Wednesday, 2 May 2012

Neuronal migration in language learning impairments: a suggestion

Specific language impairment (SLI) and dyslexia are related developmental disorders in which a child has difficulty learning to talk (SLI) or to read (dyslexia). Many children have both problems, although they can occur separately (Bishop & Snowling, 2004), and they are sometimes grouped together as ‘language learning impairments’. There's good evidence that genes are implicated in causing these conditions (Bishop, 2009).
A popular account maintains that the genes implicated in language learning impairments affect a very early process in the developing brain known as neuronal migration (Galaburda et al., 2006). It’s an attractive theory that has the potential to provide a link from genes to behaviour. However, when I looked at the evidence, I found myself not entirely convinced. Here I’ll briefly review research on this topic, explain my reservations, and conclude by proposing a study that needs doing. I’m not an expert in neuroanatomy or neuroimaging, so I’ll be interested to see if others think this proposal is sensible.
Abnormalities found in 1979 case report. Solid circles show ectopias/dysplasias, and shaded area shows micropolygyria (based on Galaburda et al, 1985) .
Over thirty years ago, Galaburda and Kemper published a post mortem study of the brain of a man with developmental dyslexia who died from an accidental fall at the age of 20 years. He’d had delayed language development, and was diagnosed with dyslexia in the first grade. His Stanford-Binet IQ of 105 was well in advance of his reading attainments. He developed epilepsy at 16 years of age. His brain showed areas of displaced neurons (ectopias) in the left cerebral hemisphere, especially around the left planum temporale. There was also an area of polymicrogyria, i.e. excessive number of small convolutions, giving a lumpy appearance to the cortex. This raised the possibility that we might find the origins of dyslexia not in the gross features of brain structure, but at the microscopic level, in the organisation of neurons. However, as the authors noted: “It is not possible to tell from a single case whether or not the anatomical findings have any causative relationship to the clinical findings – much less whether the malformation is responsible for the seizure disorder, the learning disability, both, or neither” (p. 99). They also noted that the kinds of neuroanatomical abnormality that they found in their patient were probably too rare to explain dyslexia in general, which has a prevalence of around 5-10% in the population.
A subsequent report added further evidence for a link to dyslexia (Galaburda et al, 1985). Similar abnormalities were found in three further post-mortem cases, and in none of these was epilepsy described, though one had delayed speech and one had “notable language difficulties”. Three additional cases, this time of female dyslexics, were reported by Humphreys et al (1990), but these were less compelling: the evidence for migrational abnormalities was less strong, and other pathologies could have been implicated.
There’s a general problem with the methodology of these studies, which is that they were not conducted blind. The cellular abnormalities that were described require an expert eye and clinical judgement, and you wouldn’t necessarily see them unless you were looking for them. Could they just be spurious findings? Galaburda and colleagues noted that similar anomalies are sometimes reported as incidental findings in unselected autopsy brains, and so a key question was whether the findings in dyslexic brains were really unusual. Accordingly, Kaufman and Galaburda (1989) analysed ten control brains using identical procedures to those used for dyslexic brains. They found abnormal cells in three control brains, but the anomalies were far less numerous than those seen in the dyslexic brains. This provides useful context, but ideally, we need a study where the neuroanatomist is given both dyslexic and control brains and asked to analyse them without knowing which was which, to avoid the perceptual and cognitive biases that can affect even the most scrupulous of observers.
The anomalies described by Galaburda and colleagues reflect disruption at an early stage of brain development, when neurons are being formed and organised into coherent structures. This website from Pasco Rakic has some nice animations showing how a brain is formed when neurons are first generated in the foetus. Neurons formed in the ventricular zone travel out to the surface of the cortex along radial glial fibres, gradually building up six distinct layers of the cortex from the inside out. Studies with rodents, and evidence from humans with developmental disorders, indicate that this process can be disrupted in a range of ways. In some people, a proportion of cells fail to migrate at all, and can be seen as clusters of abnormal cells around the ventricles. This condition, known as periventricular heterotopia, does not normally impair cognitive function but does cause epilepsy. In other cases, there is partial migration followed by arrest, leading to lissencephaly, typically associated with epilepsy and severe intellectual impairment(Guerrini& Parrini, 2010). In mice, a naturally-occurring genetic mutation leads to the phenotype of the reeler mouse, which has severe motor co-ordination problems linked to disorganisation of the usual laminar structure of the cortex, because the migrating neurons fail to penetrate to the surface of the brain. The cases studied by Galaburda and colleagues had a range of anomalies, described as ectopias, dysplasias, heterotopias, ‘brain warts’ and polymicrogyria, associated with disruption affecting different stages of neuronal migration and postmigrational development (Barkovich et al, 2012).
What makes this work exciting is a potential link to genetic studies of dyslexia. There are replicated associations of dyslexia with several genes, including DYX1X1, KIAA0319, DCDC2 and ROBO1. As Galaburda et al (2006) noted in their review, mutations of these genes have been linked to migrational anomalies in rodents. It looks, therefore, as though the route from brain to behaviour could be neatly explained by postulating a genetic influence on neuronal migration that leads to a brain that is not optimally connected.
Some puzzles, however, remain. First, the genetic variants associated with dyslexia are not mutations. They are common in the general population. Associations with dyslexia are found in studies with very large samples, but they are not very strong. For instance, one can deduce from the published data on the KIAA0319 locus that there is a low-risk version of the gene that is found in 39% of normal readers and 25% dyslexics, and a high-risk version that is found in 30% of normal readers and 35% dyslexics. If the dyslexic risk variant causes anomalies of neuronal migration, then we should see lots of people with those anomalies, many (most) of whom will not be dyslexic. Of course, it is all a matter of degree; it is possible that each risk variant has only minor effects on neuronal migration, and causes problems only if it occurs in conjunction with other genetic or environmental risks. Neuronal migration can be affected by environmental factors, such as toxins, nutrition, and disease or trauma affecting the brain. So the ubiquity of these risk alleles does not rule out a causal route via neuronal migration mechanisms, but it does make the story more complicated.
What if we look at the association between neuronal migration disorders and dyslexia from the other direction, i.e. assessing reading ability in individuals with known migrational abnormalities? Chang et al (2005) did this in people with periventricular nodular heterotopia - a disorder in which a proportion of neurons fail to migrate from the ventricular zone. Most of their participants had normal range IQ. On the Wide Range Achievement tests of reading and spelling, their mean scores were average or above-average. Many of them did, however, do poorly on the Nelson-Denny reading test and on this basis, the authors concluded they were dyslexic. But this test, which stresses speed, was designed for college students, not for the general population. The fact that most participants were older than college students, and all were on anti-epileptic medication, makes the claim of dyslexia in these people far from convincing. Minimally, this study should have included a comparison group to control for age, background and medication status.
A final issue is why migrational abnormalities haven’t been noted in MRI studies of dyslexia. In studies of children with specific language impairments, a Brazilian group has reported remarkably high rates of polymicrogyria (De Vasconcelos Hage et al, 2006). However, this does not seem to be a general explanation for SLI. My colleagues tell me there were no cases of this in people with SLI who participated in a recent MRI study that we published, and none was mentioned in a series reported by Webster etal (2008). MRI studies of dyslexia have been considerably more numerous, yet, as far as I can establish, none has mentioned migrational anomalies. Of course, many MRI studies focus on averaged data, which would mask individual variations. So, a key question is whether the failure to report migrational abnormalities in MRI studies is because (a) no-one was looking for them, (b) they are too subtle to see on regular MRI scan, or (c) they aren’t involved in most cases of language learning impairments.
I was intrigued by this question, so I looked for literature on detectability of neuronal migration anomalies on MRI scan. My impression is that these wouldn’t necessarily be detected unless you were looking for them, and if you were, detectability depends on the type and location of anomalies. Wagner et al (2011) devised an automated method of MRI analysis that was successful in picking up 82% of Type IIA cortical dysplasias and 92% of Type IIB, compared to 65% and 91% detected by an expert neuroradiologist. Periventricular nodular heterotopia seems a more obvious pathology that is routinely detected on MRI scan.
On this basis, I’d say there’s a study out there crying out to be done. There are plenty of reports of MRI scans comparing dyslexic vs control brains. We could revisit those scans using the automated methods developed by Wagner et al to test the hypothesis that the rate of neuromigrational anomalies is higher in the dyslexic vs control samples. It’s clear that MRI scans won’t pick up everything, and subtle anomalies may be missed. However, if the neuronal migration account of language learning impairments is correct, we should nevertheless expect to see a measureable difference in the rates of anomalies between cases of dyslexia/SLI vs. controls. And if genetic information is available as well, then a comparison could be done between those with and without risk variants.

