The Dyslexic Brain

New Pathways in Neuroscience Discovery

Glenn D. Rosen

• Publisher: Psychology Press
• Year: 2013
• Print ISBN:
  9780805858891
• Edition: 1
• eBook ISBN:
  9781134815579
• Topic: Psychology
• Subtopic: Developmental Psychology
• Index: Psychology

The Dyslexic Brain: New Pathways in Neuroscience Discovery offers a state-of-the art examination of the neural components and functions involved in reading and in the possible sources of breakdown. Suggestions for intervention are introduced throughout the book.The book is based on presentations at a summer 2004 symposium, which was part of an ongoing symposia series titled, "The Extraordinary Brain, " convened by The Dyslexia Foundation. The participants are top scholars in the multidisciplinary research programs related to the neuroscience of brain development in general and reading disorders in specific. The Dyslexic Brain: New Pathways in Neuroscience Discovery will be important to researchers and scholars interested in dyslexia, as well as those interested in issues involving the cognitive consequences of unusual brain development. Graduate students looking at reading and reading disorders in schools of education and communication disorders will also find substantial new information.

INTRODUCTION

The chapters in this section are all concerned with animal models of cortical development. From the perspective of developmental dyslexia, our interest in this topic stems from the finding of malformations in the cerebral cortex of postmortem dyslexics. What is fascinating is that these five chapters approach the investigation of these malformations from completely different perspectives. Yet even though these laboratories approach the problem from disparate points of view, there is a commonality that emerges that all point to the profound impact that small malformations occurring during brain development can have on the organization of the brain and behavior. This impact can be directly related to the malformation itself, but as a number of authors suggest, it is the developing brain's reaction to these malformations that provide the underlying substrate for the subsequent cognitive and physiologic disturbances. In short, these chapters sharply bring into focus the notion that the developing brain is not like the adult brain, and that when one considers the brain basis of any developmental disorder (including dyslexia), one needs to take this seemingly self-evident fact into account.

It is appropriate that we begin this section with Peter Crino's chapter. He commences with a detailed review of some of the different types of malformations of the cerebral cortex that have been described in the human literature, as well as their consequences. This is followed by a discussion of the genes that have been associated with some of these malformations, and how the use of mouse models (knockouts and transgenics) has helped advance our understanding of how they operate. It is clear that single gene mutations may underlie several different types of malformations, and that understanding how these genes work may lead to new therapies, and perhaps treatments to ameliorate or even prevent their emergence.

The laboratory of Pierre Gressens has been interested in exploring some of the injuries that occur in both the pre- and postnatal period in humans. Using rats as their model system, they have found that injury (the introduction of toxins injurious to neurons) induces malformations in otherwise normal animals. What is particularly fascinating is that the timing of these “neurotoxic” insults is critical in determining the type of malformation that will occur. Thus, the same type of injury can cause disorders of neuronal migration or polymicrogyria or cystic periventricular leukomalacia or stroke-like lesions, depending on the stage of brain development at the time of the injury. This work also strongly implicates a number of external factors that modulate the effects of neurotoxins. Some of these agents can, on the one hand, exacerbate the effects of the injury, while others can be strongly protective and ameliorate their effects. As they point out in their chapter, these results have potentially intriguing implications for methods of intervention following early injury on the brain.

Much of the work in my own laboratory has centered on examining anatomic consequences of early injury to the developing cortical plate. This injury, which involves a short freeze lesion of the developing cortex, results in a cortical malformation resembling human polymicrogyria. My interest in this subject was spurred by the fact that this type of malformation has been seen in some postmortem dyslexic brains. It is noteworthy that there are a number of other laboratories that are using this identical model to study epilepsy. In their chapter, Zsombok and Jacobs detail the wealth of information that has been gained concerning the electrophysiologic properties of cortex in which a microgyria has been induced. Two findings are of particular note. First, it turns out that the source of the aberrant electrophysiologic activity is not the malformation itself, but rather the areas surrounding the microgyria. This suggests that this focal injury has widespread effects on the organization and circuitry of the brain, which will be a common thread in subsequent chapters. Second, the subtle differences in the timing of the injury has remarkable effects on the electrophysiologic activity. A freeze lesion placed on the day of birth in the rat results in much less epileptiform activity than the identical lesion performed one day later. This finding echoes that of the previous chapter, again demonstrating the changing vulnerabilities of the developing nervous system.

