Testing Bidirectional, Longitudinal Associations Between Disturbed Sleep and Depressive Symptoms in Children and Adolescents Using Cross-Lagged Models.

Importance: Understanding the longitudinal, bidirectional associations between disturbed sleep and depression in childhood and adolescence is crucial for the development of prevention and intervention programs. Objective: To test for bidirectional associations and cascade processes between disturbed sleep and depressive symptoms covering both childhood and adolescence and to test for the moderating processes of sex and pubertal status in adolescence. Design, Setting, and Participants: A prospective cohort study using the Québec Longitudinal Study of Child Development (QLSCD; 1997-ongoing). QLSCD's objective is to identify early childhood factors associated with long-term psychosocial and academic adjustment. Data were collected across 8 waves between ages 5 years (2003) and 17 years (2015). Associations were tested through cross-lagged models in childhood (5, 7, and 8 years), and in adolescence (10, 12, 13, 15, and 17 years). Data were analyzed from February to October 2021. Main Outcomes and Measures: Primary outcomes were disturbed sleep and depressive symptoms. Disturbed sleep was parent-reported and included sleep duration, time awake in bed, daytime sleepiness, sleep talking, sleepwalking, night terrors, and nightmares. Depressive symptoms were parent-reported in childhood (Child Behavior Checklist and Revised Ontario Child Health Study Scales), and self-reported in adolescence (Mental Health and Social Inadaptation Assessment for Adolescents). Results: Data on 1689 children (852 female [50.4%]) and 1113 adolescents (595 female [53.5%]) were included in the analyses. In childhood, significant bidirectional associations between depressive symptoms and disturbed sleep at all time points were found, indicating cascade processes (range ß = 0.07; 95% CI, 0.02-012 to ß = 0.15; 95% CI, 0.10-0.19). In adolescence, significant bidirectional associations from depressive symptoms to disturbed sleep (ß = 0.09; 95% CI, 0.04-0.14) and vice versa (ß = 0.10; 95% CI, 0.04-0.16) between 10 and 12 years were found. Between 12 and 13 years, depressive symptoms were modestly associated with disturbed sleep (ß = 0.05; 95% CI, 0.001-0.10) but the reverse association was not significant. Cross-lagged estimates were nonsignificant after 13 years. The associations did not vary as a function of either sex or puberty-by-sex. Conclusions and Relevance: These findings suggest that disturbed sleep is associated with the consolidation of depressive symptoms starting in childhood, which, in turn, is associated with ongoing sleep problems. It is possible that timely and appropriate interventions for incipient disturbed sleep and depression prevent spiraling effects on both domains.

Altered Doppler Velocimetry of Fetal Middle Cerebral Artery in Singleton Pregnancies Complicated by Mild Well-Controlled Gestational Diabetes.

INTRODUCTION: The aim of the present study was to evaluate fetal umbilical artery (UA) and middle cerebral artery (MCA) blood flow in patients with gestational diabetes (GD), in order to determine whether minimal anomalies of glucose metabolism may influence fetal placental function. METHODS: UA and MCA flows were prospectively measured by transabdominal ultrasound in singleton pregnancies between 34 and 37 weeks of gestation. RESULTS: The study included 35 women with GD and 217 nondiabetic patients. Middle cerebral pulsatility index (PI) was significantly higher in the GD group (mean MCA-PI = 1.82 ± 0.27 vs. 1.71 ± 0.26; p < 0.02). Likewise, MCA peak systolic velocity (MCA-PSV) was higher in the GD group compared to the non-GD group, though the difference was not significant (mean of MCA-PSV = 47.14 ± 8.45 vs. 47.09 ± 11.21; p = 0.98). UA-PI resulted higher in the non-GD group without significant differences (mean of UA-PI = 0.88 ± 0.14 vs. 0.86 ± 0.15; p = 0.32). CONCLUSIONS: Our study shows that even in cases of minimal metabolic derangements, GD is characterized by a significant variation in fetal Doppler velocimetry, particularly in the brain.

Laparoscopic treatment for ventral hernia in obese patients.

