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.
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.
References
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., Guimarães, 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
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.
References
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., Guimarães, 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
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