Barkovich, A. J., Guerrini, R., Kuzniecky, R. I., Jackson, G. D., & Dobyns, W. B. (2012). A developmental and genetic classification for malformations of cortical development: update 2012. Brain, 135(5), 1348-1369. doi: 10.1093/brain/aws019
Bishop, D. V. M. (2009). Genes, cognition and communication: insights from neurodevelopmental disorders. The Year in Cognitive Neuroscience: Annals of the New York Academy of Sciences, 1156, 1-18.
Bishop, D. V. M., & Snowling, M. J. (2004). Developmental dyslexia and Specific Language Impairment: Same or different? Psychological Bulletin, 130, 858-886.
Chang, B. S., Ly, J., Appignani, B., Bodell, A., Apse, K. A., Ravenscroft, R. S., . . . Walsh, C. A. (2005). Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia. Neurology, 64(5), 799-803.
De Vasconcelos Hage, S. R., Cendes, F., Montenegro, M. A., Abramides, D. V., GuimarĂ£es, C. A., & Guerreiro, M. M. (2006). Specific language impairment: linguistic and neurobiological aspects. Arquivos de Neuro-Psiquiatria, 64, 173-180.
Galaburda, A. M., & Kemper, T. (1979). Cytoarchitectonic abnormalities in developmental dyslexia. Annals of Neurology, 6, 94-100.
Galaburda, A. M., Sherman, G. F., Rosen, G. D., Aboitiz, F., & Geschwind, N. (1985). Developmental dyslexia: four consecutive cases with cortical anomalies. Annals of Neurology, 18, 222-233.
Galaburda, A. M., LoTurco, J. J., Ramus, F., Fitch, R. H., & Rosen, G. D. (2006). From genes to behavior in developmental dyslexia. Nature Neuroscience, 9, 1213-1217.
Guerrini, R., & Parrini, E. (2010). Neuronal migration disorders. Neurobiology of Disease, 38, 154-166.
Wagner, J., Weber, B., Urbach, H., Elger, C., & Huppertz, H. (2011). Morphometric MRI analysis improves detection of focal cortical dysplasia type II Brain, 134 (10), 2844-2854 DOI: 10.1093/brain/awr204