AIM: Obese patients generally are not considered good candidates for wall defect repair, because of associated comorbidities, increased surgical risk, and high risk of surgical site infection and recurrence. The purpose of this retrospective study was to evaluate the results of laparoscopic incisional hernia repair in a group of patients with Body Mass Index (BMI)>35 kg/m2. MATERIAL AND METHOD: From January 2016 to October 2018, 15 obese patients, including 11 females (73.3%) with a BMI > 35 kg/m2 underwent laparoscopic repair of an incisional abdominal hernia. Median BMI was 40 (SD±5). No selection related to comorbidities was performed. As primary endpoints, main postoperative general complications and hernia recurrence were taken into account. Secondary endpoints were the incidence of seroma, hematoma, wound infection and length of hospitalization. In addition, a systematic review of the literature on open and laparoscopic repair techniques was carried out. RESULTS: All patients were treated by laparoscopy and no conversions were required. No intraoperative complications were observed, and no patients underwent early re-intervention. Mortality was zero. One patient (6.6%) presented a seroma, conservatively managed, and evaluated over time without the need of re-intervention. One patient (6.6%) suffered a recurrence a year later, also treated by laparoscopy. Average hospital stay was 2.79 days (DS±0.77). CONCLUSIONS: Despite positive data and good results, laparoscopic treatment of wall defects has yet to be standardized. The feasibility of the laparoscopy for ventral hernias in patients with BMI>35 kg/m2 should be considered. The proposed technique is standardizable and easily reproducible. In terms of complications in the short term (perforations, kidney and pulmonary failure, cardiovascular events) and in the long term (relapses, wound infections, seromas) our results justify recommendation of the minimally invasive approach for almost all patients with abdominal wall defects. KEY WORDS: Laparoscopy, Obese, Ventral hernia.

Animal models of developmental dyslexia: Where we are and what we are missing.

Developmental dyslexia (DD) is a complex neurodevelopmental disorder and the most common learning disability among both school-aged children and across languages. Recently, sensory and cognitive mechanisms have been reported to be potential endophenotypes (EPs) for DD, and nine DD-candidate genes have been identified. Animal models have been used to investigate the etiopathological pathways that underlie the development of complex traits, as they enable the effects of genetic and/or environmental manipulations to be evaluated. Animal research designs have also been linked to cutting-edge clinical research questions by capitalizing on the use of EPs. For the present scoping review, we reviewed previous studies of murine models investigating the effects of DD-candidate genes. Moreover, we highlighted the use of animal models as an innovative way to unravel new insights behind the pathophysiology of reading (dis)ability and to assess cutting-edge preclinical models.

White matter deficits correlate with visual motion perception impairments in dyslexic carriers of the DCDC2 genetic risk variant.

Motion perception deficits in dyslexia show a large intersubjective variability, partly reflecting genetic factors influencing brain architecture development. In previous work, we have demonstrated that dyslexic carriers of a mutation of the DCDC2 gene have a very strong impairment in motion perception. In the present study, we investigated structural white matter alterations associated with the poor motion perception in a cohort of twenty dyslexics with a subgroup carrying the DCDC2 gene deletion (DCDC2d+) and a subgroup without the risk variant (DCDC2d-). We observed significant deficits in motion contrast sensitivity and in motion direction discrimination accuracy at high contrast, stronger in the DCDC2d+ group. Both motion perception impairments correlated significantly with the fractional anisotropy in posterior ventral and dorsal tracts, including early visual pathways both along the optic radiation and in proximity of occipital cortex, MT and VWFA. However, the DCDC2d+ group showed stronger correlations between FA and motion perception impairments than the DCDC2d- group in early visual white matter bundles, including the optic radiations, and in ventral pathways located in the left inferior temporal cortex. Our results suggest that the DCDC2d+ group experiences higher vulnerability in visual motion processing even at early stages of visual analysis, which might represent a specific feature associated with the genotype and provide further neurobiological support to the visual-motion deficit account of dyslexia in a specific subpopulation.

Selecting the Most Relevant Brain Regions to Classify Children with Developmental Dyslexia and Typical Readers by Using Complex Magnocellular Stimuli and Multiple Kernel Learning.

