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Developmental dyslexia is a specific learning disorder with impairments in reading and spelling acquisition. Apart from literacy problems, dyslexics show inefficient speech encoding and deficient novel word learning, with underlying problems in phonological processing and learning. These problems have been suggested to be related to deficient specialization of the left hemisphere for language processing. To examine this possibility, we tracked with magnetoencephalography (MEG) the activation of the bilateral temporal cortices during formation of neural memory traces for new spoken word forms in 7-8-year-old children with high familial dyslexia risk and in controls. The at-risk children improved equally to their peers in overt repetition of recurring new word forms, but were poorer in explicit recognition of the recurring word forms. Both groups showed reduced activation for the recurring word forms 400-1200 ms after word onset in the right auditory cortex, replicating the results of our previous study on typically developing children (Nora et al., 2017, Children show right-lateralized effects of spoken word-form learning. PLoS ONE 12(2): e0171034). However, only the control group consistently showed a similar reduction of activation for recurring word forms in the left temporal areas. The results highlight the importance of left-hemispheric phonological processing for efficient phonological representations and its disruption in dyslexia.

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OBJECTIVE: While previous data link the use of postmenopausal hormone therapy to an increased risk for ovarian cancer, little is known about the impact of various progestins, modes or routes of administration of hormone therapy for this risk. In this nationwide study, we compared relations between different estradiol-progestin (EPT) formulations and epithelial ovarian cancer risk. METHODS: All Finnish women over 50 years using EPT for at least 6 months (224 015 women with 602 ovarian cancers) during 1994-2006 were identified from the reimbursement register. The incidence of ovarian cancer in EPT users was compared to that in the age-matched background population by means of observed to expected ratio (standardized incidence ratio, SIR). RESULTS: Ovarian cancer risk was not elevated for EPT use of < 5 years but it was elevated for EPT use of ≥5 years (SIR 1.21, 95% confidence interval (CI) 1.06-1.37). Medroxyprogesterone acetate and norethisterone acetate as components of EPT were associated with similar risks for use for ≥ 5 years (SIR 1.26, 95% CI 0.94-1.64 and SIR 1.42, 95% CI 1.11-1.77, respectively). The risk did not differ between sequential or continuous EPT regimens or between oral or transdermal EPT formulations. The risk elevation for EPT use for ≥ 5 years was seen only for serous (SIR 1.56; 95% CI 1.33-1.80) and mixed cancers (SIR 1.54; 95% CI 1.22-1.91), whereas the risk for mucinous cancer was decreased (SIR 0.47; 95% CI 0.22-0.86). CONCLUSION: The elevated risk of non-mucinous ovarian cancer in users of EPT ≥ 5 years does not depend on progestin type, mode or route of administration of EPT.

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INTRODUCTION: In Jyväskylä Longitudinal Study of Dyslexia, we have investigated neurocognitive processes related to phonology and other risk factors of later reading problems. Here we review studies in which we have investigated whether dyslexic children with familial risk background would show atypical auditory/speech processing at birth, at six months and later before school and at school age as measured by brain event-related potentials (ERPs), and how infant ERPs are related to later pre-reading cognitive skills and literacy outcome. PATIENTS AND METHODS: One half of the children came from families with at least one dyslexic parent (the at-risk group), while the other half belonged to the control group without any familial background of dyslexia. RESULTS: Early ERPs were correlated to kindergarten age phonological processing and letter-naming skills as well as phoneme duration perception, reading and writing skills at school age. The correlations were, in general, more consistent among at-risk children. Those at-risk children who became poor readers also differed from typical readers in the infant ERP measures at the group level. ERPs measured before school and at the 3rd grade also differed between dyslexic and typical readers. Further, speech perception at behavioural level differed between dyslexic and typical readers, but not in all dyslexic readers. CONCLUSIONS: These findings suggest persisting developmental differences in the organization of the neural networks sub-serving auditory and speech perception, with cascading effects on later reading related skills, in children with familial background for dyslexia. However, atypical auditory/speech processing is not likely a sufficient reason by itself for dyslexia but rather one endophenotype or risk factor.

