Functional and structural connectivity of reading networks in the adult brain Merina T Su Developmental Imaging and Biophysics Section UCL Institute of Child Health Supervisors: Prof Chris A Clark Dr Frederique Liegeois Thesis submitted for the degree of Doctor of Philosophy (PhD) at University College London I, Merina Su, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Language processing draws upon many distributed regions in the brain. Reading in particular is a skill that emerges from the interaction between brain regions involved in phonological and orthographical processing. This project examined the reading network in adults (18-35 years old) with and without developmental dyslexia. Each participant was assessed on a comprehensive battery of standardised neuropsychological tests, which assessed IQ, reading accuracy and comprehension, spelling, phonological processing, working memory, grammatical understanding, motor coordination, and expressive and receptive language skills. In addition, each participant underwent a non-invasive MRI scan, during which structural and functional images were acquired. More specifically, T1- weighted and diffusion-weighted images were acquired to assess structural networks in the brain, whereas a simple reading task and resting-state fMRI were acquired to assess the functional networks involved in reading. Individuals with dyslexia were found to show reduced activation and reduced connectivity in regions typically associated with skilled reading. Moreover, results suggested that they rely on more effortful processing and attentional mechanisms instead to compensate for their reading difficulties. All in all, results indicated that individuals with developmental dyslexia had abnormal functional and structural brain networks related to reading performance, as well as other functions, such as working memory. These findings suggest that for successful reading remediation, it is important to focus on the integration of phonology with orthography, as well as with working memory. Literacy problems such as developmental dyslexia are thus better characterised as a complex disorder with multiple deficits rather than by a single phonological deficit. 3 Table of Contents Abstract .................................................................................................................................... 3 List of Figures ........................................................................................................................... 6 List of Tables ............................................................................................................................. 8 List of Abbreviations ................................................................................................................. 9 Acknowledgements ................................................................................................................ 12 1. Developmental dyslexia ..................................................................................................... 13 Theories of developmental dyslexia .................................................................................. 13 1.1. Phonological deficit of developmental dyslexia ..................................................... 13 1.2. (Rapid) Auditory Processing Deficit Hypothesis (APDH) ........................................ 35 1.3. The magnocellular theory (MCT) of developmental dyslexia ................................ 51 1.4. Cerebellar deficit hypothesis (CDH) ....................................................................... 59 1.5. Is dyslexia a disconnection syndrome? .................................................................. 72 2. The neurobiology of dyslexia ............................................................................................. 80 2.1. Anatomical differences in developmental dyslexia .................................................... 80 2.2. White matter pathways in dyslexia ............................................................................. 83 2.3. Abnormal brain activation patterns during reading ................................................... 84 2.4. Integration of fMRI findings and cognitive models of reading ................................. 122 2.5. Disrupted functional connectivity during task and rest ............................................ 127 2.6. Altered effective connectivity ................................................................................... 131 2.7. Genetic contributions to developmental dyslexia .................................................... 132 2.8. Intervention studies .................................................................................................. 134 2.9. Conclusion ................................................................................................................. 135 3. Overview of thesis ............................................................................................................ 136 3.1. Research hypotheses................................................................................................. 137 4. Methods ........................................................................................................................... 138 4.1. Brief introduction to the principles of MRI ............................................................... 138 4.2. BOLD fMRI ................................................................................................................. 140 4.3. Functional connectivity and resting-state fMRI ........................................................ 144 4.4. Diffusion weighted imaging and tractography .......................................................... 149 4.5. Network analysis and graph theory .......................................................................... 156 4.6. Experimental procedures used in this thesis ............................................................ 160 5. Integrating RSFC and white matter tractography to characterize the intrinsic language network: a feasibility study .................................................................................................. 166 4 5.1. Introduction .............................................................................................................. 166 5.2. Materials and methods ............................................................................................. 174 5.3. Results ....................................................................................................................... 177 5.4. Discussion .................................................................................................................. 187 5.5. Conclusion ................................................................................................................. 193 6. The cognitive profiles of high achieving adult readers with dyslexia .............................. 194 6.1. Introduction .............................................................................................................. 194 6.2. Methods .................................................................................................................... 204 6.3. Results ....................................................................................................................... 208 6.4. Discussion .................................................................................................................. 213 6.5. Conclusion ................................................................................................................. 218 7. Functional and structural connectivity in compensated adults with dyslexia ................. 220 7.1. Introduction .............................................................................................................. 220 7.2. Materials and methods ............................................................................................. 226 7.3. Results ....................................................................................................................... 231 7.4. Discussion .................................................................................................................. 240 7.5. Conclusion ................................................................................................................. 249 8. Whole-brain functional networks in dyslexia .................................................................. 250 8.1 Introduction ............................................................................................................... 250 8.2. Materials and methods ............................................................................................. 265 8.3. Results ....................................................................................................................... 270 8.4. Discussion .................................................................................................................. 275 8.5. Conclusion ................................................................................................................. 278 9. Discussion and future directions ...................................................................................... 279 9.1 Overview of findings .................................................................................................