The Angular Gyrus as a Hub for Modulation of Language-related Cortex by Distinct Prefrontal Executive Control Regions.

It has become clear in recent years that reading, while relying on domain-specific language processing regions, also involves regions that implement executive processes more broadly. Such executive control is generally considered to be implemented by prefrontal regions, which exert control via connectivity that allows them to modulate processing in target brain regions. The present study examined whether three previously identified and distinct executive control regions in the pFC [Wang, K., Banich, M. T., Reineberg, A. E., Leopold, D. R., Willcutt, E. G., Cutting, L. E., et al. Left posterior prefrontal regions support domain-general executive processes needed for both reading and math. Journal of Neuropsychology, 14, 467-495, 2020] show similar patterns of functional connectivity (FC) during a reading comprehension task as compared with a symbol identification condition. Our FC results in a sample of adolescents (n = 120) suggest all three regions commonly show associations with activity in "classic" left hemisphere reading areas, including the angular and supramarginal gyri, yet each exhibits differential connectivity as well. In particular, precentral regions show differential FC to parietal portions of the dorsal language stream, the inferior frontal junction shows differential FC to middle temporal regions of the right hemisphere and other regions involved in semantic processing, and portions of the inferior frontal gyrus show differential FC to an extensive set of right hemisphere prefrontal regions. These results suggest that prefrontal control over language-related regions occurs in a coordinated yet discrete manner.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

The Differential Relations Between ADHD and Reading Comprehension: A Quantile Regression and Quantile Genetic Approach.

This paper extends the understanding of the relation between ADHD and reading comprehension, through examining how this relation differs depending on the quantile an individual falls in for each. Samples from three twin projects around the United States were used (Florida Twin Project, Colorado component of International Longitudinal Twin Study of Early Reading Development, & Western Reserve Reading and Math Projects). Phenotypic analysis using quantile regression showed relations between ADHD related behaviors and reading comprehension to be stronger in the lower quantiles of reading comprehension in two of three samples. A new method was developed extending this analysis into the bivariate genetic space. Results of this quantile genetic analysis revealed that overlapping common environmental influences accounted for a larger proportion of variance in the lower quantiles of these variables in two of three samples. Finally, in all three samples the phenotypic relation was strongest when shared environmental influences accounted for a larger proportion of the overall variance.

In Search of Cognitive Promotive and Protective Factors for Word Reading.

This study examined whether strong cognitive skills (i.e. vocabulary, rapid naming, verbal working memory [VWM], and processing speed [PS]) contributed to resilience in single-word reading skills in children at risk for reading difficulties because of low phonological awareness scores (PA). Promotive factors were identified by main effects and protective factors through PA x cognition interactions. This study included 1,807 children ages 8-16. As predicted, all cognitive skills were significantly related to reading, consistent with promotive effects. A significant, but small effect PA x vocabulary interaction (R2 change=.002, p=.00038) was detected but its form was not consistent with a classic protective effect. Rather, the PA x vocabulary interaction was consistent with a "skill-enhancement" pattern, such that children with strong PA and vocabulary skills had better than expected reading. This study provides a framework for reading resilience research and directs attention to promotive mechanisms underlying reading success.

Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African-American youth.

BACKGROUND: Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. OBJECTIVE: To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach. METHODS: We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African-American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted. RESULTS: Genome-wide significant effects were observed at rs1555839 (p=4.03×10-8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer-promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule. CONCLUSION: This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene-brain-behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

Are Sluggish Cognitive Tempo, ADHD, and Oppositional Defiant Disorder Trait- or State-Like Constructs from Prekindergarten to Fourth Grade?

The objective was to determine the proportion of trait (consistency across occasions) and occasion-specific variance in sluggish cognitive tempo (SCT), attention deficit/hyperactivity disorder (ADHD)-inattention (IN), ADHD-hyperactivity/impulsivity (HI), and oppositional defiant disorder (ODD) symptom ratings. A single trait factor-multiple state factors model was applied to parent ratings of SCT, ADHD-IN, ADHD-HI, and ODD symptoms for 978 children (50% female) across prekindergarten (M = 4.90 years), kindergarten (M = 6.27 years), 1st-grade (M = 7.42 years), 2nd-grade (M = 8.45 years), and 4th-grade (M = 10.45 years) assessments. For the prekindergarten assessment, SCT, ADHD-IN, ADHD-HI, and ODD contained more occasion-specific than trait variance (54%, 64%, 56%, and 55% occasion-specific variance, respectively). In contrast, SCT, ADHD-IN, ADHD-HI, and ODD contained more trait than occasion-specific variance for the kindergarten through 4th-grade assessments (62%-72%, 65%-68%, 71%-75%, and 60%-69% trait variance, respectively). SCT, ADHD-IN, ADHD-HI, and ODD are slightly to moderately more state-like than trait-like during the prekindergarten developmental period but are more stable traits than fluctuating states from kindergarten to 4th grade. Findings indicate that, particularly after children start formal schooling, these psychopathology dimensions are primarily stable traits; implications for assessment are discussed.

