Developmental dyslexia is characterized by the co-existence of visuospatial and phonological disorders in Chinese children

Developmental dyslexia is a neurological condition that is characterized by severe impairment in reading skill acquisition in people with adequate intelligence and typical schooling [1], [2] and [3]. For English readers, reading impairment is critically associated with a phonological processing disorder [3], [4] and [5], which may co-occur with an orthographic (visual word form) processing deficit [6], but not with a general visual processing dysfunction in most dyslexics [7]. The pathophysiology of dyslexia varies across languages [8]: for instance, unlike English, written Chinese maps visually intricate graphic forms (characters) onto meanings; pronunciation of Chinese characters must be rote memorized. This suggests that, in Chinese, a fine-grained visuospatial analysis must be performed to activate characters' phonology and meaning; consequently, disordered phonological processing may commonly co-exist with abnormal visuospatial processing in Chinese dyslexia. To test this hypothesis, we conducted an fMRI experiment in which 12 Chinese dyslexics, shown previously [9] to exhibit a phonological disorder, performed a physical size judgment measuring visuospatial dimensions. Compared with 12 control subjects, the dyslexics showed weaker activations in left intraparietal sulcus (IPS) mediating visuospatial processing. Analyses of individual dyslexics' performances further suggest that developmental dyslexia in Chinese is commonly associated with the co-existence of a visuospatial deficit and a phonological disorder.     

Visual function, fatty acids and dyslexia

There is mounting evidence that developmental dyslexia is a neurodevelopmental disorder which involves abnormalities of fatty acid metabolism, particularly with respect to certain long-chain highly unsaturated fatty acids (HUFAs). Psychophysical evidence also strongly suggests that dyslexics may have visual deficits as well as phonological problems. Specifically, these visual deficits appear to be related to the magnocellular pathway, which is specialized for processing fast, rapidly-changing information about the visual scene. It remains unclear how these two aspects of dyslexia - fatty acid processing and visual magnocellular function - could be related. We propose some hypotheses - necessarily speculative, given the paucity of biochemical research in this field to date - which address this question.     

Reading text increases binocular disparity in dyslexic children

Children with developmental dyslexia show reading impairment compared to their peers, despite being matched on IQ, socio-economic background, and educational opportunities. The neurological and cognitive basis of dyslexia remains a highly debated topic. Proponents of the magnocellular theory, which postulates abnormalities in the M-stream of the visual pathway cause developmental dyslexia, claim that children with dyslexia have deficient binocular coordination, and this is the underlying cause of developmental dyslexia. We measured binocular coordination during reading and a non-linguistic scanning task in three participant groups: adults, typically developing children, and children with dyslexia. A significant increase in fixation disparity was observed for dyslexic children solely when reading. Our study casts serious doubts on the claims of the magnocellular theory. The exclusivity of increased fixation disparity in dyslexics during reading might be a result of the allocation of inadequate attentional and/or cognitive resources to the reading process, or suboptimal linguistic processing per se.     

Dyslexia Impairs Speech Recognition but Can Spare Phonological Competence

Dyslexia is associated with numerous deficits to speech processing. Accordingly, a large literature asserts that dyslexics manifest a phonological deficit. Few studies, however, have assessed the phonological grammar of dyslexics, and none has distinguished a phonological deficit from a phonetic impairment. Here, we show that these two sources can be dissociated. Three experiments demonstrate that a group of adult dyslexics studied here is impaired in phonetic discrimination (e.g., ba vs. pa), and their deficit compromises even the basic ability to identify acoustic stimuli as human speech. Remarkably, the ability of these individuals to generalize grammatical phonological rules is intact. Like typical readers, these Hebrew-speaking dyslexics identified ill-formed AAB stems (e.g., titug) as less wordlike than well-formed ABB controls (e.g., gitut), and both groups automatically extended this rule to nonspeech stimuli, irrespective of reading ability. The contrast between the phonetic and phonological capacities of these individuals demonstrates that the algebraic engine that generates phonological patterns is distinct from the phonetic interface that implements them. While dyslexia compromises the phonetic system, certain core aspects of the phonological grammar can be spared.     

