1. LD across early childhood - BioMedical Approaches & Treatment Kenneth R. Pugh, PhD President and Director of Research, Haskins Laboratories, and Associate Professor, Yale University School of Medicine

2. Perhaps the most practical, near-term synergy between education and cognitive neuroscience …is in the service of predicting reading difficulty and then offering intervention to avoid reading failure. John Gabrielli, Science 17 July, 2009

4. Language Reading and Brain Spoken language is a biological specialization but written language is largely a cultural invention. Moreover, spoken language is mastered naturally in almost all people, without direct instruction: but reading is difficult and reading failure occurs in large numbers of children across all written languages. No brain specialization for reading. Implication: Literacy acquisition is a major challenge to brain plasticity.

5. Reading Disability: Behavioral phenotype Phonological deficits are nearly universal, but what is the underlying cause? Proposals include sensory deficits, compromised neural systems for language, metalinguistic deficits, attentional deficits. ** It is possible that there are multiple sub-types, with different pathways but a common end-state (phonological processing deficit). Neurobiological (brain) research may help address this heterogeneity.

6. Potential roles for neuroscience of reading disability 1)Neurobiological measures provide mediating levels of analysis between gene and behavioral phenotype. Also constraint on computational models. 2) Sensitivity: A potentially deeper account of individual differences in either typical or atypical development and individual differences in optimal intervention strategies for at-risk children. What works for whom. 3) Early detection of “biomarkers” predictive of risk for atypical development.

7. The Neurobiology of Reading Disability Genetics: A) heritability (co-twin) studies establish a genetic involvement in RD B) A number of molecular-genetic investigations (e.g., Fisher & DeFries, 2002) have reported linkages between reading-related processes and regions on chromosomes 2, 3, 6, 15, and 18. These studies are at an early stage thus far. Multiple genes likely. **Gene/environment interaction shapes cognitive development.

8. The Neurobiology of Reading Disability Brain anatomy in RD: 1) Early post-mortum studies implicate subtle neuronal abnormalities (ectopias) in LH language zones (Galaburda). 2) Recent structural MR studies reveal reduced grey matter density in reading-related temporo- parietal regions (Brambati). 3) New research examining cortico-cortico pathways with MRI/DTI, suggest white matter tract anomalies (Klingberg, McCandliss), between reading related subsystems.

9. The Language Brain Damage/lesion studies Broca’s area: Thought to be specialized for speech production, grammar Wernicke’s area: Thought to be specialized for speech comprehension, semantics Implication for reading: skilled reading circuits must support efficient communication between visual areas and these Left Hemisphere language zones

11. The Neurobiology of Reading Disability Functional brain imaging: 1) two major classes of techniques: electrophysiological (EEG; MEG) and hemodynamic (fMRI, PET). The former give information on timing of brain activity while the latter provide information on localization. Need both!

12. Reading Language and Brain Q) What are the underlying neurobiological mechanisms associated with the development of reading skill? Q) What are the neurobiological underpinnings of reading disability (RD)? Q) How does training and remediation modify brain organization for printed language in children and adolescents with RD?

13. Slice Locations

14. Auditory vs Visual Sentence Task Constable, Pugh et al. (2004) common print(red) speech(blue) RH on left side

15. Updated view: The Reading Network (Pugh et al., 2005) IFG MTG/ ITG OT/ VWFA SMG /STG AG Hypothesized Role of component circuits ‘Phonological’ IFG SMG/STG ‘Semantic’ MTG/ITG AG Putative ‘Visual word form Area’ “Skill Zone” is phonologically and morphologically tuned

16. Frequent finding: A large number of studies indicate that RD readers tend to under-activate both LH temporoparietal and LH ventral (occipitotemporal) regions during reading- and language tasks; this has been seen in several languages to date (Paulesu et al., 2001). RH and frontal compensatory shift in RD often reported Reading Disability Occipitotemporal Anterior Temporoparietal Left Hemisphere

17. Normal Readers Dyslexic Readers TD & RD Reading Children (Temple et al., 2003) Frontal & Temporo- parietal Frontal but NO Temporo- parietal

18. Summary of findings in RD RD children and adolescents fail to coherently engage left hemisphere (LH) temporoparietal and occipitotemporal regions robustly during reading. Additionally, recent structural neuroimaging studies reveal differences in both grey matter density and white matter connectivity in these LH regions.