Advancing the study of sluggish cognitive tempo via DSM, RDoC, and hierarchical models of psychopathology.

Sluggish cognitive tempo (SCT) is separable from attention-deficit/hyperactivity disorder (ADHD) and other psychopathologies, and growing evidence demonstrates SCT to be associated with impairment in both children and adults. However, it remains unclear how SCT should optimally be conceptualized. In this article, we argue that multiple models of psychopathology should be leveraged to make substantive advances to our understanding of SCT. Both categorical and dimensional approaches should be used, including the Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology, the Research Domain Criteria (RDoC) initiative, and hierarchical models of psychopathology. Studies are needed to determine whether individuals categorized with SCT can be reliably identified and differentiated from individuals without SCT in pathophysiological, neuropsychological, behavioral, and daily life functioning. Studies are also needed to evaluate the validity and utility of SCT as a transdiagnostic and dimensional construct. In considering SCT as a dimensional and potentially transdiagnostic construct, we describe ways in which SCT might be examined within the RDoC framework, including negative valence systems, cognitive systems, and arousal/regulatory systems, as well as within hierarchical models of psychopathology. Conceptualizing SCT within both categorical and dimensional models of psychopathology will help to better understand the causes, developmental pathways, and clinical implications of SCT, both as a construct in its own right and also in relation to other psychopathologies.

Causal Attribution Profiles as a Function of Reading Skills, Hyperactivity, and Inattention.

The causes that individuals attribute to reading outcomes shape future behaviors, including engagement or persistence with learning tasks. Although previous reading motivation research has examined differences between typical and struggling readers, there may be unique dynamics related to varying levels of reading and attention skills. Using latent profile analysis, we found 4 groups informed by internal attributions to ability and effort. Reading skills, inattention, and hyperactivity/impulsivity were investigated as functional correlates of attribution profiles. Participants were 1,312 youth (8-15 years of age) of predominantly African American and Hispanic racial/ethnic heritage. More adaptive attribution profiles had greater reading performance and lower inattention. The reverse was found for the least adaptive profile with associations to greater reading and attention difficulties. Distinct attribution profiles also existed across similar-achieving groups. Understanding reading-related attributions may inform instructional efforts in reading. Promoting adaptive attributions may foster engagement with texts despite learning difficulties and, in turn, support reading achievement.

Cross-Country Differences in Parental Reporting of Symptoms of ADHD.

Previous studies within the United States suggest there are cultural and contextual influences on how Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms are perceived. If such influences operate within a single country, they are likely to also occur between countries. In the current study, we tested whether country differences in mean ADHD scores also reflect cultural and contextual differences, as opposed to actual etiological differences. The sample for the present study included 974 participants from four countries tested at two-time points, the end of preschool and the end of 2nd grade. Consistent with previous research, we found lower mean ADHD scores in Norway and Sweden in comparison to Australia and the United States, and we tested four explanations for these country differences: 1) Genuine etiological differences, 2) Slower introduction to formal academic skills in Norway and Sweden than in the United States and Australia that indicated a context difference, 3) Under-reporting tendency in Norway and Sweden, or 4) Over-reporting tendency in the United States and Australia. Either under-or over-reporting would be examples of cultural differences in the perception of ADHD symptoms. Of these explanations, results of ADHD measurement equivalence tests across countries rejected the first three explanations and supported the fourth explanation: an over-reporting tendency in the United States and Australia. These findings indicate that parental reporting of ADHD symptoms is more accurate in Norway and Sweden than in Australia and the United States, and thus have important clinical and educational implications for how parental reporting informs an ADHD diagnosis in these countries.

Multidimensionality in the Measurement of Math-Specific Anxiety and its Relationship with Mathematical Performance.