Increasing evidence supports the presence of deficits in the visual magnocellular (M) system in developmental dyslexia (DD). The M system is related to the fronto-parietal attentional network. Previous neuroimaging studies have revealed reduced/absent activation within the visual M pathway in DD, but they have failed to characterize the extensive brain network activated by M stimuli. We performed a multivariate pattern analysis on a Region of Interest (ROI) level to differentiate between children with DD and age-matched typical readers (TRs) by combining full-field sinusoidal gratings, controlled for spatial and temporal frequencies and luminance contrast, and a coherent motion (CM) sensitivity task at 6%-CML6, 15%-CML15 and 40%-CML40. ROIs spanning the entire visual dorsal stream and ventral attention network (VAN) had higher discriminative weights and showed higher act1ivation in TRs than in children with DD. Of the two tasks, CM had the greatest weight when classifying TRs and children with DD in most of the ROIs spanning these streams. For the CML6, activation within the right superior parietal cortex positively correlated with reading skills. Our approach highlighted the dorsal stream and the VAN as highly discriminative areas between children with DD and TRs and allowed for a better characterization of the "dorsal stream vulnerability" underlying DD.

Association Between Disturbed Sleep and Depression in Children and Youths: A Systematic Review and Meta-analysis of Cohort Studies.

Importance: Disturbed sleep represents a potentially modifiable risk factor for depression in children and youths that can be targeted in prevention programs. Objective: To evaluate the association between disturbed sleep and depression in children and youths using meta-analytic methods. Data Sources: Embase, MEDLINE, PsycINFO, Scopus, Web of Science, and ProQuest Dissertations & Theses Global were searched for articles published from 1980 to August 2019. Study Selection: Prospective cohort studies reporting estimates, adjusted for baseline depression, of the association between disturbed sleep and depression in 5- to 24-year-old participants from community and clinical-based samples with any comorbid diagnosis. Case series and reports, systematic reviews, meta-analyses, and treatment, theoretical, and position studies were excluded. A total of 8700 studies met the selection criteria. This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews (PRISMA) and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology (MOOSE) statements. Data Extraction and Synthesis: Study screening and data extraction were conducted by 2 authors at all stages. To pool effect estimates, a fixed-effect model was used if I2 < 50%; otherwise, a random-effects model was used. The I2 statistic was used to assess heterogeneity. The risk of bias was assessed using the Research Triangle Institute Item Bank tool. Metaregression analyses were used to explore the heterogeneity associated with type of ascertainment, type of and assessment tool for disturbed sleep and depression, follow-up duration, disturbed sleep at follow-up, and age at baseline. Main Outcome and Measures: Disturbed sleep included sleep disturbances or insomnia. Depression included depressive disorders or dimensional constructs of depression. Covariates included age, sex, and sociodemographic variables. Results: A total of 22 studies (including 28 895 patients) were included in the study, of which 16 (including 27 073 patients) were included in the meta-analysis. The pooled ß coefficient of the association between disturbed sleep and depression was 0.11 (95% CI, 0.06-0.15; P < .001; n = 14 067; I2 = 50.8%), and the pooled odds ratio of depression in those with vs without disturbed sleep was 1.50 (95% CI, 1.13-2.00; P = .005; n = 13 006; I2 = 87.7%). Metaregression and sensitivity analyses showed no evidence that pooled estimates differed across any covariate. Substantial publication bias was found. Conclusions and Relevance: This meta-analysis found a small but statistically significant effect size indicating an association between sleep disruption and depressive symptoms in children and youths. The high prevalence of disturbed sleep implies a large cohort of vulnerable children and youths who could develop depression. Disrupted sleep should be included in multifaceted prevention programs starting in childhood.

The heritability of reading and reading-related neurocognitive components: A multi-level meta-analysis.

Reading ability is a complex task requiring the integration of multiple cognitive and perceptual systems supporting language, visual and orthographic processes, working memory, attention, motor movements, and higher-level comprehension and cognition. Estimates of genetic and environmental influences for some of these reading-related neurocognitive components vary across reports. By using a multi-level meta-analysis approach, we synthesized the results of behavioral genetic research on reading-related neurocognitive components (i.e. general reading, letter-word knowledge, phonological decoding, reading comprehension, spelling, phonological awareness, rapid automatized naming, and language) of 49 twin studies spanning 4.1-18.5 years of age, with a total sample size of more than 38,000 individuals. Except for language for which shared environment seems to play a more important role, the causal architecture across most of the reading-related neurocognitive components can be represented by the following equation a² > e² > c². Moderators analysis revealed that sex and spoken language did not affect the heritability of any reading-related skills; school grade levels moderated the heritability of general reading, reading comprehension and phonological awareness.

