Using Motor Tempi to Understand Rhythm and Grammatical Skills in Developmental Language Disorder and Typical Language Development.

Children with developmental language disorder (DLD) show relative weaknesses on rhythm tasks beyond their characteristic linguistic impairments. The current study compares preferred tempo and the width of an entrainment region for 5- to 7-year-old typically developing (TD) children and children with DLD and considers the associations with rhythm aptitude and expressive grammar skills in the two populations. Preferred tempo was measured with a spontaneous motor tempo task (tapping tempo at a comfortable speed), and the width (range) of an entrainment region was measured by the difference between the upper (slow) and lower (fast) limits of tapping a rhythm normalized by an individual's spontaneous motor tempo. Data from N = 16 children with DLD and N = 114 TD children showed that whereas entrainment-region width did not differ across the two groups, slowest motor tempo, the determinant of the upper (slow) limit of the entrainment region, was at a faster tempo in children with DLD vs. TD. In other words, the DLD group could not pace their slow tapping as slowly as the TD group. Entrainment-region width was positively associated with rhythm aptitude and receptive grammar even after taking into account potential confounding factors, whereas expressive grammar did not show an association with any of the tapping measures. Preferred tempo was not associated with any study variables after including covariates in the analyses. These results motivate future neuroscientific studies of low-frequency neural oscillatory mechanisms as the potential neural correlates of entrainment-region width and their associations with musical rhythm and spoken language processing in children with typical and atypical language development.

Exploring individual differences in musical rhythm and grammar skills in school-aged children with typically developing language.

A growing number of studies have shown a connection between rhythmic processing and language skill. It has been proposed that domain-general rhythm abilities might help children to tap into the rhythm of speech (prosody), cueing them to prosodic markers of grammatical (syntactic) information during language acquisition, thus underlying the observed correlations between rhythm and language. Working memory processes common to task demands for musical rhythm discrimination and spoken language paradigms are another possible source of individual variance observed in musical rhythm and language abilities. To investigate the nature of the relationship between musical rhythm and expressive grammar skills, we adopted an individual differences approach in N = 132 elementary school-aged children ages 5-7, with typical language development, and investigated prosodic perception and working memory skills as possible mediators. Aligning with the literature, musical rhythm was correlated with expressive grammar performance (r = 0.41, p < 0.001). Moreover, musical rhythm predicted mastery of complex syntax items (r = 0.26, p = 0.003), suggesting a privileged role of hierarchical processing shared between musical rhythm processing and children's acquisition of complex syntactic structures. These relationships between rhythm and grammatical skills were not mediated by prosodic perception, working memory, or non-verbal IQ; instead, we uncovered a robust direct effect of musical rhythm perception on grammatical task performance. Future work should focus on possible biological endophenotypes and genetic influences underlying this relationship.

Exploring the genetics of rhythmic perception and musical engagement in the Vanderbilt Online Musicality Study.

Uncovering the genetic underpinnings of musical ability and engagement is a foundational step for exploring their wide-ranging associations with cognition, health, and neurodevelopment. Prior studies have focused on using twin and family designs, demonstrating moderate heritability of musical phenotypes. The current study used genome-wide complex trait analysis and polygenic score (PGS) approaches utilizing genotype data to examine genetic influences on two musicality traits (rhythmic perception and music engagement) in N = 1792 unrelated adults in the Vanderbilt Online Musicality Study. Meta-analyzed heritability estimates (including a replication sample of Swedish individuals) were 31% for rhythmic perception and 12% for self-reported music engagement. A PGS derived from a recent study on beat synchronization ability predicted both rhythmic perception (ß = 0.11) and music engagement (ß = 0.19) in our sample, suggesting that genetic influences underlying self-reported beat synchronization ability also influence individuals' rhythmic discrimination aptitude and the degree to which they engage in music. Cross-trait analyses revealed a modest contribution of PGSs from several nonmusical traits (from the cognitive, personality, and circadian chronotype domains) to individual differences in musicality (ß = -0.06 to 0.07). This work sheds light on the complex relationship between the genetic architecture of musical rhythm processing, beat synchronization, music engagement, and other nonmusical traits.