Traditionally, mathematical anxiety has been utilized as a unidimensional construct. However, math-specific anxiety may have distinguishable factors, and taking these factors into account may better illuminate the relationship between anxiety and mathematics performance. Drawing from the Western Reserve Reading and Math Project (N = 244 children, mean age = 12.28 years), the present study examined math-specific anxiety and mathematics problem evaluation, utilizing a structural equation modeling approach with an item-level measurement model structure. Results suggested math-specific anxiety tapped into three factors: anxiety about performing mathematical calculations, anxiety about math in classroom situations, and anxiety about math tests. Among the three math anxiety factors, only calculation anxiety was significantly and negatively related to math performance while holding other anxiety factors constant. Implications for the measurement of math-specific anxiety are discussed.

Understanding Comorbidity Between Specific Learning Disabilities.

Current definitions of specific learning disability (SLD) identify a heterogeneous population that includes individuals with weaknesses in reading, math, or writing, and these academic difficulties often co-occur in many of the same individuals. The Colorado Learning Disabilities Research Center (CLDRC) is an interdisciplinary, multisite research program that uses converging levels of analysis to understand the genetic and environmental etiology, neuropsychology, and developmental outcomes of SLDs in reading (RD), math (MD), and writing (WD), along with the comorbidity between these SLDs and other developmental disorders. The latest results from the CLDRC twin study suggest that shared genetic influences contribute to the significant covariance between all aspects of reading (word reading, reading fluency, and reading comprehension) and math (calculations, math fluency, and word problems), and distinct genetic or environmental influences also contribute to weaknesses in each specific academic domain. RD and MD are associated with a range of negative outcomes on both concurrent measures and measures of functional outcomes completed 5 years after the twins were first assessed. Over the next several years the CLDRC will continue to expand on this work by administering a comprehensive test battery that includes measures of all dimensions of academic achievement that are described in current definitions of SLD and incorporating these measures in new neuroimaging and molecular genetic studies.

Differential impact of trait sluggish cognitive tempo and ADHD inattention in early childhood on adolescent functioning.

BACKGROUND: Sluggish cognitive tempo (SCT) is distinct from attention-deficit/hyperactivity disorder inattention (ADHD-IN) and concurrently associated with a range of impairment domains. However, few longitudinal studies have examined SCT as a longitudinal predictor of adjustment. Studies to date have all used a relatively short longitudinal time span (6 months to 2 years) and only rating scale measures of adjustment. Using a prospective, multi-method design, this study examined whether SCT and ADHD-IN were differentially associated with functioning over a 10-year period between preschool and the end of ninth grade. METHODS: Latent state-trait modeling determined the trait variance (i.e. consistency across occasions) of SCT and ADHD-IN across four measurement points (preschool and the end of kindergarten, first grade, and second grade) in a large population-based longitudinal sample (N = 976). Regression analyses were used to examine trait SCT and ADHD-IN factors in early childhood as predictors of functioning at the end of ninth grade (i.e. parent ratings of psychopathology and social/academic functioning, reading and mathematics academic achievement scores, processing speed and working memory). RESULTS: Both SCT and ADHD-IN contained more trait variance (Ms = 65% and 61%, respectively) than occasion-specific variance (Ms = 35% and 39%) in early childhood, with trait variance increasing as children progressed from preschool through early elementary school. In regression analyses: (a) SCT significantly predicted greater withdrawal and anxiety/depression whereas ADHD-IN did not uniquely predict these internalizing domains; (b) ADHD-IN uniquely predicted more externalizing behaviors whereas SCT uniquely predicted fewer externalizing behaviors; (c) SCT uniquely predicted shyness whereas both SCT and ADHD-IN uniquely predicted global social difficulties; and (d) ADHD-IN uniquely predicted poorer math achievement and slower processing speed whereas SCT more consistently predicted poorer reading achievement. CONCLUSIONS: Findings of this study - from the longest prospective sample to date - provide the clearest evidence yet that SCT and ADHD-IN often differ when it comes to the functional outcomes they predict.

Reading-Related Causal Attributions for Success and Failure: Dynamic Links With Reading Skill.