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OBJECTIVE: The purpose of the present study was to investigate whether children with reading disabilities (RD) process rise time and pitch changes differently to control children as a function of the interval between two tones. METHODS: Children participated in passive oddball event-related potential (ERP) measurements using paired stimuli. Mismatch negativity (MMN), P3a and late discriminative negativity (LDN) responses to rise time and pitch changes were examined. RESULTS: Control children produced larger responses than children with RD to pitch change in the P3a component but only when the sounds in the pair were close to each other. Compared to children with RD, MMN was smaller and LDN larger in control children in response to rise time change when the sounds in the pair were further apart. The non-overlap in ERP measures between the groups was 40-50%. CONCLUSIONS: Problems in rapid processing of pitch change were reflected in a component associated with attention switching while amplitude envelope processing problems were reflected in components associated with stimulus detection or discrimination. SIGNIFICANCE: Children with RD process both rise time and pitch changes differently from control children thus providing evidence for the nature of amplitude envelope processing and rapid auditory processing deficits in dyslexia.

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OBJECTIVE: The effects of within stimulus presentation rate and rise time on basic auditory processing were investigated in children with reading disabilities and typically reading children. METHODS: Children with reading disabilities (RD; N=19) and control children (N=20) were studied using event-related potentials (ERPs). Paired stimuli were used with two different within-pair-intervals (WPI; 10 and 255 ms) and two different rise times (10 and 130 ms). Each stimulus was presented with equal probability and long between-pair inter-stimulus intervals (1-5s). The study focused on N1 and P2 components. RESULTS: The P2 responses to the first tone in the pair showed differences between children with RD and control children. Also, children with RD had larger N1 response than control children to stimuli with short WPI and long rise time. CONCLUSIONS: These results provide evidence for basic auditory processing abnormalities in children with RD. This processing difference could be related to extraction of stimulus features from sounds or to attentional mechanisms. SIGNIFICANCE: Our results show support for behavioral findings that children with RD and control children process rise times differently. More than half of children with RD showed atypical auditory processing.

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Developmental dyslexia involves deficits in the visual and auditory domains, but is primarily characterized by an inability to translate the written linguistic code to the sound structure. Recent research has shown that auditory dysfunctions in dyslexia might originate from impairments in early pre-attentive processes, which affect behavioral discrimination. Previous studies have shown that whereas dyslexic individuals are deficient in discriminating sound distinctions involving consonants or simple pitch changes, discrimination of other sound aspects, such as tone duration, is intact. We hypothesized that such contrasts that can be discriminated by dyslexic individuals when heard in isolation are difficult to identify when occurring within words or structurally similar complex sound patterns. In the current study, we addressed how segments of pseudo-words and their non-speech counterparts are processed in dyslexia. We assessed the detection of long-duration differences in segments of these stimuli and identified the brain processes that could be associated with the behavioral results. Consistent with previous studies, we found no early cortical sound-duration discrimination deficit in dyslexia. However, differences between impaired and non-impaired readers were found in the brain processes associated with sound-change recognition as well as in the behavioral performance. This suggests that even when the early, automatic, sound discrimination processes are intact in dyslexic individuals, deficits in the later, attention-dependent processes may lead to impaired perception of speech and other complex sounds.

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Low sensitivity to amplitude modulated (AM) sounds is reported to be associated with dyslexia. An important aspect of amplitude modulation cycles are the rise and fall times within the sound. In this study, simplified stimuli equivalent to just one cycle were used and sensitivity to varying rise times was explored. Adult participants with dyslexia or compensated dyslexia and a control group performed a detection task with sound pairs of different rise times. Results showed that the participants with dyslexia differed from the control group in rise time detection and a correlation was found between rise time detection and reading and phonological skills. A subgroup of participants with lower sensitivity to rise time detection characterized by low accuracy in syllable-level phonological skills was found within the dyslexic group. Short stimuli containing only one rise time produced associations with phonological skills and reading, even in a language where the perception of rise time contrasts are not crucial for the signaling of phonemic contrast.

