The DCDC2 deletion is not a risk factor for dyslexia.

Dyslexia is a specific impairment in learning to read and has strong heritability. An intronic deletion within the DCDC2 gene, with ~8% frequency in European populations, is increasingly used as a marker for dyslexia in neuroimaging and behavioral studies. At a mechanistic level, this deletion has been proposed to influence sensory processing capacity, and in particular sensitivity to visual coherent motion. Our re-assessment of the literature, however, did not reveal strong support for a role of this specific deletion in dyslexia. We also analyzed data from five distinct cohorts, enriched for individuals with dyslexia, and did not identify any signal indicative of associations for the DCDC2 deletion with reading-related measures, including in a combined sample analysis (N=526). We believe we conducted the first replication analysis for a proposed deletion effect on visual motion perception and found no association (N=445 siblings). We also report that the DCDC2 deletion has a frequency of 37.6% in a cohort representative of the general population recruited in Hong Kong (N=220). This figure, together with a lack of association between the deletion and reading abilities in this cohort, indicates the low likelihood of a direct deletion effect on reading skills. Therefore, on the basis of multiple strands of evidence, we conclude that the DCDC2 deletion is not a strong risk factor for dyslexia. Our analyses and literature re-evaluation are important for interpreting current developments within multidisciplinary studies of dyslexia and, more generally, contribute to current discussions about the importance of reproducibility in science.

Genome-wide screening for DNA variants associated with reading and language traits.

Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome-wide association scan (GWAS) meta-analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading- and language-related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10(-7) for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on-going international efforts to identify genes contributing to reading and language skills.

Sensory thresholds obtained from MEG data: cortical psychometric functions.

Sensory sensitivity is typically measured using behavioural techniques (psychophysics), which rely on observers responding to very large numbers of stimulus presentations. Psychophysics can be problematic when working with special populations, such as children or clinical patients who may lack the compliance or cognitive skills to perform the behavioural tasks. We used an auditory gap-detection paradigm to develop an accurate measure of sensory threshold derived from passively-recorded magnetoencephalographic (MEG) data. Auditory evoked responses were elicited by silent gaps of varying durations in an on-going noise stimulus. Source modelling was used to spatially filter the MEG data and sigmoidal 'cortical psychometric functions' relating response amplitude to gap duration were obtained for each individual participant. Fitting the functions with a curve and estimating the gap duration at which the amplitude of the evoked response exceeded one standard deviation of the prestimulus brain activity provided an excellent prediction of psychophysical threshold. Accurate sensory thresholds can therefore be reliably extracted from MEG data recorded while participants listen passively to a stimulus. Because our paradigm required no behavioural task, the method is suitable for studies of populations where variations in cognitive skills or vigilance make traditional psychophysics unsuitable.

Timing continuous or discontinuous movements across effectors specified by different pacing modalities and intervals.

Sensorimotor synchronization is hypothesized to arise through two different processes, associated with continuous or discontinuous rhythmic movements. This study investigated synchronization of continuous and discontinuous movements to different pacing signals (auditory or visual), pacing interval (500, 650, 800, 950 ms) and across effectors (non-dominant vs. non-dominant hand). The results showed that mean and variability of asynchronization errors were consistently smaller for discontinuous movements compared to continuous movements. Furthermore, both movement types were timed more accurately with auditory pacing compared to visual pacing and were more accurate with the dominant hand. Shortening the pacing interval also improved sensorimotor synchronization accuracy in both continuous and discontinuous movements. These results show the dependency of temporal control of movements on the nature of the motor task, the type and rate of extrinsic sensory information as well as the efficiency of the motor actuators for sensory integration.

Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects.

Dyslexia (or reading disability) and specific language impairment (or SLI) are common childhood disorders that show considerable co-morbidity and diagnostic overlaps and have been suggested to share some genetic aetiology. Recently, genetic risk variants have been identified for SLI and dyslexia enabling the direct evaluation of possible shared genetic influences between these disorders. In this study we investigate the role of variants in these genes (namely MRPL19/C20RF3, ROBO1, DCDC2, KIAA0319, DYX1C1, CNTNAP2, ATP2C2 and CMIP) in the aetiology of SLI and dyslexia. We perform case-control and quantitative association analyses using measures of oral and written language skills in samples of SLI and dyslexic families and cases. We replicate association between KIAA0319 and DCDC2 and dyslexia and provide evidence to support a role for KIAA0319 in oral language ability. In addition, we find association between reading-related measures and variants in CNTNAP2 and CMIP in the SLI families.