Association of Developmental Language Disorder With Comorbid Developmental Conditions Using Algorithmic Phenotyping.

Importance: Developmental language disorder (DLD) is a common (with up to 7% prevalence) yet underdiagnosed childhood disorder whose underlying biological profile and comorbidities are not fully understood, especially at the population level. Objective: To identify clinically relevant conditions that co-occur with DLD at the population level. Design, Setting, and Participants: This case-control study used an electronic health record (EHR)-based population-level approach to compare the prevalence of comorbid health phenotypes between DLD cases and matched controls. These cases were identified using the Automated Phenotyping Tool for Identifying Developmental Language Disorder algorithm of the Vanderbilt University Medical Center EHR, and a phenome enrichment analysis was used to identify comorbidities. An independent sample was selected from the Geisinger Health System EHR to test the replication of the phenome enrichment using the same phenotyping and analysis pipeline. Data from the Vanderbilt EHR were accessed between March 2019 and October 2020, while data from the Geisinger EHR were accessed between January and March 2022. Main Outcomes and Measures: Common and rare comorbidities of DLD at the population level were identified using EHRs and a phecode-based enrichment analysis. Results: Comorbidity analysis was conducted for 5273 DLD cases (mean [SD] age, 16.8 [7.2] years; 3748 males [71.1%]) and 26 353 matched controls (mean [SD] age, 14.6 [5.5] years; 18 729 males [71.1%]). Relevant phenotypes associated with DLD were found, including learning disorder, delayed milestones, disorders of the acoustic nerve, conduct disorders, attention-deficit/hyperactivity disorder, lack of coordination, and other motor deficits. Several other health phenotypes not previously associated with DLD were identified, such as dermatitis, conjunctivitis, and weight and nutrition, representing a new window into the clinical complexity of DLD. Conclusions and Relevance: This study found both rare and common comorbidities of DLD. Comorbidity profiles may be leveraged to identify risk of additional health challenges, beyond language impairment, among children with DLD.

The Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) Framework for Understanding Musicality-Language Links Across the Lifespan.

Using individual differences approaches, a growing body of literature finds positive associations between musicality and language-related abilities, complementing prior findings of links between musical training and language skills. Despite these associations, musicality has been often overlooked in mainstream models of individual differences in language acquisition and development. To better understand the biological basis of these individual differences, we propose the Musical Abilities, Pleiotropy, Language, and Environment (MAPLE) framework. This novel integrative framework posits that musical and language-related abilities likely share some common genetic architecture (i.e., genetic pleiotropy) in addition to some degree of overlapping neural endophenotypes, and genetic influences on musically and linguistically enriched environments. Drawing upon recent advances in genomic methodologies for unraveling pleiotropy, we outline testable predictions for future research on language development and how its underlying neurobiological substrates may be supported by genetic pleiotropy with musicality. In support of the MAPLE framework, we review and discuss findings from over seventy behavioral and neural studies, highlighting that musicality is robustly associated with individual differences in a range of speech-language skills required for communication and development. These include speech perception-in-noise, prosodic perception, morphosyntactic skills, phonological skills, reading skills, and aspects of second/foreign language learning. Overall, the current work provides a clear agenda and framework for studying musicality-language links using individual differences approaches, with an emphasis on leveraging advances in the genomics of complex musicality and language traits.

A potential role for zinc in restless legs syndrome.