Evaluation of visual motion perception ability in mice with knockout of the dyslexia candidate susceptibility gene Dcdc2

Developmental dyslexia is a heritable disability characterized by difficulties in learning to read and write. The neurobiological and genetic mechanisms underlying dyslexia remain poorly understood; however, several dyslexia candidate risk genes have been identified. One of these candidate risk genes—doublecortin domain containing 2 (DCDC2)—has been shown to play a role in neuronal migration and cilia function. At a behavioral level, variants of DCDC2 have been associated with impairments in phonological processing, working memory and reading speed. Additionally, a specific mutation in DCDC2 has been strongly linked to deficits in motion perception—a skill subserving reading abilities. To further explore the relationship between DCDC2 and dyslexia, a genetic knockout (KO) of the rodent homolog of DCDC2 (Dcdc2) was created. Initial studies showed that Dcdc2 KOs display deficits in auditory processing and working memory. The current study was designed to evaluate the association between DCDC2 and motion perception, as these skills have not yet been assessed in the Dcdc2 KO mouse model. We developed a novel motion perception task, utilizing touchscreen technology and operant conditioning. Dcdc2 KOs displayed deficits on the Pairwise Discrimination task specifically as motion was added to visual stimuli. Following behavioral assessment, brains were histologically prepared for neuroanatomical analysis of the lateral geniculate nucleus (LGN). The cumulative distribution showed that Dcdc2 KOs exhibited more small neurons and fewer larger neurons in the LGN. Results compliment findings that DCDC2 genetic alteration results in anomalies in visual motion pathways in a subpopulation of dyslexic patients.     

Altered low-γ sampling in auditory cortex accounts for the three main facets of dyslexia

It has recently been conjectured that dyslexia arises from abnormal auditory sampling. What sampling rate is altered and how it affects reading remains unclear. We hypothesized that by impairing phonemic parsing abnormal low-gamma sampling could yield phonemic representations of unusual format and disrupt phonological processing and verbal memory. Using magnetoencephalography and behavioral tests, we show in dyslexic subjects a reduced left-hemisphere bias for phonemic processing, reflected in less entrainment to ≈30?Hz acoustic modulations in left auditory cortex. This deficit correlates with measures of phonological processing and rapid naming. We further observed enhanced cortical entrainment at rates beyond 40?Hz in dyslexics and show that this particularity is associated with a verbal memory deficit. These data suggest that a single auditory anomaly, i.e., phonemic oversampling in left auditory cortex, accounts for three main facets of the linguistic deficit in dyslexia.     

Could platelet activating factor play a role in developmental dyslexia?

Post-mortem studies by Galaburda and colleagues on the brains of developmental dyslexics found characteristic neuronal abnormalities: ectopias, microgyria, and fewer large-soma cells in sensory thalamus. An association between dyslexia and immune dysfunction has also been proposed. We describe a mechanism which may explain these observations. Platelet-activating factor (PAF) is a pro-inflammatory lipid implicated in neurological disorders. We propose that PAF may also be involved in dyslexia.     

Palmar dermatoglyphics of dyslexia

Palmar dermatoglyphic prints were taken of 261 dyslexics (173 males and 88 females) and compared against those of 707 controls (372 males and 335 females). Dyslexics of both sexes were found to exhibit greater complexity in terms of ridge count and pattern location than controls, particularly on the left hand. Specifically, both male and female dyslexics exhibited higher left a-b counts, wider atd angles on both palms, and higher frequencies of pattern in left interdigital area IV. Additionally, male dyslexics also had higher right a-b counts and greater frequency of pattern in the left hypothenar area. Dyslexics of both sexes were also found to have more distally located axial triradii, and investigation of bilateral asymmetry found dyslexics to exhibit more directional asymmetry than controls in the variable of a-b count, with the left value for both groups being greater than the right. It was concluded that the study evidenced strong support for the hypothesis that some causative factor relating to the development of dyslexia is operating during the time period in which dermatoglyphic features are formed. The relevance of these findings in terms of the Geschwind hypothesis and the possible importance of prenatal testosterone are discussed.     