The “tish” (an acronym for “telencephalic internal structural heterotopias”) rat was a fortuitous discovery of Kevin Lee and colleagues. This spontaneous mutation was originally identified by the presence of seizures. Subsequent investigations identified a malformation of development of the cerebral cortex consisting of subcortical band heterotopia. Lee and colleagues have done an extensive categorization of the anatomic, electrophysiologic, and behavioral consequences of these malformations. Similar to the induced malformations studied by Zsombok and Jacobs, the actual source of the electrophysiological disturbance that causes the seizures is not the malformation itself, but rather lies in areas just outside the malformation. Of particular interest is the finding that there are disturbances in behavior and anatomy in individuals that are heterozygous for the allele that causes the malformation. Lee et al. suggest that much of the behavioral and electrophysiologic effects may be independent of the direct effects of the malformation. Rather, it may well be the case that the subcortical band heterotopia are just the most obvious manifestations of a series of problems that occur during development. Importantly, they suggest that changes in circuitry that evolve as a consequence of the malformation may be the cause of much of the underlying difficulty associated with this disorder. This recapitulates the conclusions of the previous chapters, namely that the malformation itself may just be an obvious flag telling us that this brain is organized differently.

At some level, the suggestion of an animal model of developmental dyslexia may generate more than a little skepticism. After all, reading is most certainly a uniquely human characteristic. But as we've seen in the previous sections, there are other biological characteristics that seem to co-occur with developmental dyslexia. For the past decade, Holly Fitch and colleagues have investigated the link between malformations of the cerebral cortex (see Galaburda, this volume) to defects in rapid auditory processing (see Tallal, this volume). In the last chapter of this section, Fitch and Peiffer review their extensive collection of studies on this topic. They have found that rats and mice with malformations— some induced and some spontaneous—appear to have difficulties in the processing of rapid auditory information, and that these are more severe in younger animals. These difficulties appear more commonly in males as compared to females, which is fascinating when considered in light of evidence suggesting that males have a higher incidence of dyslexia. How exactly malformations of the cerebral cortex affect the low level processing of auditory signals is not known, but Fitch and Peiffer propose a testable model for how the system might operate.

MALFORMATIONS OF CORTICAL DEVELOPMENT:
OVERVIEW

Malformations of cortical development (MCD) are characterized by disruption of the normal cytoarchitecture of the cerebral cortex and altered cellular morphologies (for review see Walsh, 1999; Andermann, 2000; Crino, Miyata, & Vinters, 2002). MCD can affect broad regions of the cerebral cortex as in lissencephaly and hemimegalencephaly, or may be restricted to focal areas such as tubers in the tuberous sclerosis complex (TSC) or focal cortical dysplasia (FCD) with balloon cells. In lissencephaly and polymicrogyria, the normal six-layered organization of the cerebral cortex is replaced by a more primitive four-layered arrangement (Leventer, Mills, & Dobyns, 2000), whereas in FCD or tubers of TSC, there is a virtual loss of all lamination. Large collections of heterotopic neurons are identified in subcortical band heterotopia and periventricular nodular heterotopia. The morphology of individual neurons in many MCD subtypes is abnormal, suggesting a pervasive disruption of steps necessary for intact cortical development (Ferrer et al., 1992). Recent studies have

---

This work was supported by MH01658, NS39938, the Esther A. and Joseph Klingenstein Fund, the Tuberus Sclerosis Alliance/Center Without Walls, and Parents Against Childhood Epilepsy (PBC).

identified gene mutations responsible for select MCDs. However, the developmental pathogenesis of most MCD has not been defined. As a result of defining how gene mutations lead to abnormal cortical development, a recent scheme classifies MCD according to distinct neurodevelopmental stages including cell proliferation, migration, and cortical laminar organization (Barchovich & Kuziecky, 2000).