The present study investigated the relation among reading skills and attributions, naming speed, and phonological awareness across a wide range of reading skill. Participants were 1,105 school-age children and youths from two understudied populations: African Americans and Hispanic Americans. Individual assessments of children ranging in age from 8 to 15 years were conducted for reading outcomes, cognitive and linguistic predictors of reading, and attributions for success and failure in reading situations. Quantile regressions were formulated to estimate these relations across the full skill span of each outcome. Reading-related attributions predicted contextual word recognition, sight word and decoding fluency, and comprehension skills. Attributions to ability in success situations were positively related to each outcome across the full span. On three reading outcomes, this relation strengthened at higher skill levels. Attributions to effort in success situations were consistently and negatively related to all reading outcomes. The results provide evidence that the strength of the relation between reading and attributions varies according to reading skill levels, with the strongest evidence for ability-based attributions in situations of reading success.

Achievement attributions are associated with specific rather than general learning delays.

The causal attributions that children make for success and failure have been associated with later reading motivation and ability perceptions, which have the potential to impact future task engagement. Few studies have investigated whether such attributions are domain specific, that is linked with the specific skill in question, or a general motivational set. Even fewer studies have examined these relationships among diverse racial and ethnic subgroups. The present study examined differences in success and failure attributions among children with and without reading delay (RD) and general language impairments (LI), in a predominately Hispanic and African American sample. Participants were 1311 children, 8 to 15 years old. Significant differences in ability attributions were observed between participants with and without RD and LI, with no additive effect for cases with co-occurring reading and language impairments. When reading and vocabulary were evaluated continuously, significant and substantial positive relationships were observed between skill and ability attributions in situations of success, and negative associations observed in situations of failure. Weaker relationships were observed for vocabulary, though vocabulary did function as a moderator in the relationship between reading skill and ability attributions, with stronger associations at higher vocabulary levels. Overall, the findings suggest that ability attributions for reading success and failure are linked with reading skill and/or deficits, and not with general language impairments.

Enrichment of putatively damaging rare variants in the DYX2 locus and the reading-related genes CCDC136 and FLNC.

Eleven loci with prior evidence for association with reading and language phenotypes were sequenced in 96 unrelated subjects with significant impairment in reading performance drawn from the Colorado Learning Disability Research Center collection. Out of 148 total individual missense variants identified, the chromosome 7 genes CCDC136 and FLNC contained 19. In addition, a region corresponding to the well-known DYX2 locus for RD contained 74 missense variants. Both allele sets were filtered for a minor allele frequency ≤0.01 and high Polyphen-2 scores. To determine if observations of these alleles are occurring more frequently in our cases than expected by chance in aggregate, counts from our sample were compared to the number of observations in the European subset of the 1000 Genomes Project using Fisher's exact test. Significant P values were achieved for both CCDC136/FLNC (P = 0.0098) and the DYX2 locus (P = 0.012). Taken together, this evidence further supports the influence of these regions on reading performance. These results also support the influence of rare variants in reading disability.

Explaining the sex difference in dyslexia.

BACKGROUND: Males are diagnosed with dyslexia more frequently than females, even in epidemiological samples. This may be explained by greater variance in males' reading performance. METHODS: We expand on previous research by rigorously testing the variance difference theory, and testing for mediation of the sex difference by cognitive correlates. We developed an analytic framework that can be applied to group differences in any psychiatric disorder. RESULTS: Males' overrepresentation in the low performance tail of the reading distribution was accounted for by mean and variance differences across sex. There was no sex difference at the high performance tail. Processing speed (PS) and inhibitory control partially mediated the sex difference. Verbal reasoning emerged as a strength in males. CONCLUSIONS: Our results complement a previous finding that PS partially mediates the sex difference in symptoms of attention deficit/hyperactivity disorder (ADHD), and helps explain the sex difference in both dyslexia and ADHD and their comorbidity.

Development in reading and math in children from different SES backgrounds: the moderating role of child temperament.

Socioeconomic risks (SES risks) are robust risk factors influencing children's academic development. However, it is unclear whether the effects of SES on academic development operate universally in all children equally or whether they vary differentially in children with particular characteristics. The current study aimed to explore children's temperament as protective or risk factors that potentially moderate the associations between SES risks and academic development. Specifically, latent growth modeling (LGM) was used in two longitudinal datasets with a total of 2236 children to examine how family SES risks and children's temperament interactively predicted the development of reading and math from middle childhood to early adolescence. Results showed that low negative affect, high effortful control, and low surgency mitigated the negative associations between SES risks and both reading and math development in this developmental period. These findings underline the heterogeneous nature of the negative associations between SES risks and academic development and highlight the importance of the interplay between biological and social factors on individual differences in development.

The regulatory element READ1 epistatically influences reading and language, with both deleterious and protective alleles.

