neurology of learning desabilities

8/13/2019 Neurology of Learning Desabilities

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NEUROLOGY OF LEARNING DISABILITIES W HATWILL THE FUTURE BRING?

THE ANSWER COMES FROM THE SUCCESSESOF THE RECENT PAST

Albert M. Galaburda

ALBERT M. GALABUR DA M.D. is the Emily Fisher Landau rofessorof Neurology and N euroscience Harvard MedicalSchool and chief of the Division of Behavioral Neurology at Beth Israel Deaconess Medical Center.

My involv eme nt with learnin g disabilities LD) beganapproximately 25 years ago, at a time when formalresearch training was uncommon for medical doctors,and the apprenticeship model was the way most of usbegan our research careers. Of all the top ics I had heardNorman Geschwind - at that time my neurology chair-man and mentor - speak about, language held particu-lar fascination for me, perhaps because of my ownexperience with having to learn and become competi-tive in a new language at age 15. After completing myresidency, I began to work on anatom ic brain asymm e-tries in an attempt to further understand the biologicalspecialization of the left hem isphere for m any aspects oflanguage function. Then, Geschwind invited FriedrichSanides, a late student of Oskar and Cecile Vogt Brodmann was an earlier student), to travel to Bostonfrom West Germany and spend a year here teaching m eabout cytoarchitectonics as a neuroanatomical tool todeepen the study of brain asymmetries. This took placein 1977.In 1978, Geschwind suggested that I take over a proj-ect begun by Dr. Brooke Seckel, a resident two years m ysenior, wh o had decided to chang e careers I often won-dered whether it was the project that did it). It con-cerned the study of a brain from an individual withdevelop me ntal dyslexia who had died as a result of a falldown an elevator shaft. His brain had become part ofthe Yakovlev Gollection at the Boston City Hospital,where all of this took place. Brooke had b een testing thehypothesis, advanced by Geschwind, that the brain ofa dyslexic would show two small plana temporale. In1968 Geschwind and his then student Walter Levitsky

had shown in the general population that the planumtemporale comprising part of the auditory associationcortex involved in linguistic functions, was large on theleft and small orvthe right, perhaps explaining languagelateralization to the left hemisphere. Some normalbrains showed the reverse asymmetry, and still othersshowed lack of asymmetry, with a large planum onboth sides. It made sense to Geschwind, a believer inthe phrenological principles that had been launched atthe start of the nineteenth century, that in a conditionwith poor language function, the plana would be bilat-erally small in one interpretation of phreno logy, morebrain tissue means more function). Here is where Ibecame involved.

it turned out, theplana temporalewere not sm all inthe dyslexic brain, bu t were show n to be large in severalspecimens of dyslexic brains; later, additional alter-ations in planum asymmetry were reported. Animalexperiments showed that under some conditions sym-metry in a cortical area could be a response to a disorderof neuronal migration. In fact, the first dyslexic brainand many other brains showed cortical dysplasias andectopias resulting from abnormal neuronal migration tothe cerebral cortex during mid-gestation.This finding began a productive area of research thatlasted the better part of two decades. Initially, it wasimportant to establish that these focal cortical malfor-mations significantly disrupted cortico-cortical organi-zation and cortico-thalamic interactions, to explainlinguistic deficits, which was done after it was possibleto model the anomalies in experimental rodent m odels.Second, it was necessary to show that the cortical mal-