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We review the main findings of the Jyväskylä Longitudinal study of Dyslexia (JLD) which follows the development of children at familial risk for dyslexia (N = 107) and their controls (N = 93). We will illustrate the development of these two groups of children at ages from birth to school entry in the skill domains that have been connected to reading and reading disability in the prior literature. At school entry, the highest score on the decoding task among the poorer half (median) of the at risk children--i.e. of those presumably being most likely genetically affected--is 1 SD below the mean of the control group. Thus, the familial risk for dyslexia shows expected consequences. Among the earliest measures in which group differences as well as significant predictive associations with the first steps in reading have emerged, are indices of speech processing in infancy. Likewise, various measures of early language including pronunciation accuracy, phonological, and morphological skills (but not performance IQ) show both group differences and predictive correlations, the majority of which become stronger as the reliability of the measures increases by age. Predictive relationships tend to be strong in general but higher in the at risk group because of its larger variance in both the predictor variables and in the dependent measures, such as early acquisition of reading. The results are thus promising in increasing our understanding needed for early identification and prevention of dyslexia.

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Differences revealed by factor scores extracted by principal component analysis (PCA) from event-related potential (ERP) data of newborns with and without familial risk for dyslexia were examined and compared to results obtained by using original averaged ERPs. ERPs to consonant-vowel syllables (synthetic /ba/, /da/, /ga/; and natural /paa/, /taa/, /kaa/) were recorded from 26 at-risk and 23 control 1-7 day-old infants. The stimuli were presented equiprobably and with interstimulus intervals varying at random from 3,910 to 7,285 ms. Statistically significant between-group differences were found to be relatively similar irrespective of the methods of analysis (original ERPs vs. factor scores from PCA). Responses to /ga/ differed from those to /ba/ and /da/ between the groups in the right hemisphere at the latencies of 50-170 ms (Factor 4) and 540-630 ms (Factor 3). The groups differed also in their responses to /da/ in the posterior electrode sites at 740-940 ms (Factor 2). There were no group differences in the natural stimulus set. These results demonstrate that brain activation differences may be implicated in risk for dyslexia immediately after birth. The results also show that the PCA-ANOVA procedure is an effective way of identifying the group-related variance in the ERP-data when the component structure, such as those of infants, is not well-known in advance.

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Developmental dyslexia is a distinct learning disability with unexpected difficulty in learning to read despite adequate intelligence, education, and environment, and normal senses. The genetic aetiology of dyslexia is heterogeneous and loci on chromosomes 2, 3, 6, 15, and 18 have been repeatedly linked to it. We have conducted a genome scan with 376 markers in 11 families with 38 dyslexic subjects ascertained in Finland. Linkage of dyslexia to the vicinity of DYX3 on 2p was confirmed with a non-parametric linkage (NPL) score of 2.55 and a lod score of 3.01 for a dominant model, and a novel locus on 7q32 close to the SPCH1 locus was suggested with an NPL score of 2.77. The SPCH1 locus has previously been linked with a severe speech and language disorder and autism, and a mutation in exon 14 of the FOXP2 gene on 7q32 has been identified in one large pedigree. Because the language disorder associated with the SPCH1 locus has some overlap with the language deficits observed in dyslexia, we sequenced the coding region of FOXP2 as a candidate gene for our observed linkage in six dyslexic subjects. No mutations were identified. We conclude that DYX3 appears to be important for dyslexia susceptibility in many Finnish families, and a suggested linkage of dyslexia to chromosome 7q32 will need verification in other data sets.