The Mediation Role of Dynamic Multisensory Processing Using Molecular Genetic Data in Dyslexia.

Although substantial heritability has been reported and candidate genes have been identified, we are far from understanding the etiopathogenetic pathways underlying developmental dyslexia (DD). Reading-related endophenotypes (EPs) have been established. Until now it was unknown whether they mediated the pathway from gene to reading (dis)ability. Thus, in a sample of 223 siblings from nuclear families with DD and 79 unrelated typical readers, we tested four EPs (i.e., rapid auditory processing, rapid automatized naming, multisensory nonspatial attention and visual motion processing) and 20 markers spanning five DD-candidate genes (i.e., DYX1C1, DCDC2, KIAA0319, ROBO1 and GRIN2B) using a multiple-predictor/multiple-mediator framework. Our results show that rapid auditory and visual motion processing are mediators in the pathway from ROBO1-rs9853895 to reading. Specifically, the T/T genotype group predicts impairments in rapid auditory and visual motion processing which, in turn, predict poorer reading skills. Our results suggest that ROBO1 is related to reading via multisensory temporal processing. These findings support the use of EPs as an effective approach to disentangling the complex pathways between candidate genes and behavior.

Do insomnia and/or sleep disturbances predict the onset, relapse or worsening of depression in community and clinical samples of children and youth? Protocol for a systematic review and meta-analysis.

INTRODUCTION: Disturbed sleep represents a potentially important modifiable risk factor for the development of depression in children and youth. This protocol for a systematic review proposes to investigate whether insomnia and/or sleep disturbances predict child and youth depression in community and clinical-based samples. METHODS AND ANALYSIS: The protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines. English-written, longitudinal studies that quantitatively estimated the prediction of depression by insomnia and/or sleep disturbances in individuals 5-24 years of age will be included. EMBASE, MEDLINE, PsychINFO, Scopus and Web of Science and grey literature will be searched from 1980 to the present. For the selection of studies, two reviewers will be involved. Data extraction will be conducted by one author and checked independently by a second author. Risk of bias will be appraised using the Research Triangle Institute Item Bank tool. Heterogeneity will be measured using the I2 statistics. Meta-analysis will be carried out if ≥3 results are available and if outcome measures can be pooled. The choice between a random-effect or fixed-effect model will be based both on the I2 statistics and the participant and study characteristics of the combined studies. Results of the meta-analyses will be summarised by a forest plot. Analyses will be performed in subgroups stratified by key variables defined depending on the amount and type of information retrieved.A narrative synthesis will be conducted in place of the meta-analysis should the pooling of data not be possible. Quality of evidence will be rated using the Grading of Recommendations Assessment, Development and Evaluation guidelines.As this is a protocol for systematic review and meta-analysis of published data, ethics review and approval are not required. The findings will be published in a peer-reviewed journal and disseminated at scientific conferences and in patient advocacy organisations. PROSPERO REGISTRATION NUMBER: CRD42019136729.

Is my patient ready for a safe transfer to a lower-intensity care setting? Nursing complexity as an independent predictor of adverse events risk after ICU discharge.

BACKGROUND: Patients discharged from intensive care units (ICUs) are at risk for adverse events (AEs). Establishing safe discharge criteria is challenging. No available criteria consider nursing complexity among risk factors. OBJECTIVES: To investigate whether nursing complexity upon ICU discharge is an independent predictor for AEs. METHODS: Prospective observational study. The Patient Acuity and Complexity Score (PACS) was developed to measure nursing complexity. Its predictive power for AEs was tested using multivariate regression analysis. RESULTS: The final regression model showed a very-good discrimination power (AUC 0.881; p<0.001) for identifying patients who experienced AEs. Age, ICU admission reason, PACS, cough strength, PaCO2, serum creatinine and sodium, and transfer to Internal Medicine showed to be predictive of AEs. Exceeding the identified PACS threshold increased by 3.3 times the AEs risk. CONCLUSIONS: The level of nursing complexity independently predicts AEs risk and should be considered in establishing patient's eligibility for a safe ICU discharge.

Paternal-but Not Maternal-Autistic Traits Predict Frontal EEG Alpha Asymmetry in Infants with Later Symptoms of Autism.