STUDY OBJECTIVES: Evaluate serum and brain noniron metals in the pathology and genetics of restless legs syndrome (RLS). METHODS: In two independent studies (cohorts 1 and 2), in which subjects either remained on medications or tapered off medications, we analyzed serum levels of iron, calcium, magnesium, manganese, copper, and zinc both in RLS patients and controls, and assessed the prevalence of the MEIS1 and BTBD9 risk alleles previously established through genome-wide association studies. Human brain sections and a nematode genetic model were also quantified for metal levels using mass spectrometry. RESULTS: We found a significant enrichment for the BTBD9 risk genotype in the RLS affected group compared to control (p = 0.0252), consistent with previous literature. Serum (p = 0.0458 and p = 0.0139 for study cohorts 1 and 2, respectively) and brain (p = 0.0413) zinc levels were significantly elevated in the RLS patients versus control subjects. CONCLUSION: We show for the first time that serum and brain levels of zinc are elevated in RLS. Further, we confirm the BTBD9 genetic risk factor in a new population, although the zinc changes were not significantly associated with risk genotypes. Zinc and iron homeostasis are interrelated, and zinc biology impacts neurotransmitter systems previously linked to RLS. Given the modest albeit statistically significant increase in serum zinc of ~20%, and the lack of association with two known genetic risk factors, zinc may not represent a primary etiology for the syndrome. Further investigation into the pathogenetic role that zinc may play in restless legs syndrome is needed.

Automated Phenotyping Tool for Identifying Developmental Language Disorder Cases in Health Systems Data (APT-DLD): A New Research Algorithm for Deployment in Large-Scale Electronic Health Record Systems.

Purpose Data mining algorithms using electronic health records (EHRs) are useful in large-scale population-wide studies to classify etiology and comorbidities (Casey et al., 2016). Here, we apply this approach to developmental language disorder (DLD), a prevalent communication disorder whose risk factors and epidemiology remain largely undiscovered. Method We first created a reliable system for manually identifying DLD in EHRs based on speech-language pathologist (SLP) diagnostic expertise. We then developed and validated an automated algorithmic procedure, called, Automated Phenotyping Tool for identifying DLD cases in health systems data (APT-DLD), that classifies a DLD status for patients within EHRs on the basis of ICD (International Statistical Classification of Diseases and Related Health Problems) codes. APT-DLD was validated in a discovery sample (N = 973) using expert SLP manual phenotype coding as a gold-standard comparison and then applied and further validated in a replication sample of N = 13,652 EHRs. Results In the discovery sample, the APT-DLD algorithm correctly classified 98% (concordance) of DLD cases in concordance with manually coded records in the training set, indicating that APT-DLD successfully mimics a comprehensive chart review. The output of APT-DLD was also validated in relation to independently conducted SLP clinician coding in a subset of records, with a positive predictive value of 95% of cases correctly classified as DLD. We also applied APT-DLD to the replication sample, where it achieved a positive predictive value of 90% in relation to SLP clinician classification of DLD. Conclusions APT-DLD is a reliable, valid, and scalable tool for identifying DLD cohorts in EHRs. This new method has promising public health implications for future large-scale epidemiological investigations of DLD and may inform EHR data mining algorithms for other communication disorders. Supplemental Material https://doi.org/10.23641/asha.12753578.

Identification of a selective manganese ionophore that enables nonlethal quantification of cellular manganese.

Available assays for measuring cellular manganese (Mn) levels require cell lysis, restricting longitudinal experiments and multiplexed outcome measures. Conducting a screen of small molecules known to alter cellular Mn levels, we report here that one of these chemicals induces rapid Mn efflux. We describe this activity and the development and implementation of an assay centered on this small molecule, named manganese-extracting small molecule (MESM). Using inductively-coupled plasma-MS, we validated that this assay, termed here "manganese-extracting small molecule estimation route" (MESMER), can accurately assess Mn in mammalian cells. Furthermore, we found evidence that MESM acts as a Mn-selective ionophore, and we observed that it has increased rates of Mn membrane transport, reduced cytotoxicity, and increased selectivity for Mn over calcium compared with two established Mn ionophores, calcimycin (A23187) and ionomycin. Finally, we applied MESMER to test whether prior Mn exposures subsequently affect cellular Mn levels. We found that cells receiving continuous, elevated extracellular Mn accumulate less Mn than cells receiving equally-elevated Mn for the first time for 24 h, indicating a compensatory cellular homeostatic response. Use of the MESMER assay versus a comparable detergent lysis-based assay, cellular Fura-2 Mn extraction assay, reduced the number of cells and materials required for performing a similar but cell lethality-based experiment to 25% of the normally required sample size. We conclude that MESMER can accurately quantify cellular Mn levels in two independent cells lines through an ionophore-based mechanism, maintaining cell viability and enabling longitudinal assessment within the same cultures.