Are poor mathematics skills associated with visual deficits in temporal processing?

Developmental learning disabilities such as dyslexia and dyscalculia have a high rate of co-occurrence in pediatric populations, suggesting that they share underlying cognitive and neurophysiological mechanisms. Dyslexia and other developmental disorders with a strong heritable component have been associated with reduced sensitivity to coherent motion stimuli, an index of visual temporal processing on a millisecond time-scale. Here we examined whether deficits in sensitivity to visual motion are evident in children who have poor mathematics skills relative to other children of the same age. We obtained psychophysical thresholds for visual coherent motion and a control task from two groups of children who differed in their performance on a test of mathematics achievement. Children with math skills in the lowest 10% in their cohort were less sensitive than age-matched controls to coherent motion, but they had statistically equivalent thresholds to controls on a coherent form control measure. Children with mathematics difficulties therefore tend to present a similar pattern of visual processing deficit to those that have been reported previously in other developmental disorders. We speculate that reduced sensitivity to temporally defined stimuli such as coherent motion represents a common processing deficit apparent across a range of commonly co-occurring developmental disorders.

Do 'clumsy' children have visual deficits.

Visual processing by 10-year-old children diagnosed on the basis of standardised tests as having developmental 'clumsiness' syndrome, and by a control group of children without motor difficulties, was tested using three different psychophysical tasks. The tasks comprised a measure of global motion processing using a dynamic random dot kinematogram, a measure of static global pattern processing where the position of the target was randomised, and a measure of static global pattern processing in which the target position was fixed. The most striking finding was that the group of clumsy children, who were diagnosed solely on the basis of their motor difficulties, were significantly less sensitive than the control group on all three tasks of visual sensitivity. Clumsy children may have impaired visual sensitivity in both the dorsal and ventral streams in addition to their obvious problems with motor control. These results support the existence of generalised visual anomalies associated with impairments of cerebellar function.

Auditory frequency discrimination in adult developmental dyslexics.

Developmental dyslexics reportedly discriminate auditory frequency poorly. A recent study found no such deficit. Unlike its predecessors, however, it employed multiple exposures per trial to the standard stimulus. To investigate whether this affects frequency discrimination in dyslexics, a traditional two-interval same-different paradigm (2I_1A_X) and a variant with six A-stimuli per trial (2I_6A_X) were used here. Frequency varied around 500 Hz; interstimulus interval (ISI) ranged between 0 and 1,000 msec. Under 2I_1A_X, dyslexics always had larger just noticeable differences (JNDs) than did controls. Dyslexic and control JNDs were equal at shorter ISIs under 2I_6A_X, but dyslexics became worse than controls at longer ISIs. Signal detection analysis suggests that both sensory variance and trace variance are larger in dyslexics than in controls.

Investigation of quantitative measures related to reading disability in a large sample of sib-pairs from the UK.

We describe a family-based sample of individuals with reading disability collected as part of a quantitative trait loci (QTL) mapping study. Eighty-nine nuclear families (135 independent sib-pairs) were identified through a single proband using a traditional discrepancy score of predicted/actual reading ability and a known family history. Eight correlated psychometric measures were administered to each sibling, including single word reading, spelling, similarities, matrices, spoonerisms, nonword and irregular word reading, and a pseudohomophone test. Summary statistics for each measure showed a reduced mean for the probands compared to the co-sibs, which in turn was lower than that of the population. This partial co-sib regression back to the mean indicates that the measures are influenced by familial factors and therefore, may be suitable for a mapping study. The variance of each of the measures remained largely unaffected, which is reassuring for the application of a QTL approach. Multivariate genetic analysis carried out to explore the relationship between the measures identified a common factor between the reading measures that accounted for 54% of the variance. Finally the familiality estimates (range 0.32-0.73) obtained for the reading measures including the common factor (0.68) supported their heritability. These findings demonstrate the viability of this sample for QTL mapping, and will assist in the interpretation of any subsequent linkage findings in an ongoing genome scan.