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formations and the cortico-thalamic anomalies pro-duced and were not simply correlated with) functionaldeficits. Thus, it was shown that induction of corticalmalformations in the rat, similar to those found in thedyslexic brain, produced a variety of cognitive deficits,and that disturbances in cortico-thalamic networkswere associated with perceptual deficits involvingprocessing of rapidly changing sound stimuli. Thus, acausal interaction was established between focal disor-ders of neuronal migration and some behaviors thatmimicked deficits found in populations of dyslexicindividuals. second focus of research concerned the origin of thecortical and thalamic malformations in the dyslexicbrain. A variety of sources were considered. Initially,immunological damage to the developing cortex wasthought to be an etiologic factor because of an epi-demiological study published by Geschwind and hiscolleague in Glasgow, Peter Behan, showing a linkbetween immunological disorders, left-handedness, anddyslexia. However, sufficient support for this hypothesiswas not obtained, but it has been found since then thatcytokines may indeed modulate the cortical injury thatleads to neuronal migration defects.Hormonal effects were sought, too, since a sex differ-ence in dyslexia was widely believed to exist, and sexsteroids are known to modulate immunological func-tion and are suspected to modulate cerebral lateral-ization. It was discovered that the male hormone testos-terone was capable of modifying t he th alam ic plasticitythat resulted from early cortical injury that led to neu-ronal migration defects. Male rats responded maladap-tively to cortical injury, developing changes in thethalamus and deficits in auditory temporal processing,while females were eminently resistant. Immunomod-ulators such as IL-9 enlarged the size of the damage inmales, but not in females. These observations w ere com-patible with the findings of male predominant sexratios in most studies looking at the prevalence ofdyslexia.Ultimately, it became clear from population geneticsstudies th at the main precursors of dyslexia were abnor-

mal gen es. A num ber of susceptibility loci on severaldistinct human chromosomes have been reported, andmore recently a susceptibility gene, DYX ICI akaEKNl), was described first in a Finn ish kind red seeTaipale et al., 2004). This same locus failed to associatein two other popu lations from the United Kingdomand Canada), although an additional single nucleotidepolymorphism within one of the DYXICI introns didassociate significantly with dyslexia in the Canadianpopu lation see Wiggs et al., 2004, and Scerri et al.,2004). Ongoing research from our laboratories seems toindicate t hat this dyslexia susceptibility gen e is part of a

molecular pathway for the migration of young neuronsto the cerebral cortex, the interference with w hich leadsto neuronal migration disorders comparable to thoseseen in dyslexic brains. There is preliminary evidencethat at least another susceptibility gene on chromosome6 may work this way, too.Dyslexia may represent the first example of a LDwhereby a possible pathway may link the observedbehavior to an underlying neurological substrate thathas a neurodevelopmental history beginning with anabnormal gene. Similar efforts are being made to linkother cognitive disorders of development to a molecularpathway involved in brain development. The objectiveis to disclose a developmental brain pathway leading toa brain that has a particular structure and physiology, aset of perceptual, cognitive, and metacognitive associa-tions,and a behavior explained by these cognitive struc-tures and processes. Environments and learning are apt

to play their respective roles, but their full impact canonly be understood in terms of the brain they impingeupon.THE FUTURESo,what is in store for the future? tentative pathwaynow exists between a gene m utatio n of DY XIC I),abnormal cortical and thalamic development, and anauditory behavior that comprises at least one of thedyslexia behavioral phenotypes. However, several can-didate loci need further clarification. What is the con-tribution to dyslexia of genes on susceptibility loci onchromosomes 1-3, 6, 11, 15,18 and theXchromosome,among others, that may eventually be found to associ-ate with dyslexia? I predict that genes will be discoveredat these chromosomal loci that will have neuronalmigration effects similar to those of DYXICI, eitherbecause they work along the same pathway or in otherneuronal migration pathways. If the latter, it will befound that variability in the dyslexia phenotype will beexplained by the specific pathway that is affected.Additional work is needed to specify the plasticitymechanisms relating genetic mutations, cortical devel-opm ent, and secondary changes in the brain m odulatedby imm une modulators and hormon es, as well as other

factors not yet identified.Additional work is also needed to further characterizethe behavioral phenotype in dyslexia. The exact natureof the phonological defect in dyslexia is not yet known.The exact developmental interaction between generaland linguistic auditory processing needs be worked out.Other, non-phonological components may be identi-fied as important explanatory mechanisms. The contri-bution of the visual system remains speculative. Therole of the cerebellum remains c ircumstantial. A dvancesin neuroimaging research, including functional imaging


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and the new tract tracing techniques, will link specificbehavioral phenotypes to areas of abnormal activationand, hopefully, specific mutations. Finally, improvedclassification on the basis of identified gene mutations,brain activation patterns, and behavioral phenotypeswill trigger the design and testing of specific therapiesimplemented at earlier and earlier stages of develop-ment, with the promise of much improved success forthe expression of each child's full potential.