All MCD are highly associated with epilepsy (Andermann, 2000; Crino & Chou, 2000) in infants, (especially infantile spasms, IS), children, and adults. MCD is the most common neuropathologic abnormality encountered when cortical resection is performed to treat IS (Vinters et al., 1992, Vinters, De Rosa, & Farrell, 1993; Vinters, 2002; Prayson, 2000). MCD may account for 20% of all epilepsies (Brodtkorb, Nilsen, Smevik, & Rinck, 1992; Hauser, Annegers, & Kurland, 1993) and in some extensive MCD such as lissencephaly, hemimegalencephaly, and TSC, seizures may occur in 70%–90% of affected patients. More anatomically restricted malformations such as focal heterotopia or FCD with balloon cells are also associated with medically intractable seizures that persist into adulthood (Farrell et al., 1992). Estimates are that nearly 30% of cortical specimens resected as treatment for neocortical epilepsy contain some type of MCD (Vinters, 2000). Indeed, recent advances in neuroimaging have demonstrated that many cases of “cryptogenic” epilepsy actually result from subtle cytoarchitectural abnormalities (microdysgenesis). Finally, a subgroup of adult patients with temporal lobe epilepsy exhibit radiographic and histopathologic evidence of MCD, either alone or in combination with hippocampal sclerosis (“dual pathology;” Levesque, Nakasato, Vinters, & Babb, 1991; Ho, Kuzniecky, Gilliam, Faught, & Morawetz, 1998).

From a clinical perspective, virtually all seizure subtypes (e.g., generalized tonic-clonic, complex partial, atonic, myoclonic, atypical absence seizures, and infantile spasms) have been described in MCD. Anti-epileptic drug therapy in patents with MCD often fails and surgical therapy provides the only hope for seizure remission (Engel, 1996; Mathern et al., 1999; Peacock et al., 1996). Unfortunately, seizure cure following surgical resection of focal CDs is successful in less than 50% of patients. Even worse, a subgroup of patients may not be surgical candidates at all. The mechanisms of seizure initiation and epileptogenesis are unknown in MCD. Thus, the challenges to neurobiologists and neuropathologists who examine tissue from patients with MCDs are to explain the origin of the structural findings in the resected tissue, and to define precisely how and why these aberrations of the cerebral cortex produce intractable seizures.

MOLECULAR NEUROBIOLOGY OF FOCAL MCD

Recent studies have identified no fewer that 11 genes responsible for MCD associated with epilepsy. Subtle developmental malformations have been observed in a variety of neurological and psychiatric disorders without a definitive molecular correlate such as dyslexia, autism, and schizophrenia. The genes responsible for MCD have important functions in one or more stages of normal cortical development. All MCD result from loss of function gene mutations, and thus, the histopathologic features of each MCD yields a view of the role that the responsible gene plays in cortical development. In addition, the effect of each gene mutation also highlights the developmental epoch in which that gene is active in corticogenesis. These critical time-points provide a framework to understand the interface between gene mutations and abnormal neural development. For example, gene mutations that affect cell mitosis will disrupt the proliferative phases of cortical development but may have little effect on postmitotic neurons. Similarly, a gene mutation that alters cytoskeletal assembly during dynamic phases of neuronal migration will have distinct effects in an actively migrating neuron versus a neuron that has already achieved its laminar destination. In sum, a defined molecula...

Table of contents

• Cover
• Half Title
• Full Title
• Copyright
• Contents
• Preface
• Foreword
• Acknowledgments
• Contributors
• Section I The Phenotype of Dyslexia
• Section II The Genetics of Dyslexia and Cortical Development
• Section III Animal Models of Cortical Development
• Section IV Brain Plasticity
• Author Index
• Subject Index