Dyslexia

Overview of Dyslexia

Dyslexia, in general, is a specific learning disability that is neurobiological. It is characterized by difficulties in word recognition, spelling, and decoding due to a deficit in phonological processing irrespective of healthy IQ and effective educational provision. It is classified into two categories, acquired and developmental dyslexia (DD). Acquired dyslexia is patients lose some of their reading ability because of neuropathological diseases such as stroke, dementia, multiple sclerosis, and brain damage. DD is a complicated neurodevelopmental disorder, which affects 5-12% of children, characterized by difficulty in reading accuracy and fluency, despite normal intelligence and education.

Research shows DD is a complex multifactorial disorder that usually co-occurs with other conditions, including attention deficit hyperactivity disorder (ADHD), developmental language disorder, and mathematical disability. According to the twin studies, DD is highly heritable and has a heritability estimate of 40%-70%. DD may cause many adverse events in children, including internalizing problems (anxiety, depression), academic underachievement, and reduced educational attainment. So, it is necessary to make early interventions to improve their outcome.

The Neural Basis of Dyslexia

Evidence of dysfunction in people with dyslexia in neural systems implicated in reading and related cognitive functions has come from functional brain imaging studies. In dyslexics, reduced gray matter volume is observed in the occipitotemporal and parietotemporal areas. Further, structural alteration of gray matter in the left temporal lobe, white matter in the left posterior superior temporal gyrus, and arcuate fasciculus correlate to reading and spelling deficit among dyslexics. Moreover, the deleterious activation of brain regions among dyslexics is either due to hypoactivation in the left parietal, parietotemporal, and bilateral fusiform cortices or hyperactivation in the caudate, thalamus, left inferior gyrus, and middle frontal gyrus.

Fig.1 Changes in the functional MRI signal between normal and dyslexic readers. (Rahul, 2021)

Dyslexia and Brain Metabolism

Neurotransmitters are the chemical messengers that help in transferring signals across neurons that either have an excitatory or an inhibitory effect. These neurotransmitters are classified into two categories as amino acids and biogenic amines. A defect in the synthesis or degradation of neurotransmitters will influence neurotransmitter disorders that include learning disabilities. The brain chemicals associated with phonological processing and reading are glutamate, choline, N-acetylaspartate (NAA), and creatine. These neurochemicals are subject to synaptic potentiation and depression during the complex process of reading and are identified to have a significant correlation with reading difficulties.

Glutamate, the excitatory amino acid, is associated with a brain network responsible for learning. Elevated glutamate levels in the temporoparietal and occipitotemporal regions have a significant correlation with substandard vocabulary and reading performance. Similarly, elevated lactate levels in the lateral sulcus, frontal operculum, inferior frontal gyrus, and superior temporal gyrus are related to dyslexia.

Brain Imaging Findings in Dyslexia

• Findings from MRI Studies

The study results suggest that alterations in gray matter are present in the brain cortex, subcortical regions, and cerebellum in dyslexic children, adolescents, and adults. Another study found that the right planum temporale (PT) area was similar in dyslexic and control groups, but that the left PT was significantly smaller in the dyslexic group.

• Findings from functional MRI (fMRI) Studies

Reduced activation in the left posterior temporoparietal cortex and abnormal activation in the perisylvian and extrasylvian temporal cortex during an auditory rhyming task in dyslexics were found using fMRI. Functional imaging studies of developmental dyslexia have reported reduced task-related neural activity in the temporal and inferior parietal cortices.

• Findings from MRS Studies

Biochemical differences were found in the left temporoparietal lobe and the right cerebellum between dyslexic men and controls using proton-MRS. Dyslexic boys showed a greater area of elevated brain lactate in the left anterior quadrant compared with the control group during a phonological task.

Fig.2 The magnetic resonance spectroscopy findings showed the elevated lactate peak (A) in the left anterior quadrant as a white square in the dyslexic brain (B) during the phonological task (C) but not during the passive listening. (Sun, 2010)

• Findings from PET Studies

The PET studies confirm the fact that dyslexic brains are activated differently from those of non-dyslexics during phonological tasks.