Webster, R. I., Erdos, C., Evans, K., Majnemer, A., Saigal, G., Kehayia, E., . . . Shevell, M. I. (2008). Neurological and magnetic resonance Imaging findings in children with developmental language impairment. Journal of Child Neurology, 23(8), 870-877. doi: 10.1177/0883073808315620 


  1. Interesting post.

    I don't know if this is relevant but Manuel Casanova (he of the minicolumns) has just published a new paper on surface complexity of the brain in dyslexia, autism and "asymptomatic" controls:

    Neuronal migration was listed in his phenotypic suggestions.

  2. Uta Frith kindly sent me this comment which for some reason Blogger would not accept!

    Not only a great post, Dorothy, but a most constructive call for crucial research that should now be feasible.

    The idea that neuronal migration hazards are at the origin of neuro-developmental disorders is very plausible. It is a pity that it has not yet been vigorously investigated. Galaburda's theory of dyslexia as a type of migration failure that specifically affects left hemisphere speech and language areas, remains attractive. In our own VBM structural analysis of dyslexic brains we have speculatively used this theory to interpret our findings (see abstract below).

    I completely agree that a study should now be done and your suggestion is eminently practical. I would add my own suggestion that there should also be a new study with cognitively well defined cases using high field scanners. I imagine that a 7-Tesla scanner would unequivocally show up ektopias. I would be very curious to see what they look like in the living brain as opposed to the microscopic pictures we have from post-mortem tissue.

    There is of course a danger in being misled when analysing data of mixed quality from existing samples that may not be as well defined as they might be. However, it is a start. As ever, we should expect that no one theory can explain all cases of dyslexia. The deeper genetic causes are likely to result in a whole variety of neuronal migration hazards not all of which might be manifest in visible dysplasias. Normally invisible processes at the level of the synapse should also not be discounted, nor should misconnections between regions within the left hemisphere.

  3. I agree with Uta that it's very plausible that cell migration defects are involved in neurodevelopmental disorders, but I'm surprised you don't mention Reelin. (Perhaps Barkovich et al discuss it, but I don't have access to the paper.)

    Reelin is a glycoprotein that's essential for the migrations that occur during cortical development. Neuroblasts need it to adhere to the radial glial fibres that they migrate along to get from the subventricular zone to the developing cortex. Reelin mutant mice have abnormal cortical layers, and serve as a model for human developmental disorders. Reelin is also implicated in autism and schizophrenia. And Rakic, who described the radial migration of neurons in the early 70s, published a study in 2006 showing that exposure to ultrasound waves can affect neuronal migration in mice.

  4. Thanks for your suggestion! very helpfull.

    Zubair Amjad

  5. Thanks Mo. I didn’t want to raise the topic of reelin because as far as I am aware any link to dyslexia/language impairments is very speculative. The real point I wanted to stress in this post was that there’s lots of speculation about neuronal migration impairments in these disorders, but the amount of hard evidence behind that speculation is surprisingly meagre. The reeler mouse model is wonderful for illustrating how migration can be disrupted, but my understanding is that in humans reelin is definitely implicated only in certain severe migrational disorders associated with epilepsy. Yes, it’s plausible that this mechanism may be implicated, at least in some cases, but there are other postmigrational processes, such as development of synaptic connectivity, myelination, or apoptosis that also need to be considered. If there is evidence for reelin genes associated with dyslexia or SLI I’m sure someone will put me right!
    As noted above, I’m a psychologist and my knowledge about neuroanatomy is pretty slender. I found this a very useful reference - it gives quite a lot of information about reelin, but does not mention dyslexia or language impairments.
    Gleeson, J. G., & Walsh, C. A. (2000). Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends in neurosciences, 23(8), 352-359. doi: 10.1016/s0166-2236(00)01607-6

  6. In one of those interactions that makes blogging so worth while, I've just been contacted by someone who is assembling the kind of big dyslexia MRI bank I had dreamed of. Will blog about this soon!