semantic procedures (Fig. 1),Paulesu and colleagues1 asked Italian andEnglish subjects to read aloud a variety ofwords and nonwords. It took the Englishsubjects significantly longer to begin read-ing each word. The differences becameeven more pronounced when the stimuliwere nonwords. Control experimentsindicated that the English subjects werenot just slow speakers. For instance, Eng-lish and Italian subjects took the sameamount of time to produce a word for apicture of an object. The faster reading

Sound and meaning: how nativelanguage affects reading strategiesJulie A. Fiez

In the Italian language, spelling is consistently related to pronunciation, whereas Englishwords that are spelled similarly are often pronounced differently. An imaging study nowshows that native language affects the brain regions activated by reading aloud.

dure, in which an entire written word isrepresented as a set of component lettersor letter clusters, and then these ortho-graphic subcomponents are associatedwith corresponding sounds or phonolog-ical subcomponents2. These subcompo-nents can be used to build up arepresentation of an entire word sound.Sublexical procedures take advantage ofthe consistent mappings between orthog-raphy and phonology (such as that ‘bad’,‘dad’, ‘tad’, ‘bat’, ‘dat’, ‘tat’, ‘dab’ and ‘tab’are different combinations of the samefour letters and sounds) to avoid havingseparate representations of the ortho-graphic–phonological relationship foreach word in a language. Paulesu and col-leagues theorized that the high degree ofconsistency in the Italian language per-mits Italian readers to rely heavily on asublexical procedure for reading wordsaloud.

Most models of word reading also con-tain one or more additional proceduresthat do not depend on sublexical ortho-graphic structure. For instance, in oneclass of models, a lexical procedure isthought to permit access to stored infor-mation about the association betweenwhole word forms and their correspond-ing sounds3. In another class of models4,phonological representations can beaccessed indirectly, by first forming asso-

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Julie Fiez is in the Department of Psychology,605 LRDC, University of Pittsburgh, Pittsburgh,Pennsylvania 15260, USA.e-mail: fiez+@pitt.edu

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Fig. 1. Italian and English subjects place different emphasis on the two processes used to deter-mine how to pronounce written words. English speakers rely more heavily on lexical and/orsemantic translation, whereas Italian speakers rely more on sublexical translation (left). Thesestrategies lead to differences in the brain activation evoked by reading aloud (right).

Christie Albin

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4 nature neuroscience • volume 3 no 1 • january 2000

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times for Italians are consistent with thehypothesis that Italian subjects can relyalmost exclusively on a sublexical proce-dure, whereas English subjects have to usean additional lexical/semantic procedureto guide phonological output.

If the difference in reading speed forItalian versus English subjects reflects adifferential emphasis upon sublexical ver-sus lexical/semantic procedures, then thetwo groups should have different patternsof brain activity during a reading task. Totest this idea, the authors1 used positronemission tomography to measure bloodflow (a measure of neuronal activity) inthe brains of Italian and English subjectswhile they read words and nonwords. Asexpected, in both groups, this task acti-vated a widespread network of brainregions previously associated with read-ing5. The novel finding is that brain acti-vation in three areas of this largernetwork depended on subjects’ nativelanguage. Italians had greater activationin a left superior temporal region duringboth word and nonword reading thanEnglish subjects, who showed greateractivation in a left frontal and a posteri-or inferior temporal region during non-word reading (Fig. 1).

Paulesu and colleagues1 suggest thata sublexical procedure can be localizedto the superior temporal region, and alexical/semantic procedure to the leftfrontal and posterior inferior temporalregions. This interpretation is based inpart on the implicit logic that increasingthe emphasis on a particular procedurewill produce more activation in regionsthat implement the procedure. Thus,because Italians emphasize a sublexicalprocedure, the left superior temporalregion that shows greater activation inItalian subjects is likely to contribute tothis process. The converse is true for theleft frontal and posterior inferior tem-poral regions. Neuroimaging work inother domains provides support for thislogic. For instance, piano players havemore activation in motor-related regionsthan non-musicians when they performa simple finger-movement task6. To fur-ther support their interpretation, Paule-su and colleagues compare their resultsto those of previous neuroimaging stud-ies. They note that the left superior tem-poral region is activated by other tasksthat are thought to emphasize sublexi-cal phonology (reading nonwords ascompared to reading words), whereasthe left frontal and posterior inferiortemporal regions are activated by tasksthat are thought to emphasize lexical and

should help constrain interpretations ofactivation differences within the systemand theoretical models of reading.