Previous research found that the parental autism phenotype is associated with child autism spectrum disorder (ASD), even if the pathway between autistic traits in parents and child ASD is still largely unknown. Several studies investigated frontal asymmetry in alpha oscillation (FAA) as an early marker for ASD. However, no study has examined the mediational effect of FAA between parental autistic traits and child ASD symptoms in the general population. We carried out a prospective study of 103 typically developing infants and measured FAA as a mediator between both maternal and paternal autistic traits and child ASD traits. We recorded infant baseline electroencephalogram (EEG) at 6 months of age. Child ASD symptoms were measured at age 24 months by the Child Behavior Checklist 1½-5 Pervasive Developmental Problems Scale, and parental autistic traits were scored by the Autism spectrum Quotient questionnaire. The mediation model showed that paternal vs. maternal autistic traits are associated with greater left FAA which, in turn, is associated with more child ASD traits with a significant indirect effect only in female infants vs. male infants. Our findings show a potential cascade of effects whereby paternal autistic traits drive EEG markers contributing to ASD risk.

Postnatal maternal symptoms of depression and child emotion dysregulation: The mediation role of infant EEG alpha asymmetry.

In a community-based sample of 104 infants and their mothers, we hypothesized a pathway from postnatal maternal symptoms of depression to child emotion dysregulation, and tested at 6 months of age the mediation role of alpha asymmetry at frontal and parietal sites. We recorded infant resting-state EEG at 6 months of age. Child emotion dysregulation was measured at 24 months by the Child Behavior Checklist Dysregulation Profile derived from the CBCL 1½-5. Maternal depression symptoms were scored 6 months after the delivery by the Anxious/Depressed scale of the Adult Self-Report. We used structural equation modeling to test the mediation model from maternal depression symptoms to child emotion dysregulation mediated by frontal and parietal alpha asymmetry. The mediation model provided an excellent fit to the data [χ2(3) = 3.088, p = .378; RMSEA = .017, CFI = .1.00; SRMR = 0.040] and explained 23.3% of the variance in child emotion dysregulation. The indirect path via parietal alpha asymmetry was significant (ß = .065; SE = .033; 95% CI = .001-.139; p = .048), i.e. greater levels of maternal depression symptoms predicted left parietal alpha asymmetry, which predicted higher levels of child emotion dysregulation. The direct effect, i.e. the pathway linking maternal depression symptoms and child emotion dysregulation above and beyond the indirect effects, was also significant. We found evidence for a partial mediation role of left parietal alpha asymmetry in a longitudinal pathway from postnatal maternal symptoms of depression to child emotion dysregulation, providing support for left parietal asymmetry as an index of biological vulnerability to emotion dysregulation in the first years of life.

Clinical utility of the CBCL Dysregulation Profile in children with disruptive behavior.

BACKGROUND: Children who are severely dysregulated experience a range of concurrent and long-term impairments and psychopathology and are particularly at-risk for mood and anxiety disorders. The Child Behavior Checklist Dysregulation Profile (CBCL-DP) may be useful in identifying children who are highly dysregulated, which could facilitate early intervention. METHODS: We examined the prevalence, gender differences, parent-teacher agreement, and concurrent validity of two categorical definitions of the CBCL-DP in 348 children ages 6-12 who were clinic-referred for assessment and treatment because of disruptive behavior. RESULTS: Rates of the CBCL-DP were 3 times higher when a less stringent versus a more stringent definition of the CBCL-DP was used (46.8% vs. 15.2%). Girls were more likely than boys to meet criteria for the CBCL-DP when the more stringent definition was used. Parent-teacher agreement was low, particularly when the more stringent definition of the CBCL-DP was used. Children with the CBCL-DP were rated by their parents, but not their teachers, as more impaired than other children, regardless of the definition of the CBCL-DP used, and even when compared to children with clinically elevated scores on other CBCL subscales. LIMITATIONS: Our cross-sectional data did not allow us to examine the predictive validity of the CBCL-DP, informant effects may have inflated associations between CBCL-DP and parent-rated impairment, and teacher ratings were missing for many children. CONCLUSIONS: Our findings support other reports that provide evidence that the CBCL-DP may identify a particularly symptomatic and impaired group of children with disruptive behavior, as rated by their parents.

Reduced left-lateralized pattern of event-related EEG oscillations in infants at familial risk for language and learning impairment.