Are dyslexics' visual deficits limited to measures of dorsal stream function?

We tested the hypothesis that the differences in performance between developmental dyslexics and controls on visual tasks are specific for the detection of dynamic stimuli. We found that dyslexics were less sensitive than controls to coherent motion in dynamic random dot displays. However, their sensitivity to control measures of static visual form coherence was not significantly different from that of controls. This dissociation of dyslexics' performance on measures that are suggested to tap the sensitivity of different extrastriate visual areas provides evidence for an impairment specific to the detection of dynamic properties of global stimuli, perhaps resulting from selective deficits in dorsal stream functions.

Selective deficits of vibrotactile sensitivity in dyslexic readers.

Developmental dyslexia is a disability of literacy skill that has also been associated with sensory processing deficits, primarily for the detection of dynamic auditory and visual stimuli. Here we examined whether analogous deficits extend into the domain of somatosensory perception. Detection thresholds for each of three frequencies of vibration were obtained for 11 readers with a prior history of dyslexia and 14 similarly aged adult controls. The poor readers were significantly less sensitive to vibration at 3 Hz (P<0. 01) but not at either 30 or 100 Hz. Detection of each of these three vibration rates is mediated primarily by a separate somatosensory fiber tract; deficits selective to 3 Hz therefore suggest an impairment within the slow-adapting I (SAI) fiber system beginning with Merkel-cell mechanoreceptors in the glabrous skin. Such evidence is compatible with the hypothesis of a generalized, multisensory deficit of temporal processing functions in dyslexia.

Fatty acid deficiency signs predict the severity of reading and related difficulties in dyslexic children.

It has been proposed that developmental dyslexia may be associated with relative deficiencies in certain highly unsaturated fatty acids (HUFA). In children with attention-deficit/hyperactivity disorder, minor physical signs of fatty acid deficiency have been shown to correlate with blood biochemical measures of HUFA deficiency. These clinical signs of fatty acid deficiency were therefore examined in 97 dyslexic children in relation to reading and related skills, and possible sex differences were explored. Children with high fatty acid deficiency ratings showed poorer reading (P<0.02) and lower general ability (P<0.04) than children with few such clinical signs. Within males (n=72) these relationships were stronger, and fatty acid deficiency signs were also associated with poorer spelling and auditory working memory (P<0.05, P<0.005 respectively). Within females (n=25) no associations were significant. These results support the hypothesis that fatty acid deficiency may contribute to the severity of dyslexic problems, although sex differences merit further investigation.

Visual motion sensitivity in dyslexia: evidence for temporal and energy integration deficits.

In addition to poor literacy skills, developmental dyslexia has been associated with multisensory deficits for dynamic stimulus detection. In vision these deficits have been suggested to result from impaired sensitivity of cells within the retino-cortical magnocellular pathway and extrastriate areas in the dorsal stream to which they project. One consequence of such selectively reduced sensitivity is a difficulty in extracting motion coherence from dynamic noise, a deficit associated with both developmental dyslexia and persons with extrastriate, dorsal stream lesions. However the precise nature of the mechanism(s) underlying these perceptual deficits in dyslexia remain unknown. In this study, we obtained motion detection thresholds for 10 dyslexic and 10 control adults while varying the spatial and temporal parameters of the random dot kinematogram (RDK) stimuli. In Experiment 1 stimulus duration was manipulated to test whether dyslexics are specifically impaired for detecting short duration, rather than longer stimuli. Dot density was varied in Experiment 2 to examine whether dyslexics' reduced motion sensitivity was affected by the amount of motion energy present in the RDKs. Dyslexics were consistently less sensitive to coherent motion than controls in both experiments. Increasing stimulus duration did not improve dyslexics' performance, whereas increasing dot density did. Thus increasing motion energy assisted the dyslexics, suggesting that their motion detectors have a lower signal to noise ratio, perhaps due to spatial undersampling.

Dynamic sensory sensitivity and children's word decoding skills.