Indeed, these data1 already provide anexciting glimpse into the neural basis ofreading. The finding that the left superi-or temporal, posterior inferior temporaland frontal areas are sensitive to theorthographic consistency of a subject’snative language suggests that they are crit-ically involved in the derivation ofphonology from orthography, even if thespecific contributions that each makes isdebatable. There is growing evidencefrom reading researchers and educatorsthat the ability to manipulate and derivephonological representations is a funda-mental aspect of skilled reading9. By fur-thering our understanding of the brainregions and cognitive processes involvedin the analysis of phonology, we shouldbe in a better position to diagnose andeventually treat reading disorders. We canalready form some tantalizing linksbetween normal and impaired perfor-mance and the areas identified by Paule-su and colleagues. For instance, the leftsuperior temporal region identified intheir study is near a region that is acti-vated below normal levels when dyslexicsubjects attempt to read words10. Arecently developed technique for exam-ining the connections between brainregions indicates that this reduced acti-vation may arise from abnormal connec-tions between left temporal and frontalregions in dyslexic subjects (T. Klingberget al. Soc. Neurosci. Abstr. 25, 654.7, 1999.

Equally exciting are the implicationsof this work for our understanding ofhow experience can shape the organiza-tion of our cognitive systems. Both theItalian and English subjects studied byPaulesu and colleagues1 can use sublexi-cal and lexical procedures, but experi-ence has optimized their use of theseprocedures for the language they read.Our perceptual systems have a remark-able ability to self-organize based onsensory experience11. Reading proce-dures may become tuned through simi-lar mechanisms, with much of theoptimization occurring automaticallyand continually. An interesting theoret-ical issue with profound practical impli-cations is how much this tuning may beinfluenced by instructional strategy andthe initial structure of reading materials.For instance, an early instructional strat-egy (such as phonics) that emphasizesthe consistent features of orthographic-to-phonological transformation in Eng-lish may lead children to emphasize a

semantic processing (naming of bothwords and pictures, generating seman-tic associations).

Although Paulesu and colleagues1

develop a compelling interpretation fortheir results, it will not be received with-out controversy. One reason is that theexisting imaging literature supports mul-tiple interpretations. For instance, manyimaging studies show that practice andrepetition can also produce relativedecreases in regional blood flow7. Indeed,whether a particular region shows anexperience-related increase or decreaseseems to reflect several factors, such as itsrole in the learning process and theamount of practice given8. This suggestsa different possible logic: that the more asublexical, lexical or semantic procedureis used, the more efficient the brainregions that implement the proceduremight become, with increases in efficien-cy detected as smaller increases in activity.Thus, the smaller left frontal and posteri-or inferior temporal responses for Italiansubjects could reflect their greater skill rel-ative to English subjects at a sublexicalprocedure that is particularly importantfor nonword reading. Similarly, the small-er left superior temporal response forEnglish subjects could reflect their greaterskill at a lexical or semantic procedure.This alternative interpretation is also con-sistent with some imaging results, such asnonword versus word differences in leftfrontal cortex activation5.

A second issue is that the work ofPaulesu and colleagues1 leaves funda-mental differences in cognitive models ofword reading unresolved. We may nowknow which brain regions are involved insublexical and lexical/semantic proce-dures, but we still do not know how theseprocedures work. For instance, do wedevelop ‘rules’ that codify consistentspelling-to-sound relationships in our lan-guage3, or do we form distributed repre-sentations that capture the statisticallikelihood of both consistent and incon-sistent pronunciations4? Such questionshave remained unresolved because exist-ing behavioral data about the reading per-formance of normal and brain-damagedsubjects is compatible with multiple mod-els of reading. Paulesu and colleagues pro-vide a striking demonstration of howneuroimaging can be used to provide anew type of data, in which the behaviorof individual components of the readingsystem can be teased apart. Further inves-tigation of how the brain areas involvedin reading are affected by experimentaland experience-dependent manipulations

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nature neuroscience • volume 3 no 1 • january 2000 5

Building inhibitory synapses:exchange factors gettinginto the act?Justin R. Fallon

Gephyrin is a synaptic protein that is required for clusteringof glycine and GABAA receptors. Gephyrin itself may beregulated by a newly identified protein named collybistin.

The precise localization of neuro-transmitter receptors is essential forsynaptic function. For a neuron torespond to neurotransmitter release, itmust maintain a high density of recep-tors on the postsynaptic membrane, andactivity-dependent modification ofsynaptic efficacy is now known to be atleast partly due to changes in numberand density of receptors. Thus it is notsurprising that the mechanisms under-lying receptor clustering have comeunder close scrutiny2–4. Many differentmolecules are implicated in receptorclustering at various types of synapses,and one of the major challenges now fac-ing the field is to determine how theclustering machinery is regulated bysynaptic activity5.