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The purposes of this study were to investigate (a) whether children in families with a positive history of dyslexia were more likely to show delays in language development than children without family risk and (b) whether a delayed onset of expressive language (late talking) predicted later language development. We analyzed the language development of 200 children longitudinally at 14, 24, 30, and 42 months and assessed their symbolic play at 14 months. Half of the children (N = 106) were from families with a history of dyslexia (the Dyslexia Risk [DR] group), and other children served as age-matched controls. Parental reports and structured tests were used to assess children's receptive and expressive language and symbolic play. No differences emerged between the two groups in receptive language, symbolic play, or on the Bayley MDI. The groups, however, diverged in expressive language measures. The maximum sentence length at 2 years and object naming and inflectional morphology skills at 3.5 years were higher for the control group than for the DR group. Reynell receptive score at 2.5 years provided the greatest unique contribution to the prediction of the children's receptive and expressive language. Children's risk status did not contribute to receptive language, but provided a significant contribution to their expressive language at 3.5 years, even after the variance associated with parental education and children's previous language skills was controlled. Late talkers in the DR group differed from the other members of the DR group in both receptive and expressive language at 3.5 years, although in the control group children with a late-talking history performed at age-level expectations. The findings suggest that children with a familial risk for dyslexia and with a history of late talking are at higher risk for delays in language acquisition than children without the familial risk for dyslexia.

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Practice effects on a visuomotor test (the Developmental Test of Visuo-Motor Integration), a timed visual discrimination test (the Underlining Test), and two problem-solving tests (the Porteus Mazes Test and the Tower of Hanoi Test) were analyzed. Children of two age groups (Ms: 7.7 and 11.6 yr.) were chosen to study the effect of age on practice effects. The tests were repeated nine times with test-retest intervals of 2 mo. The Developmental Test of Visuo-Motor Integration showed no practice effects, while the Porteus Mazes Test, the Underlining Test, and the Tower of Hanoi Test showed significant practice effects. Practice effects were larger for the older age group on all the tests, except the Developmental Test of Visuo-Motor Integration. The Developmental Test of Visuo-Motor Integration and the Underlining Test showed good reliability, but those of the problem-solving tasks were less satisfactory. The stability of all the tests, except the Tower of Hanoi Test, was good.

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Comparisons of the developmental pathways of the first 5 years of life for children with (N = 107) and without (N = 93) familial risk for dyslexia observed in the Jyväskylä Longitudinal study of Dyslexia are reviewed. The earliest differences between groups were found at the ages of a few days and at 6 months in brain event-related potential responses to speech sounds and in head-turn responses (at 6 months), conditioned to reflect categorical perception of speech stimuli. The development of vocalization and motor behavior, based on parental report of the time of reaching significant milestones, or the growth of vocabulary (using the MacArthur Communicative Development Inventories) failed to reveal differences before age 2. Similarly, no group differences were found in cognitive and language development assessed by the Bayley Scales of Infant Development and the Reynell Developmental Language Scales before age 2.5. The earliest language measure that showed lower scores among the at-risk group was maximum sentence length at age 2. Early gross motor development had higher correlation to later language skills among the at-risk group rather than the control children. The most consistent predictor of differential development between groups was the onset of talking. Children who were identified as late talkers at age 2 were still delayed at the age 3.5 in most features of language-related skills-but only if they belonged to the group at familial risk for dyslexia. Several phonological and naming measures known to correlate with reading from preschool age differentiated the groups consistently from age 3.5. Our findings imply that a marked proportion of children at familial risk for dyslexia follow atypical neurodevelopmental paths. The signs listed previously comprise a pool of candidates for early predictors and precursors of dyslexia, which await validation.

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We measured event-related potentials (ERPs) to synthetic consonant-vowel syllables (/ba/, /da/, /ga/) from 26 newborns with familial risk for dyslexia and 23 control infants participating in the Jyväskylä Longitudinal Study of Dyslexia. The syllables were presented with equal probability and with interstimulus intervals ranging from 3,010 to 7,285 ms. Analyses of averaged ERPs from the latencies identified on the basis of principal component analysis (PCA) revealed significant group differences in stop-consonant processing in several latency ranges. At the latencies of 50-170 ms and 540-630 ms, the responses to /ga/ were larger and more positive than those to /ba/ and /da/ in the right hemisphere in the at-risk group. Between 740 and 940 ms, the responses to /ba/ and /da/ differed between anterior and posterior electrode sites in the control group. These results indicate that the cortical electric activation evoked by speech elements differs between children with and without risk for dyslexia even immediately after birth. Group-related effects at early and late latency ranges of ERPs suggest differences both in the early sound processing based on activation of afferent elements and in later phases of syllable encoding.