The ability to rapidly discriminate successive auditory stimuli within tens-of-milliseconds is crucial for speech and language development, particularly in the first year of life. This skill, called Rapid Auditory Processing (RAP), is altered in infants at familial risk for language and learning impairment (LLI) and is a robust predictor of later language outcomes. In the present study, we investigate the neural substrates of RAP, i.e., the underlying neural oscillatory patterns, in a group of Italian 6-month-old infants at risk for LLI (FH+, n = 24), compared to control infants with no known family history of LLI (FH-, n = 32). Brain responses to rapid changes in fundamental frequency and duration were recorded via high-density electroencephalogram during a non-speech double oddball paradigm. Sources of event-related potential generators were localized to right and left auditory regions in both FH+ and FH- groups. Time-frequency analyses showed variations in both theta (Ɵ) and gamma (ɣ) ranges across groups. Our results showed that overall RAP stimuli elicited a more left-lateralized pattern of oscillations in FH- infants, whereas FH+ infants demonstrated a more right-lateralized pattern, in both the theta and gamma frequency bands. Interestingly, FH+ infants showed reduced early left gamma power (starting at 50 ms after stimulus onset) during deviant discrimination. Perturbed oscillatory dynamics may well constitute a candidate neural mechanism to explain group differences in RAP. Additional group differences in source location suggest that anatomical variations may underlie differences in oscillatory activity. Regarding the predictive value of early oscillatory measures, we found that the amplitude of the source response and the magnitude of oscillatory power and phase synchrony were predictive of expressive vocabulary at 20 months of age. These results further our understanding of the interplay among neural mechanisms that support typical and atypical rapid auditory processing in infancy.

Distinct ERP profiles for auditory processing in infants at-risk for autism and language impairment.

Early identification of autism spectrum disorder (ASD) is crucial for the formulation of effective intervention programs. Language deficits may be a hallmark feature of ASD and language delay observed in ASD shows striking similarities to that observed in children with language impairment (LI). Auditory processing deficits are seen in both LI and ASD, however, they have not previously been compared directly using Event-Related Potentials (ERPs) in the two at-risk populations. This study aims to characterize infants at-risk for ASD (HR-ASD) at the electrophysiological level and to compare them with infants at-risk for LI (HR-LI) and controls, to find specific markers with predictive value. At 12-month-old, auditory processing in HR-ASD, HR-LI and controls was characterized via ERP oddball paradigm. All infants were then evaluated at 20 months, to investigate the associations between auditory processing and language/ASD-related outcomes. In both HR-ASD and HR-LI, mismatch response latency was delayed compared to controls, whereas only HR-ASD showed overall larger P3 amplitude compared to controls. Interestingly, these ERP measures correlated with later expressive vocabulary and M-CHAT critical items in the whole sample. These results may support the use of objective measurement of auditory processing to delineate pathophysiological mechanisms in ASD, as compared to LI.

From CNTNAP2 to Early Expressive Language in Infancy: The Mediation Role of Rapid Auditory Processing.

Although it is clear that early language acquisition can be a target of CNTNAP2, the pathway between gene and language is still largely unknown. This research focused on the mediation role of rapid auditory processing (RAP). We tested RAP at 6 months of age by the use of event-related potentials, as a mediator between common variants of the CNTNAP2 gene (rs7794745 and rs2710102) and 20-month-old language outcome in a prospective longitudinal study of 96 Italian infants. The mediation model examines the hypothesis that language outcome is explained by a sequence of effects involving RAP and CNTNAP2. The ability to discriminate spectrotemporally complex auditory frequency changes at 6 months of age mediates the contribution of rs2710102 to expressive vocabulary at 20 months. The indirect effect revealed that rs2710102 C/C was associated with lower P3 amplitude in the right hemisphere, which, in turn, predicted poorer expressive vocabulary at 20 months of age. These findings add to a growing body of literature implicating RAP as a viable marker in genetic studies of language development. The results demonstrate a potential developmental cascade of effects, whereby CNTNAP2 drives RAP functioning that, in turn, contributes to early expressive outcome.

The role of READ1 and KIAA0319 genetic variations in developmental dyslexia: testing main and interactive effects.