The present story began several yearsago with the identification of gephyrin6,a protein that is now known to beinvolved in anchoring glycine receptorsand GABAA receptors at postsynapticsites. Gephyrin is enriched at glyciner-gic synapses and binds the cytoplasmicdomain of the glycine receptor β-sub-unit as well as microtubules. Neuronsfrom mutant mice lacking gephyrin failto cluster glycine receptors at synapses7.However, although these findings con-firm that gephyrin is an anchoring mol-ecule, our understanding is far fromcomplete. For instance, how is gephyrinheld in place? Although it binds micro-tubules, this is only part of the story,

For centuries, artists have depicted Atlasholding up the world, providing theancients with a neat explanation for howthe Earth stays in its place and making agood story to this day. Even in ancienttimes, though, children must have won-dered what Atlas is standing on, and inthe post-Copernican age, they might alsoask how this arrangement can work if theEarth is constantly moving. Students ofthe synapse face a similar conundrum.They learn that anchoring moleculeshold neurotransmitter receptors in thepostsynaptic membrane. Yet whatanchors the anchors, and if they are sofirmly held in place, how can synapseschange over time?

A paper by Kins and colleagues1 in thisissue is likely to represent an importantstep toward answering these questions.The authors describe two new guanosinediphosphate/guanosine triphosphate(GDP/GTP) exchange factors, collybistinI and II, which may regulate the distribu-tion of glycine receptors, and perhaps alsoGABAA receptors, at inhibitory synapses.This advance is noteworthy because itprovides a potential mechanism for inte-grating three major elements of the clus-tering machinery at this synapse: glycinereceptors, gephyrin and the cytoskeleton.

because the size and shape of postsy-naptic specializations, as well asgephyrin density, depend on actin fila-ments as well as microtubules. We wouldalso like to know how this putativeanchor–cytoskeleton link is regulated, aquestion that is likely to be central tounderstanding the mechanism of synap-tic plasticity.

A first step toward answering thesequestions is to identify other moleculesthat interact with gephyrin. Kins and col-leagues used the yeast two-hybrid system,a powerful genetic technique that has ledto the identification of manyprotein–protein interactions at synapsesand elsewhere2,3,8,9. By screening a braincDNA library for proteins that could bindto gephyrin, the authors identified colly-

Justin Fallon is at the Department of Neuroscience,Brown University, Box 1953, 190 Thayer Street,Providence, Rhode Island 02912, USA.e-mail: justin_fallon@brown.edu

sublexical transformation procedure thatinvolves the superior temporal region,compared to an early instructional strat-egy (for example, whole language) thatfocuses on the relationships betweenentire word forms and their corre-sponding pronunciations and meanings.

1. Paulesu, E. et al. Nat. Neurosci. 3, 91–96(2000).

2. Patterson, K. & Behrmann, M. J. Exp. Psychol.Hum. Percept. Perform. 23, 1217–1231 (1997).

3. Coltheart, M., Curtis, B., Atkins, P. & Haller,M. Psychol. Rev. 100, 589–608 (1993).

4. Plaut, D. C., McClelland, J. F., Seidenberg, M. S.& Patterson, K. Psychol. Rev. 103, 56–115(1996).

5. Fiez, J. A. & Petersen, S. E. Proc. Natl. Acad.Sci. USA 94, 914–921 (1998).

6. Hund-Georgiadis, M. & von Cramon, D. Y.Exp. Brain Res. 125, 417–425 (1999).

7. Raichle, M. E. et al. Cereb. Cortex 4, 8–26(1994).

8. Karni, A. et al. Proc. Natl. Acad. Sci. USA 95,861–868 (1998).

9. Share, D. L. & Stanovich, K. E. Issues inEducation 1, 1–57 (1995).

10. Rumsey, J. M. et al. Arch. Neurol. 54, 562–573(1997).

11. Recanzone, G. H., Merzenich, M. M., Jenkins,W. M., Grajski, K. A. & Dinse, H. R. J. Neurophysiol. 67, 1031–1056 (1992).

Fig. 1. A hypothetical model for the role ofcollybistin II in clustering glycine receptorsbased on findings1 from heterologous cells.Glycine receptors are expressed in the mem-brane but are not clustered until engaged bygephyrin. The translocation of gephyrin to themembrane requires interaction with theGDP/GTP exchange factor collybistin II. Thisprotein presumably activates one or more smallG proteins, which may in turn regulate the orga-nization of the cytoskeleton.

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