BACKGROUND: Reading disability (RD) and language impairment (LI) are heritable learning disabilities that obstruct acquisition and use of written and spoken language, respectively. We previously reported that two risk haplotypes, each in strong linkage disequilibrium (LD) with an allele of READ1, a polymorphic compound short tandem repeat within intron 2 of risk gene DCDC2, are associated with RD and LI. Additionally, we showed a non-additive genetic interaction between READ1 and KIAHap, a previously reported risk haplotype in risk gene KIAA0319, and that READ1 binds the transcriptional regulator ETV6. OBJECTIVE: To examine the hypothesis that READ1 is a transcriptional regulator of KIAA0319. METHODS: We characterised associations between READ1 alleles and RD and LI in a large European cohort, and also assessed interactions between READ1 and KIAHap and their effect on performance on measures of reading, language and IQ. We also used family-based data to characterise the genetic interaction, and chromatin conformation capture (3C) to investigate the possibility of a physical interaction between READ1 and KIAHap. RESULTS AND CONCLUSIONS: READ1 and KIAHap show interdependence--READ1 risk alleles synergise with KIAHap, whereas READ1 protective alleles act epistatically to negate the effects of KIAHap. The family data suggest that these variants interact in trans genetically, while the 3C results show that a region of DCDC2 containing READ1 interacts physically with the region upstream of KIAA0319. These data support a model in which READ1 regulates KIAA0319 expression through KIAHap and in which the additive effects of READ1 and KIAHap alleles are responsible for the trans genetic interaction.

Approximate Number Sense Shares Etiological Overlap with Mathematics and General Cognitive Ability.

Approximate number sense (ANS), the ability to rapidly and accurately compare quantities presented non-symbolically, has been proposed as a precursor to mathematics skills. Earlier work reported low heritability of approximate number sense, which was interpreted as evidence that approximate number sense acts as a fitness trait. However, viewing ANS as a fitness trait is discordant with findings suggesting that individual differences in approximate number sense acuity correlate with mathematical performance, a trait with moderate genetic effects. Importantly, the shared etiology of approximate number sense, mathematics, and general cognitive ability has remained unexamined. Thus, the etiology of approximate number sense and its overlap with math and general cognitive ability was assessed in the current study with two independent twin samples (N = 451 pairs). Results suggested that ANS acuity had moderate but significant additive genetic influences. ANS also had overlap with generalist genetic mechanisms accounting for variance and covariance in mathematics and general cognitive ability. Furthermore, ANS may have genetic factors unique to covariance with mathematics beyond overlap with general cognitive ability. Evidence across both samples was consistent with the proposal that the etiology of approximate number sense functions similar to that of mathematics and general cognitive skills.

Attention-deficit/hyperactivity disorder and sluggish cognitive tempo throughout childhood: temporal invariance and stability from preschool through ninth grade.

BACKGROUND: Although multiple cross-sectional studies have shown symptoms of sluggish cognitive tempo (SCT) and attention-deficit/hyperactivity disorder (ADHD) to be statistically distinct, studies have yet to examine the temporal stability and measurement invariance of SCT in a longitudinal sample. To date, only six studies have assessed SCT longitudinally, with the longest study examining SCT over a 2-year period. The overall goals of this study were to assess the 10-year longitudinal stability and interfactor relationships of ADHD and SCT symptoms among a community sample of children. METHODS: Confirmatory factor analysis was used to assess the temporal invariance of ADHD and SCT symptoms in a large population-based longitudinal sample (International Longitudinal Twin Study of Early Reading Development) that included children assessed at preschool and after kindergarten, first, second, fourth, and ninth grades (n = 489). Latent autoregressive models were then estimated to assess the stability of these constructs. RESULTS: Results demonstrated invariance of item loadings and intercepts from preschool through ninth grades, as well as invariance of interfactor correlations. Results further indicated that both ADHD and SCT are highly stable across these years of development, that these symptom dimensions are related but also separable, and that hyperactivity/impulsivity and SCT are both more strongly correlated with inattention than with each other and show differential developmental trajectories. Specifically, even in the presence of latent simplex analyses providing support for the developmental stability of these dimensions, linear comparisons indicated that that mean levels of hyperactivity/impulsivity decreased with time, inattentive ratings were generally stable, and SCT tended to increase slightly across development. CONCLUSIONS: This study adds to the current literature by being the first to systematically assess and demonstrate the temporal invariance and stability of ADHD and SCT across a span of 10 years.