Developmental dyslexia (DD) is a complex heritable condition characterized by impaired reading abilities. Two well-replicated candidate risk factors are as follows: (1) regulatory element associated with dyslexia 1 (READ1), which is located in intron 2 of DCDC2 and acts as a binding site for protein regulation of DCDC2 expression; and (2) a three-single-nucleotide polymorphism risk haplotype spanning KIAA0319. Phylogenetically similar READ1 variants showed synergistic effects with the KIAA0319 risk haplotype on reading-related phenotypes in a general population sample. Here we examine the association between different allele classes in READ1, the KIAA0319 risk haplotype and reading-related traits in a cohort of 368 Italian children with DD and their siblings (n=266) by testing both main and non-additive effects. We replicated the deleterious main effects upon both reading accuracy and speed exerted by the longer READ1 alleles. We further supported the interdependence through non-additive, possibly antagonistic, effects between READ1 and the KIAA0319 risk haplotype on reading accuracy. By suggesting the presence of common biological processes underlying reading (dis)ability, these findings represent initial support for a generalist effect of the non-additive interdependence between READ1 and the KIAA0319 risk haplotype. Moreover, our results confirm that using as much information as possible about genetic interdependence among dyslexia-candidate genes can help in clinically assessing the individual risk for DD.

ERP responses to lexical-semantic processing in typically developing toddlers, in adults, and in toddlers at risk for language and learning impairment.

Children begin to establish lexical-semantic representations during their first year of life, resulting in a rapid growth of vocabulary around 18-24 months of age. The neural mechanisms underlying this initial ability to map words onto conceptual representations remain relatively unknown. In the present study, the electrophysiological underpinnings of these mechanisms are explored during the critical phase of lexical acquisition using a picture-word matching paradigm. Event-Related Potentials (ERPs) elicited by words (either congruous or incongruous with the previous picture context) and pseudo-words are investigated in 20-month-old toddlers (N = 20) and compared to those elicited in a sample of adults (N = 20), reflecting the final and efficient system, and a sample of toddlers at familial risk for language and learning impairment (LLI, N = 15). The results suggest that the architecture underlying spoken word representation and processing is constant throughout development, even if some differences between children and adults emerged. Interestingly, children seem to be faster than adults in processing incongruent words, probably because relying on a different and more superficial strategy. This early strategy does not seem to be present in children at risk for LLI. In addition, both groups of children do not show different and specific electrophysiological underpinnings in response to real but incongruent words and unknown words, suggesting that during the critical phase of lexical acquisition any potential word is processed in a similar way. Overall, children at risk for LLI turned out to be sensitive to verbal incongruity of the lexical-semantic context, although some differences from typically developing children emerged, reflecting slower processing and less automatic responses. Taken together, the findings of this study pave the way to further research to investigate these effects in clinical and at-risk populations with the general purpose of disentangling the underlying mechanisms of lexical acquisition, and potentially predicting later language (dis)abilities.

A common genetic variant in FOXP2 is associated with language-based learning (dis)abilities: Evidence from two Italian independent samples.

Language-based Learning Disabilities (LLDs) encompass a group of complex, comorbid, and developmentally associated deficits in communication. Language impairment and developmental dyslexia (DD) represent the most recognized forms of LLDs. Substantial genetic correlations exist between language and reading (dis)abilities. Common variants in the FOXP2 gene were consistently associated with language- and reading-related neuropsychological and neuroanatomical phenotypes. We tested the effect of a FOXP2 common variant, that is, rs6980093 (A/G), on quantitative measures of language and reading in two independent Italian samples: a population-based cohort of 699 subjects (3-11 years old) and a sample of 572 children with DD (6-18 years old). rs6980093 modulates expressive language in the general population sample, with an effect on fluency scores. In the DD sample, the variant showed an association with the accuracy in the single word reading task. rs6980093 shows distinct genetic models of association in the two cohorts, with a dominant effect of the G allele in the general population sample and heterozygote advantage in the DD cohort. We provide preliminary evidence that rs6980093 associates with language and reading (dis)abilities in two independent Italian cohorts. rs6980093 is an intronic SNP, suggesting that it (or a linked variant) modulates phenotypic association via regulation of FOXP2 expression. Because FOXP2 brain expression is finely regulated, both temporally and spatially, it is possible that the two alleles at rs6980093 differentially modulate expression levels in a developmental stage- or brain area-specific manner. This might help explaining the heterozygote advantage effect and the different genetic models in the two cohorts.