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A random sample of 91 preschool children was assessed prior to receiving formal reading instruction. Verbal and nonverbal measures were used as predictors for the time of instruction required to accurately decode pseudowords in the highly orthographically regular Finnish language. After 2 years, participants were divided into four groups depending on the duration of instruction they had required to reach 90 % accuracy in their reading of pseudowords. Participants were classified as precocious decoders (PD), who could read at school entry; early decoders (ED), who learned to read within the first 4 months of Grade 1; ordinary decoders (OD), who learned to read within 9 months; and late decoders (LD), who failed to reach the criterion after 18 months of reading instruction at Grade 2. Phonological awareness played a significant role only in differentiating PD from ED and OD. However, phonological awareness failed to predict the delayed learning process of LD. LD differed from all other groups in visual analogical reasoning in an analysis not containing phonological awareness measures. Letter knowledge and visual analogical reasoning explained above 90% of the PD-LD difference. Preschool composite (objects, colors, and digits) naming speed measures best predicted reading fluency at the end of Grade 2. The supportive role of orthographic knowledge in phonological awareness, the role of visual analogical reasoning, and the inability of phonological measures to discriminate late decoders are discussed.

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The purpose of this research was to analyze the effects of repeating an executive function test. Three versions of the Tower of Hanoi (TOH) test were repeated three times each, with test-retest intervals of 2 months. Two groups of children participated in the research (7.7 and 11.6 years, n = 22 and n = 28). Repeating the assessment improved the performance and decreased the total performance time in both of the groups. The older participants improved their performance faster than the younger ones. The reliability of all the scores, besides the error scores, seemed to be satisfactory after the first few assessments. The stability of the scores was maintained through all the assessments. The planning time did not explain the variations of the achieved score. The reasons for the initially low reliabilities are discussed, and modifications for the test administration and scoring are suggested.

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Detailed time and error analyses of the Tower of Hanoi (TOH) test was performed using four repeated assessments of eight children (ages 9-12 years), who had perceptual and problem solving deficits. The time before each move was measured. In addition to the traditionally counted time scores, new, relative time scores were computed in order to separate the planning time from the general reaction speed. New error scores were defined and sum scores of serious errors (perserative moves, illegal moves, and wrong results) and mild errors (self-corrected moves, almost performed moves, and interrupted trials) were computed. The relative planning time correlated positively with the achieved score, and negatively with the serious errors. The serious errors correlated negatively with the achieved score. The relative planning time seems to measure the quality of planning better than does the raw planning time, and it is a recommended score for TOH analysis. The value of new error scores requires additional research.

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Potential use of different auditory evoked brain responses for determining cerebral lateralization of speech function was evaluated. Cortical magnetic fields elicited by plosive syllables or complex non-speech sounds analogous to them were recorded with 122-channel magnetometer. We estimated parameters of magnetic P1, N1 and P2 responses to both stimuli in the two hemispheres and found no hemispheric asymmetry for any of the responses. No correlation between the right-ear advantage, determined with dichotic listening test, and any of asymmetry indexes, calculated for the speech-elicited responses, was observed. These results suggest that P1, N1 and P2 responses to speech signals do not indicate lateralization of speech function in the brain. The results are discussed in relation to previous studies suggesting that the mismatch negativity (MMN) seems to be the only early auditory cortex response sensitive to the lateralization of speech function.

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The goal of the present study was to evaluate the differences between dichotic listening and mismatch negativity as measures of speech lateralization in the human brain. For this purpose, we recorded the magnetic equivalent of the mismatch negativity, elicited by consonant-vowel syllable change, and tested the same subjects in the dichotic listening procedure. The results showed that both methods indicated left-hemisphere dominance in speech processing. However, the mismatch negativity, as compared to the right-ear advantage, suggested slightly stronger left-hemisphere dominance in speech processing. No clear correlation was found between the laterality indexes of mismatch negativity and right-ear advantage calculated from dichotic listening results. The possible explanation for this finding would be that these two measures reflect different stages of speech processing in the human brain.

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