The relationship between sensory sensitivity and reading performance was examined to test the hypothesis that the orthographic and phonological skills engaged in visual word recognition are constrained by the ability to detect dynamic visual and auditory events. A test battery using sensory psychophysics, psychometric tests, and measures of component literacy skills was administered to 32 unselected 10-year-old primary school children. The results suggest that children's sensitivity to both dynamic auditory and visual stimuli are related to their literacy skills. Importantly, after controlling for intelligence and overall reading ability, visual motion sensitivity explained independent variance in orthographic skill but not phonological ability, and auditory FM sensitivity covaried with phonological skill but not orthographic skill. These results support the hypothesis that sensitivity at detecting dynamic stimuli influences normal children's reading skills. Vision and audition separately may affect the ability to extract orthographic and phonological information during reading.

Can sensitivity to auditory frequency modulation predict children's phonological and reading skills?

Understanding how letter units represent particular speech sounds is a crucial skill for developing competent reading skills. However it is not known whether such phonological ability is constrained by basic auditory capacities such as those necessary for detecting the frequency modulations characteristic of many phonemes. Here we show that nearly 40% of the variability in normal children's phonological and reading skills can be predicted from their sensitivity to 2 Hz frequency modulated (FM) tones. This relationship does not hold for sensitivity to 240 Hz FM. Because lower but not higher rates of FM provide information important for speech comprehension, dynamic auditory sensitivity is likely to play an important role in children's phonological and reading skill development.

Sensitivity to dynamic auditory and visual stimuli predicts nonword reading ability in both dyslexic and normal readers.

BACKGROUND: Developmental dyslexia is a specific disorder of reading and spelling that affects 3-9% of school-age children and adults. Contrary to the view that it results solely from deficits in processes specific to linguistic analysis, current research has shown that deficits in more basic auditory or visual skills may contribute to the reading difficulties of dyslexic individuals. These might also have a crucial role in the development of normal reading skills. Evidence for visual deficits in dyslexia is usually found only with dynamic and not static stimuli, implicating the magnocellular pathway or dorsal visual stream as the cellular locus responsible. Studies of such a dissociation between the processing of dynamic and static auditory stimuli have not been reported previously. RESULTS: We show that dyslexic individuals are less sensitive both to particular rates of auditory frequency modulation (2 Hz and 40 Hz but not 240 Hz) and to dynamic visual-motion stimuli. There were high correlations, for both dyslexic and normal readers, between their sensitivity to the dynamic auditory and visual stimuli. Nonword reading, a measure of phonological awareness believed crucial to reading development, was also found to be related to these sensory measures. CONCLUSIONS: These results further implicate neuronal mechanisms that are specialised for detecting stimulus timing and change as being dysfunctional in many dyslexic individuals. The dissociation observed in the performance of dyslexic individuals on different auditory tasks suggests a sub-modality division similar to that already described in the visual system. These dynamic tests may provide a non-linguistic means of identifying children at risk of reading failure.

Flicker sensitivity and fundus appearance in pre-exudative age-related maculopathy.

PURPOSE: To evaluate whether foveal flicker sensitivity and fundus appearance are good predictors of exudative age-related maculopathy (ARM) when the effects of aging, retinal illuminance, and criterion differences are controlled. METHODS: Fellow eyes of monocular exudative ARM patients were tested at baseline. Seven of these eyes have now developed exudative ARM. Therefore, at baseline they were in pre-exudative stages of ARM. The foveal flicker sensitivity and fundus appearance of the pre-exudative and nonconverted eyes were compared with healthy, age-matched eyes. The flicker stimulus was a uniform, 2.8 deg circular field at 660 nm, modulated sinusoidally at frequencies from 2.5 to 50 Hz. Fundus photographs were evaluated using the Wisconsin ARM grading system. RESULTS: Flicker modulation sensitivity at two frequencies discriminated pre-exudative from healthy older eyes with 100% accuracy. Using the same criterion, pre-exudative eyes also were discriminated from nonconverted eyes with 100% accuracy. Whereas an overall fundus ARM risk score discriminated pre-exudative from healthy older eyes with 100% accuracy, it did not discriminate pre-exudative from nonconverted eyes at better than chance levels. CONCLUSIONS: There were functional changes in the retina preceding development of exudative ARM. Foveal flicker sensitivity at low- to mid-temporal frequencies seemed highly sensitive to these pre-exudative changes in this relatively small group of subjects. The authors hypothesize that foveal flicker sensitivity is a good predictor of exudative ARM and a sensitive monitor of retinal function in pre-exudative ARM. These predictions are being tested on a larger, independent sample.