Niacin skin test response in dyslexia

The niacin skin test reflects a flush and oedema owing to the production of prostaglandin D2 from arachidonic acid. A diminished response may indicate abnormalities in the phospholipid metabolism, which has been shown in schizophrenia. There is evidence that dyslexia might also involve phospholipid abnormalities, therefore we examined the skin response in 51 dyslexics and 45 controls. Four concentrations of aqueous methyl nicotinate were applied topically to the forearm. Flushing was rated using a seven-point scale at 3 min intervals over 21 min. Repeated measures ANOVA for the four concentrations across all seven time-points showed no significant effect of subject group, but when analyses were confined to the first 9 min, flushing was reduced in dyslexics. Significant group differences were also found for the lowest niacin concentration (0.0001M) across six out of seven time-points. The results indicate a slightly reduced and delayed response to niacin in dyslexia.     

Direct Viewing of Dyslexics’ Compensatory Strategies in Speech in Noise Using Auditory Classification Images

A vast majority of dyslexic children exhibit a phonological deficit, particularly noticeable in phonemic identification or discrimination tasks. The gap in performance between dyslexic and normotypical listeners appears to decrease into adulthood, suggesting that some individuals with dyslexia develop compensatory strategies. Some dyslexic adults however remain impaired in more challenging listening situations such as in the presence of background noise. This paper addresses the question of the compensatory strategies employed, using the recently developed Auditory Classification Image (ACI) methodology. The results of 18 dyslexics taking part in a phoneme categorization task in noise were compared with those of 18 normotypical age-matched controls. By fitting a penalized Generalized Linear Model on the data of each participant, we obtained his/her ACI, a map of the time-frequency regions he/she relied on to perform the task. Even though dyslexics performed significantly less well than controls, we were unable to detect a robust difference between the mean ACIs of the two groups. This is partly due to the considerable heterogeneity in listening strategies among a subgroup of 7 low-performing dyslexics, as confirmed by a complementary analysis. When excluding these participants to restrict our comparison to the 11 dyslexics performing as well as their average-reading peers, we found a significant difference in the F3 onset of the first syllable, and a tendency of difference on the F4 onset, suggesting that these listeners can compensate for their deficit by relying upon additional allophonic cues.     

Dyslexia in adults is associated with clinical signs of fatty acid deficiency

Developmental dyslexia is a complex syndrome whose exact cause remains unknown. It has been suggested that a problem with fatty acid metabolism may play a role, particularly in relation to the visual symptoms exhibited by many dyslexics. We explored this possibility using two self-report questionnaires, designed on the basis of clinical experience, to assess (1) clinical signs of fatty acid deficiency; and (2) symptoms associated with dyslexia in known dyslexic and non-dyslexic subjects. Dyslexic signs and symptoms included the auditory-linguistic and spoken language difficulties traditionally associated with the disorder, as well as visual problems (both with reading and more generally) and motor problems. Fatty acid deficiency signs were significantly elevated in dyslexic subjects relative to controls, particularly within males (P<0.001). In addition, the severity of these clinical signs of fatty acid deficiency was strongly correlated with the severity of dyslexic signs and symptoms not only in the visual domain, but also with respect to auditory, linguistic and motor problems. The pattern of relationships differed somewhat between dyslexic and control groups, and sex differences were also observed. Our findings support the hypothesis that fatty acid metabolism may be abnormal in developmental dyslexia, and indicate the need for further studies using more objective measures.     

Neural changes following remediation in adult developmental dyslexia

Brain imaging studies have explored the neural mechanisms of recovery in adults following acquired disorders and, more recently, childhood developmental disorders. However, the neural systems underlying adult rehabilitation of neurobiologically based learning disabilities remain unexplored, despite their high incidence. Here we characterize the differences in brain activity during a phonological manipulation task before and after a behavioral intervention in adults with developmental dyslexia. Phonologically targeted training resulted in performance improvements in tutored compared to nontutored dyslexics, and these gains were associated with signal increases in bilateral parietal and right perisylvian cortices. Our findings demonstrate that behavioral changes in tutored dyslexic adults are associated with (1) increased activity in those left-hemisphere regions engaged by normal readers and (2) compensatory activity in the right perisylvian cortex. Hence, behavioral plasticity in adult developmental dyslexia involves two distinct neural mechanisms, each of which has previously been observed either for remediation of developmental or acquired reading disorders.     