Manganese Acts upon Insulin/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington's Disease Cells.

Perturbations in insulin/IGF signaling and manganese (Mn2+) uptake and signaling have been separately reported in Huntington's disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn2+-responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn2+ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn2+ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn2+-dependent AKT signaling is predominantly mediated by direct Mn2+ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn2+ bioavailability. We examined the combined effects of IGF-1 and/or Mn2+ treatments on AKT signaling in multiple HD cellular models. Mn2+ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70-80% of Mn2+-associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn2+-induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn2+ and IGF-1. Lastly, Mn2+-induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn2+ supplementation. Our data demonstrate that Mn2+ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn2+ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.

Acute manganese treatment restores defective autophagic cargo loading in Huntington's disease cell lines.

The molecular etiology linking the pathogenic mutations in the Huntingtin (Htt) gene with Huntington's disease (HD) is unknown. Prior work suggests a role for Htt in neuronal autophagic function and mutant HTT protein disrupts autophagic cargo loading. Reductions in the bioavailability of the essential metal manganese (Mn) are seen in models of HD. Excess cellular Mn impacts autophagic function, but the target and molecular basis of these changes are unknown. Thus, we sought to determine if changes in cellular Mn status impact autophagic processes in a wild-type or mutant Htt-dependent manner. We report that the HD genotype is associated with reduced Mn-induced autophagy and that acute Mn exposure increases autophagosome induction/formation. To determine if a deficit in bioavailable Mn is mechanistically linked to the autophagy-related HD cellular phenotypes, we examined autophagosomes by electron microscopy. We observed that a 24 h 100 uM Mn restoration treatment protocol attenuated an established HD 'cargo-recognition failure' in the STHdh HD model cells by increasing the percentage of filled autophagosomes. Mn restoration had no effect on HTT aggregate number, but a 72 h co-treatment with chloroquine (CQ) in GFP-72Q-expressing HEK293 cells increased the number of visible aggregates in a dose-dependent manner. As CQ prevents autophagic degradation this indicates that Mn restoration in HD cell models facilitates incorporation of aggregates into autophagosomes. Together, these findings suggest that defective Mn homeostasis in HD models is upstream of the impaired autophagic flux and provide proof-of-principle support for increasing bioavailable Mn in HD to restore autophagic function and promote aggregate clearance.

Meiotic Interactors of a Mitotic Gene TAO3 Revealed by Functional Analysis of its Rare Variant.

Studying the molecular consequences of rare genetic variants has the potential to identify novel and hitherto uncharacterized pathways causally contributing to phenotypic variation. Here, we characterize the functional consequences of a rare coding variant of TAO3, previously reported to contribute significantly to sporulation efficiency variation in Saccharomyces cerevisiae During mitosis, the common TAO3 allele interacts with CBK1-a conserved NDR kinase. Both TAO3 and CBK1 are components of the RAM signaling network that regulates cell separation and polarization during mitosis. We demonstrate that the role of the rare allele TAO3(4477C) in meiosis is distinct from its role in mitosis by being independent of ACE2-a RAM network target gene. By quantitatively measuring cell morphological dynamics, and expressing the TAO3(4477C) allele conditionally during sporulation, we show that TAO3 has an early role in meiosis. This early role of TAO3 coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation identified regulators of carbon and lipid metabolic pathways as candidate mediators. We show experimentally that, during sporulation, the TAO3(4477C) allele interacts genetically with ERT1 and PIP2, regulators of the tricarboxylic acid cycle and gluconeogenesis metabolic pathways, respectively. We thus uncover a meiotic functional role for TAO3, and identify ERT1 and PIP2 as novel regulators of sporulation efficiency. Our results demonstrate that studying the causal effects of genetic variation on the underlying molecular network has the potential to provide a more extensive understanding of the pathways driving a complex trait.