• Findings from EEG Studies

Quantitative EEG and neuropsychological tests were used to investigate the underlying neural processes in dyslexia.

Key Factors in Dyslexia

Reading is a complex learned skill depending on the integration of multiple visual, linguistic, and cognitive abilities. The relationship between the brain regions and reading abilities has been revealed with neuroimaging methods, including electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI). Research suggested these regions are in the left hemisphere of the brain, including the inferior frontal gyrus, the inferior parietal area, the arcuate fasciculus (green), and the fusiform gyrus.

Fig.3 Schematic of the aspects of the reading brain in the left hemisphere. (Asim, 2015)

Critical Genes Associated with Dyslexia

Recent genetic studies have suggested several genes could affect reading development by affect neuron migration, cortical morphogenesis, and the outgrowth of neurites. These genes include DYX1C1, DCDC2, KIAA0319, C2ORF3, MRPL19, ROBO1, FOXP2, etc.

• DYX1C1

Research shows a functional effect of two single-nucleotide polymorphisms (SNPs) in DYX1C1, rs3743205 (-3G→A) and rs57809907 (1249C→T), are significantly related to susceptibility to dyslexia. Besides, rs17819126, rs3743204, rs685935, rs12899331 in DYX1C1 are reported to be associated with reading spelling level and reading-related cognitive ability. There is evidence that mutations of the DYX1C1 gene could interfere with the activity of cilia, which play an important role in cell signaling transduction and cell movement.

Fig.4 RNA interference against key DD susceptibility genes impairs neuronal migration of rats. (Guidi, 2018)

• DCDC2

A recent study suggested the absence of a short tandem repeat (BV677278) in the intron 2 of the DCDC2 gene leads to reading and memory disorders in DD, as it could affect the DCDC2 gene expression. Besides, markers (rs793862, rs807701, and rs807724) in the DCDC2 gene are reported to be strongly associated with dyslexia susceptibility, reading fluency, and spelling ability.

• KIAA0319

A three-SNP risk haplotype spanning across TTRAP, THEM2, and KIAA0319 genes, has been shown to associate with DD in three independent clinical samples. This risk haplotype is on 40% lower levels of the expression of the KIAA0319 gene compared with the non-risk haplotype. Recent studies of rodent models have shown that knocking out the KIAA0319 gene in the rat brain affects not only neuronal migration but also dendritic growth and differentiation.

• ROBO1

In one research, the DD candidate gene ROBO1 was shown to be associated with cell migration and axon growth, which can affect the connectivity of the brain. This evidence led to the hypothesis that DD is a disorder of neuronal migration.

• C2ORF3&MRPL19

In a study of DD, C2ORF3 was suggested to have a potential function in ribosomal RNA (rRNA) processing. MRPL19 is highly expressed in all areas of the fetal and adult brain. Research has suggested that the expression of these two candidate genes of DD was strongly correlated with DYX1C1, ROBO1, DCDC2, and KIAA0319 across different brain regions. and this evidence suggested that DD is a disorder in neuronal positioning and axonal outgrowth.

• FOXP2

Some research has reported that language-based learning disabilities could have been caused by variants disrupting one copy of FOXP2. In one rodent model, mice carrying mutant FOXP2 exhibit disorders including developmental delay and deficits in learning.

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References

1. Rahul, D.R.; Ponniah, R.J. The Modularity of Dyslexia. Pediatr Neonatol. 2021 May;62(3):240-248.
2. Sun, Y.F.; et al. Brain imaging findings in dyslexia. Pediatr Neonatol. 2010 Apr;51(2):89-96.
3. Norton, E.S.; et al. Neurobiology of dyslexia. Current opinion in neurobiology. 2015,30: 73-78.
4. Guidi, L.G.; et al. The neuronal migration hypothesis of dyslexia: A critical evaluation 30 years on. European Journal of Neuroscience. 2018,48(10): 3212-3233.