TDT-association analysis of EKN1 and dyslexia in a Colorado twin cohort

A candidate gene, EKN1, was recently described in a cohort from Finland for the dyslexia locus on chromosome 15q, DYX1. This report described a (2;15) (q11;21) translocation disrupting EKN1 that cosegregated with dyslexia in a two-generation family. It also characterized a sequence polymorphism in the 5′ untranslated region and a missense mutation that showed significant association in 109 dyslexics compared to 195 controls (p=0.002 and p=0.006, respectively). To confirm these results we interrogated the same polymorphisms in a cohort of 150 nuclear families with dyslexia ascertained through the Colorado Learning Disabilities Research Center. Using QTDT analysis with nine individual quantitative tasks and two composite measures of reading performance, we could not replicate the reported association. We conclude that the polymorphisms identified in the Finland sample are unlikely to be functional DNA changes contributing to dyslexia, and that if variation in EKN1 is causal such changes are more likely to be in regulatory regions that were not sequenced in this study. Alternatively, the published findings of association with markers in EKN1 may reflect linkage disequilibrium with variation in another gene(s) in the region.     

Association of short-term memory with a variant within DYX1C1 in developmental dyslexia

A substantial genetic contribution in the etiology of developmental dyslexia (DD) has been well documented with independent groups reporting a susceptibility locus on chromosome 15q. After the identification of the DYX1C1 gene as a potential candidate for DD, several independent association studies reported controversial results. We performed a family-based association study to determine whether the DYX1C1 single nucleotide polymorphisms (SNPs) that have been associated with DD before, that is SNPs '-3GA' and '1249GT', influence a broader phenotypic definition of DD. A significant linkage disequilibrium was observed with 'Single Letter Backward Span' (SLBS) in both single-marker and haplotype analyses. These results provide further support to the association between DD and DYX1C1 and it suggests that the linkage disequilibrium with DYX1C1 is more saliently explained in Italian dyslexics by short-term memory, as measured by 'SLBS', than by the categorical diagnosis of DD or other related phenotypes.     

Differential Entrainment of Neuroelectric Delta Oscillations in Developmental Dyslexia

Oscillatory entrainment to the speech signal is important for language processing, but has not yet been studied in developmental disorders of language. Developmental dyslexia, a difficulty in acquiring efficient reading skills linked to difficulties with phonology (the sound structure of language), has been associated with behavioural entrainment deficits. It has been proposed that the phonological ‘deficit’ that characterises dyslexia across languages is related to impaired auditory entrainment to speech at lower frequencies via neuroelectric oscillations (<10 Hz, ‘temporal sampling theory’). Impaired entrainment to temporal modulations at lower frequencies would affect the recovery of the prosodic and syllabic structure of speech. Here we investigated event-related oscillatory EEG activity and contingent negative variation (CNV) to auditory rhythmic tone streams delivered at frequencies within the delta band (2 Hz, 1.5 Hz), relevant to sampling stressed syllables in speech. Given prior behavioural entrainment findings at these rates, we predicted functionally atypical entrainment of delta oscillations in dyslexia. Participants performed a rhythmic expectancy task, detecting occasional white noise targets interspersed with tones occurring regularly at rates of 2 Hz or 1.5 Hz. Both groups showed significant entrainment of delta oscillations to the rhythmic stimulus stream, however the strength of inter-trial delta phase coherence (ITC, ‘phase locking’) and the CNV were both significantly weaker in dyslexics, suggestive of weaker entrainment and less preparatory brain activity. Both ITC strength and CNV amplitude were significantly related to individual differences in language processing and reading. Additionally, the instantaneous phase of prestimulus delta oscillation predicted behavioural responding (response time) for control participants only.     