SUGGESTED READINGSBerm an, J. I., Berger, M. S., Muk herjee, P., Henry , R. G. (2004).Diffusion-tensor imaging-guided tracking of fibers of thepyramidal tract combined with intraoperative cortical stimula-tion m apping in patients w ith gliomas. /Neurosurg 101 1),66-72 .De hae ne, S., Le Clec, H. G., Poline, J. B., Le Bihan, D., Co hen ,L. (2002). The visual word form area: A prelexical representa-

tion of visual words in the fusiform gyrus. Neuroreport 13{3),321-325.Fisher, S. E., DeFries, J. C. (2002). De velo pm enta l dyslexia:Genetic dissection of a complex cognitive trait. Nat RevNeurosci, 3(10), 767-780.Fitch, R. H., Tallal, P., Brown, C. P., Gala burda , A. M., Rosen,G. D. (1994). Induced microgyria and auditory temporal pro-cessing in rats: model for language impairment? erebCortex,4(3), 260-270.Galabu rda, A. M. (1994). Deve lopm ental dyslexia and a nim alstudies: At the interface between cognition and neurology.Cognition, 50(1-3), 133-149.

Galaburda, A. M., Sherman, G. F., Rosen, G. D., Aboitiz, F.,Geschwind, N. (1985). Developmental dyslexia: Four consecu-tive patients with cortical anomalies.ArmNeurol 18 2), 222-233.Grigorenko, E. L. (2003). The first candidate gene for dyslexia:Turning the page of a new chapter of research.ProcNatl AcadSci USA, 100 20), 11190-11192.Herman, A. E., Galaburda, A. M., Fitch, R. H., Carter, A. R.,Rosen, G. D. (1997). Cerebral microgyria, thala mic cell size andauditory temporal processing in male and female rats. CerebCortex, 7(5), 453-464.Lee, S. K., Kim, D. I., Mori, S., Kim, J., Kim, H. D., Heo, K., et al.(2004). Diffusion tensor MRI visualizes decreased subcorticalfiber connectivityn focal cortical dysplasia. Neuroimage, 22 4),1826-1829.Pugh, K. R., Mencl, W.E.,Jenner, A. R., Katz, L., Frost,S J., Lee, J.R., et al. (2000). Functional neuroimaging studies of readingand reading disability (developmental dyslexia). MentRetardDevDisabilRes Rev, 6 3),207-213.Ramus, F. (2003). Developmental dyslexia: Specific phonologicaldeficit or general sensorimotor dysfunction? Curr OpinNeiirobiol 13 2),212-218.Scerri, T. S., Fisher, S. E., Franck s, S. E., Franc ks, C , M acP hie, 1. L.,Paracchini, S., et al. (2004). Putative functional alleles ofDYXIGI are not associated with dyslexia susceptibility in a largesample of sibling pairs from the UK. /.Med.Genet. 41 , 1-5.Taipale, M., Kaminen, N., Nopola-Hemmi, J. , Haltia, T.,Myllyluoma, B., Lyytinen, H., et al. (2003). A cand idate genefor developmental dyslexia encodes a nuclear tetratricopeptiderepeat domain protein dynamically regulated in brain. ProcNatl AcadSciUSA, 100 20),11553-11558.Wigg, K. G., Couto, J. M., Feng, Y., Anderson, B., Gate-Garter, T.D., Macciardi, F., et al. (2004). Support for EKNl as the suscep-tibility locus for dyslexia on 15q21.MolPsychiatry,9(12), 1111-1121.


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