Dysle yslexia To a Today: ay: Lesso ssons ns fro from m the Past Past and and Hopes Hopes for or the the Futu ture Ele lena L a L. Grig rigore renk nko Yale ale Unive Universi rsity
I I am fa m faci cing a an n impo impossible ta task… k… elena.grigorenko@yale.edu
Goal oal & & Struct Structure • Goal – Summary of the field • Neurobiological and genetic correlates of … – Developmental dyslexia – Specific reading disability (disabilities) – Reading difficulties – Reading • Structure – Eight statements • Numbered
Cont Contex ext Reading (as is the case with any acquired academic skill) is a complex skill that evolves from a solid foundation of componential cognitive skills.
Poi Points ts of of the the ei eight statem ght statemen ents • Bad teaching & • Reading & the genome reading – Where • Biological bases of – What reading – How • Heritable ≠ • Correlation & causation unmodifiable • Reading & the brain • Environmental – In SRD/DD influences on the – In reading acquisition genome – In remediation • SRD/DD assessment and the relevance of RTI to studies of the brain and the genes
SR SRD/DD D/DD does es no not aris arise fro e from m bad bad t teac eachi hing g (1) (1)
SR SRD/DD D/DD does es no not aris arise fro e from m bad bad t teac eachi hing • SRD/DD has a specific etiology & genesis • 15-20% school-aged children have difficulties reading, but only 85% of them have SRD/DD – http://www.interdys.org, Fact Sheet #62-05/00 • Bad teaching makes SRD/DD worse – But bad teaching does not cause SRD/DD • Reading problems generated by bad teaching/bad schooling are preventable and remediable
“True “True” SR ” SRD/DD D/DD is is bio biolo logic gicall lly y gro groun unded (2) (2)
“True “True” SR ” SRD/DD D/DD is is bio biolo logic gicall lly y groun gro unded • SRD/DD has its own biological signature – Where? • In the eyes • In the blood • In the belly • In the brain • In the genes • SRD/DD is a disorder of genetic origin with a basis in the brain
We We kno know w a a lo lot abo about ut the e correl elates tes of SR f SRD/DD in D/DD in the e brain brain and and in in the genes e genes (3 (3)
SR SRD/DD D/DD in in the brain & e brain & in in the e genes genes • We know a lot about the correlates • We know little about the causes • What we know is – Who the “players” are – Where things are happening • What we do not know – How things are happening – Why they are happening
Th The brain e brain does es no not h have “t ave “the e part part(s (s)” fo )” for r rea readin ing g (4) (4)
Th The brain e brain does es no not h have “t ave “the e part part(s (s)” fo )” for r rea readin ing • Reading in the brain unfolds via a complex chain of activation of various structures, which is distributed in space and in time – There is no brain “locus” for reading, but there is a “reading brain” – The “reading brain” is a developmental stage of the brain – We are born with an “illiterate brain” that has the capacity to become a “reading/literate brain” • This chain is malleable – Developmentally – As a result of interventions
Readi Reading brai ng brain n (1) (1) • A number of areas appear to be engaged in reading • Robust multivariate differences between people w and w/o difficulties • Developmental differences (before and after the onset of reading) • Differences between remediated and nonremediated readers
Readi Reading brai ng brain n (2) (2) Elliott & Grigorenko, 2014
Readi Reading brai ng brain n (3) (3) Elliott & Grigorenko, 2014
Readi Reading brai ng brain n (4) (4) Elliott & Grigorenko, 2014
Il Illustr lustrati tion One: on One: Pa Pathwa thway(s y(s) f ) for rea or readin ing Elliott & Grigorenko, 2014
Illustr llustration tion O One: ne: Pathw Pathway(s (s) fo ) for r read reading Attenuated activity: Single words Pseudowords Rapid naming Enhanced activity: Articulatory recodibng Word reading Abnormal activity: Pseudoword reading Phonological processing (rhymes, segmentation) Word reading Schulte-Körne et al., 2007
Illust strati ration on Two: Two: Readi Reading ng ac acqu quis isiti tion Schlagger & McCandliss, 2007
Illust strati ration on Th Three: ree: Readi Reading ng i interv nterventi ention on (1 (1) Simos et al., 2002