19. Next steps in establishing a neurobiological account It is critical that we move beyond identification of structural and functional neuro-phenotypes in RD toward learning models focused on how and why brain differences impede literacy skill acquisition. Focus on how to facilitate learning and plasticity. A gene-brain-behavior account will be key to understanding individual differences and eventually tailoring treatment to the brain. Treatment studies are key to understanding potential to change brain in RD children.

20. Plasticity and Remediation in Reading Development Anterior Occipitotemporal Temporoparietal Increases in reading skill are associated with increased specialization of ventral LH areas for print

21. RD readers do not tend to show this neurodevelopmental trend. Trajectory is rightward and frontward. Question: Does remediation normalize this trajectory? Anterior Occipitotemporal Temporoparietal

22. Remediation in RD Are these under-engaged LH systems fundamentally disrupted, or does observed de- activation reflect an unstable but potentially “trainable” state? Can remediation focused on training up phonemic awareness (PA) skills modulate the neurocognitive risk profile in beginning reading.

23. Testing effects of intensive phonological remediation in RD in emergent readers (Shaywitz et al., 2004)Overview: In collaboration with Dr. Benita Blachman (Syracuse University) we examined neurobiological changes associated with a nine month intervention emphasizing phonemic awareness, alphabet principle, and vocabulary development in young children (Shaywitz et al., 2004). 3 Groups: NI (N = 28); RD control (N =12), RD Treatment (N = 32). Each group scanned at baseline (average age = 6.5), one year later (post- treatment), and for the RD Treatment Group at one year follow up. (see Simos et al.,2002 Temple et al.,2003 for similar findings with different phonological training protocols)

24. Training 50 min tutoring, 5 days per week, 9 months (105 hours total) 5 step plan (unscripted) & individualized Letter-sound associations Phoneme manipulation Reading words Reading text Assessment

25. Key behavioral result: Reliable improvement on a battery of reading- related tests for the treatment relative to the control RD group (Blachman et al., 2005) after nine months of intensive evidence based training. Effects stable at one year follow up.

26. Treatment Group: Year 3 (follow- up) minus Year 1 (Pre- Treatment)

27. Temple et al. (2003): fMRI Data L. Inferior frontal and L. temporo-parietal activation Some L.inferior frontal but no L. temporo- parietal activation Increases in L.inferior frontal and L. temporo- parietal activation and right hemisphere comologues

28. We thus have evidence that appropriate training has a normalizing effect on the neurobiological trajectory in emergent in a large percentage of “at risk” readers. Plasticity can be strong even in struggling beginning readers. LH posterior system appears to be unstable but trainable in young at risk readers.

29. Conclusions Early language development is key to later reading success. RD has been associated with a variety of functional and structural brain differences to date. Left hemisphere problems are frequently implicated. We need integrative neural models that predict reading acquisition; longitudinal research to establish key gene- brain-behavior links. Early and intense remediation can promote good brain development in a large number of reading disabled childre, but we need to learn more about the brains of treatment resistors.

30. Collaborators Haskins Laboratories: Einar Mencl, Rebecca Sandak, Stephen Frost, Dina Moore, Nicole Landi, Leonard Katz, Jay Rueckl, Jim Magnuson, Donald Shankweiler, Jun Ren Lee, Carol Fowler, Alvin Liberman Yale Reading Center: Ken Pugh (Director), Gina Della Porta, Eleanor Tejada, Kelley Delaney, Ashley Zennis, Priya Pugh, Yale Center for the Study of Learning and Attention: Bennett Shaywitz, Sally Shaywitz, Karen Marchione, John, Holahan, Jack Fletcher Yale University/Diagnostic Radiology: John Gore, Todd Constable, Robert Fulbright, Doug Rothman, Graeme Mason, Pawel Skudlarski, Cheryl Lacadie Yale University/Psychiatry: Leslie Jacobsen Yale Child Study Center: Elena Grigorenko