Grey Matter Alterations Co-Localize with Functional Abnormalities in Developmental Dyslexia: An ALE Meta-Analysis

The neural correlates of developmental dyslexia have been investigated intensively over the last two decades and reliable evidence for a dysfunction of left-hemispheric reading systems in dyslexic readers has been found in functional neuroimaging studies. In addition, structural imaging studies using voxel-based morphometry (VBM) demonstrated grey matter reductions in dyslexics in several brain regions. To objectively assess the consistency of these findings, we performed activation likelihood estimation (ALE) meta-analysis on nine published VBM studies reporting 62 foci of grey matter reduction in dyslexic readers. We found six significant clusters of convergence in bilateral temporo-parietal and left occipito-temporal cortical regions and in the cerebellum bilaterally. To identify possible overlaps between structural and functional deviations in dyslexic readers, we conducted additional ALE meta-analyses of imaging studies reporting functional underactivations (125 foci from 24 studies) or overactivations (95 foci from 11 studies ) in dyslexics. Subsequent conjunction analyses revealed overlaps between the results of the VBM meta-analysis and the meta-analysis of functional underactivations in the fusiform and supramarginal gyri of the left hemisphere. An overlap between VBM results and the meta-analysis of functional overactivations was found in the left cerebellum. The results of our study provide evidence for consistent grey matter variations bilaterally in the dyslexic brain and substantial overlap of these structural variations with functional abnormalities in left hemispheric regions.     

Relative burden of large CNVs on a range of neurodevelopmental phenotypes

While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.58 × 10(-11), odds ratio = 4.59), dyslexia (p = 3.81 × 10(-18), odds ratio = 14.45), or controls (p = 2.75 × 10(-17), odds ratio = 13.71). There is a striking difference in the frequency of rare CNVs (>50 kbp) in autism (10%, p = 2.4 × 10(-6), odds ratio = 6) or ID (16%, p = 3.55 × 10(-12), odds ratio = 10) compared to dyslexia (2%) with essentially no difference in large CNV burden among dyslexia patients compared to controls. Rare CNVs were more likely to arise de novo (64%) in ID when compared to autism (40%) or dyslexia (0%). We observed a significantly increased large CNV burden in individuals with ID and multiple congenital anomalies (MCA) compared to ID alone (p = 0.001, odds ratio = 2.54). Our data suggest that large CNV burden positively correlates with the severity of childhood disability: ID with MCA being most severely affected and dyslexics being indistinguishable from controls. When autism without ID was considered separately, the increase in CNV burden was modest compared to controls (p = 0.07, odds ratio = 2.33).     

The molecular genetics and neurobiology of developmental dyslexia as model of a complex phenotype

Among complex disorders, those concerning neuropsychiatric phenotypes involve particular challenges compared to disorders with more easily distinguished clinical signs and measures. One such common and unusually challenging phenotype to disentangle genetically is developmental dyslexia (DD), or reading disability, defined as the inability to learn to read and write for an otherwise normally intelligent child with normal senses and educational opportunity. There is presently ample evidence for the strongly biological etiology for DD, and a dozen susceptibility genes have been suggested. Many of these genes point to common but previously unsuspected biological mechanisms, such as neuronal migration and cilia functions. I discuss here the state-of-the-art in genomic and neurobiological aspects of DD research, starting with short general background to its history.     

A causal link between visual spatial attention and reading acquisition

Reading is a unique, cognitive human skill crucial to life in modern societies, but, for about 10% of the children, learning to read is extremely difficult. They are affected by a neurodevelopmental disorder called dyslexia. Although impaired auditory and speech sound processing is widely assumed to characterize dyslexic individuals, emerging evidence suggests that dyslexia could arise from a more basic cross-modal letter-to-speech sound integration deficit. Letters have to be precisely selected from irrelevant and cluttering letters by rapid orienting of visual attention before the correct letter-to-speech sound integration applies. Here we ask whether prereading visual parietal-attention functioning may explain future reading emergence and development. The present 3 year longitudinal study shows that prereading attentional orienting--assessed by serial search performance and spatial cueing facilitation--captures future reading acquisition skills in grades 1 and 2 after controlling for age, nonverbal IQ, speech-sound processing, and nonalphabetic cross-modal mapping. Our findings provide the first evidence that visual spatial attention in preschoolers specifically predicts future reading acquisition, suggesting new approaches for early identification and efficient prevention of dyslexia.     

A problem with auditory processing?

Recent studies have found associations between auditory processing deficits and language disorders such as dyslexia; but whether the former cause the latter, or simply co-occur with them, is still an open question.