Illust strati ration on Th Three: ree: Readi Reading ng i interv nterventi ention on (2) (2) Elliott & Grigorenko, 2014
The The readi reading brai g brain • Is a dynamic system that – Is characterized by temporal and spatial distribution of activity – Is sensitive to the nature of stimuli – Changes developmentally – Is malleable in response to intervention
Both t th typic pical and l and at atypi pical (DD) (DD) reading read g are are familial familial and and herita eritabl ble (5) e (5)
Read eadin ing g is is familial and familial and herita eritabl ble • Family studies – High risk for relatives of probands with DD – High relative risk • Twin studies – Reading itself and all its components (e.g., phonemic awareness, decoding, single-word reading) are heritable
Illustr llustration tion O One: ne: Famil Family St y Stud udie ies • First observations on the familiality of DD – Thomas, 1905; Orton, 1937; Norrie, 1939; Kagen, 1943 • Multiple prospective, retrospective, and concurrent family studies – Familiality is very high – Estimates (Ziegler et al., 2005): • Spelling (cutoff at 10%): GRR S = 3.813 (CI: 3.217 – 4.437) • Reading (cutoff at 10%): GRR S = 3.516 (CI: 2.825 – 4.257)
Illustr llustration tion Two Two: : Twin st Twin stud udies es 1 0.8 The C e Colorado L o Lear arni ning ng D Disabi abilities lities h 2 0.6 0.4 Resea Re earch C Cent nter er 0.2 0 Davis et al., 2001 Gayán & Olson, 2001, 2003 1 0.8 The L e London ndon Twin S Studies ies 0.6 c 2 0.4 Stevenson et al., 1987 0.2 0 Hohnen & Stevenson, 1999 Twins E s Early Devel elop opment ental S al Study 1 (TE (TEDS DS) 0.8 0.6 e 2 Harlaar, Spinath, Dale, & Plomin, 2004 0.4 0.2 0 Grigorenko, 2004
There i re is no “ o “gene f ne for r r read eading ing”
Read eadin ing g the geno e genome me fo for r “rea “readin ing” genes g” genes • There is no single “gene” for reading • There are many genes that contribute to the formation of the biological bases of both typical and atypical (SRD/DD) reading acquisition • These genes exert small effects • These genes are multi-task genes
Illustr llustration tion O One: ne: Wh Where in e in the geno e genome me (1) (1) Schulte-Körne et al., 2007
Il Illustr lustrati tion One: on One: Wher Where i in n the the gen genome ome (2) (2) Elliott & Grigorenko, 2014
Illustr llustration tion Two Two: Cand : Candidate genes te genes • DYX1C1 (also known as EKN1 ) – Dyslexia Candidate Region 1, Candidate 1 • KIAA0319 – Human Unidentified Gene-Encoded (HUGE) protein, cDNAs identified in the Kazusa cDNA sequencing project • DCDC2 – Doublecortin domain containing 2 • SEMA6D – Sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6D • ROBO1 – Roundabout 1
Candidate gene expression patterns in the brain Paracchini et al., 2007
Disrupted migration in the developing rat neocortex Joe LoTurco et al., 2006-2007
Prot Protei ein-pr prot otein in interac acti tion ( on (1)
Prot Protei ein-pr prot otein in interac acti tion ( on (2)
Illustr llustration tion Th Three ee: : Ty Types pes o of f genes genes • The “migration” genes can, indeed, contribute to the initial anatomical differences characteristic of the brains of individuals with SRD/DD; they cannot explain the whole story • There are many types of genes and genetic mechanisms that could potentially be involved in the manifestation of SRD/DD – Brain development – Brain connectivity – Signal transduction
Key Key indi ndicat cators (1) (1) Oligogenic Substantial relative risk regions genes & Familial markers Congenital Genetic Molecular CDCV 1900s 1950s 1960s-… 1983-… CDRV SV Heritable Differentiated by… (age, ethnicity/language, severity, IQ, environment –SES, instruction,…)
Key Key indi ndicat cators (2) (2) AC & NGS Transcriptome Exome Genome Methylome Modeling iPSC In vitro In vivo
Di Discovery scovery cycl cycle Pri rime S Stru tructure (Genom nome) Epi (der Epi ( erived) Struc uctur ure Behavi avior (Epigen igenome) Acquis isit itio ion Develo elopmen ent Cha Change Expresse ssed Struc uctur ure In vi vivo vo models ls (Transcript iptome) e) In v n vitr tro models els
Heritable ≠ Unmodifiable (6)
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