Population-based genetic effects for developmental stuttering.

Despite a lifetime prevalence of at least 5%, developmental stuttering, characterized by prolongations, blocks, and repetitions of speech sounds, remains a largely idiopathic speech disorder. Family, twin, and segregation studies overwhelmingly support a strong genetic influence on stuttering risk; however, its complex mode of inheritance combined with thus-far underpowered genetic studies contribute to the challenge of identifying and reproducing genes implicated in developmental stuttering susceptibility. We conducted a trans-ancestry genome-wide association study (GWAS) and meta-analysis of developmental stuttering in two primary datasets: The International Stuttering Project comprising 1,345 clinically ascertained cases from multiple global sites and 6,759 matched population controls from the biobank at Vanderbilt University Medical Center (VUMC), and 785 self-reported stuttering cases and 7,572 controls ascertained from The National Longitudinal Study of Adolescent to Adult Health (Add Health). Meta-analysis of these genome-wide association studies identified a genome-wide significant (GWS) signal for clinically reported developmental stuttering in the general population: a protective variant in the intronic or genic upstream region of SSUH2 (rs113284510, protective allele frequency = 7.49%, Z = -5.576, p = 2.46 × 10-8) that acts as an expression quantitative trait locus (eQTL) in esophagus-muscularis tissue by reducing its gene expression. In addition, we identified 15 loci reaching suggestive significance (p < 5 × 10-6). This foundational population-based genetic study of a common speech disorder reports the findings of a clinically ascertained study of developmental stuttering and highlights the need for further research.

Tools for standardized data collection: Speech, Language, and Hearing measurement protocols in the PhenX Toolkit.

The PhenX Toolkit (https://www.phenxtoolkit.org/) is an online catalog of recommended measurement protocols to facilitate cross-study analyses for biomedical research. An expert review panel (ERP) reviewed and updated the PhenX Toolkit Speech and Hearing domain to improve the precision and consistency of speech, language, and hearing disorder phenotypes. A three-member ERP convened in August 2018 to review the measurement protocols in the PhenX Speech and Hearing domain. Aided by three additional experts in voice assessment, vertigo, and stuttering, the ERP updated the 28 protocols to reflect the latest science and technology. ERP recommendations include six new protocols, five updated protocols (from the same source), and one retired protocol. New additions include two voice-related, three hearing-related, and two speech-related protocols. Additions reflect new phone/tablet applications for hearing and language, and clinical evaluations of voice. "Language" was added to the domain name, which is now "Speech, Language, and Hearing," to represent language-related protocols. These protocols can facilitate the assessment of speech, language, and hearing in clinical and population research. Common data elements (i.e., use of the same variables across studies) used by geneticists, otolaryngologists, audiologists, speech-language pathologists, and in other disciplines can lead to cross-study data integration and increased statistical power when studies are combined.

Phenome risk classification enables phenotypic imputation and gene discovery in developmental stuttering.

Developmental stuttering is a speech disorder characterized by disruption in the forward movement of speech. This disruption includes part-word and single-syllable repetitions, prolongations, and involuntary tension that blocks syllables and words, and the disorder has a life-time prevalence of 6-12%. Within Vanderbilt's electronic health record (EHR)-linked biorepository (BioVU), only 142 individuals out of 92,762 participants (0.15%) are identified with diagnostic ICD9/10 codes, suggesting a large portion of people who stutter do not have a record of diagnosis within the EHR. To identify individuals affected by stuttering within our EHR, we built a PheCode-driven Gini impurity-based classification and regression tree model, PheML, by using comorbidities enriched in individuals affected by stuttering as predicting features and imputing stuttering status as the outcome variable. Applying PheML in BioVU identified 9,239 genotyped affected individuals (a clinical prevalence of ∼10%) for downstream genetic analysis. Ancestry-stratified GWAS of PheML-imputed affected individuals and matched control individuals identified rs12613255, a variant near CYRIA on chromosome 2 (B = 0.323; p value = 1.31 × 10-8) in European-ancestry analysis and rs7837758 (B = 0.518; p value = 5.07 × 10-8), an intronic variant found within the ZMAT4 gene on chromosome 8, in African-ancestry analysis. Polygenic-risk prediction and concordance analysis in an independent clinically ascertained sample of developmental stuttering cases validate our GWAS findings in PheML-imputed affected and control individuals and demonstrate the clinical relevance of our population-based analysis for stuttering risk.

Deficit or Difference? Effects of Altered Auditory Feedback on Speech Fluency and Kinematic Variability in Adults Who Stutter.

Purpose The purpose of this study was to test whether adults who stutter (AWS) display a different range of sensitivity to delayed auditory feedback (DAF). Two experiments were conducted to assess the fluency of AWS under long-latency DAF and to test the effect of short-latency DAF on speech kinematic variability in AWS. Method In Experiment 1, 15 AWS performed a conversational speaking task under nonaltered auditory feedback and 250-ms DAF. The rates of stuttering-like disfluencies, other disfluencies, and speech errors and articulation rate were compared. In Experiment 2, 13 AWS and 15 adults who do not stutter (AWNS) read three utterances under four auditory feedback conditions: nonaltered auditory feedback, amplified auditory feedback, 25-ms DAF, and 50-ms DAF. Across-utterance kinematic variability (spatiotemporal index) and within-utterance variability (percent determinism and stability) were compared between groups. Results In Experiment 1, under 250-ms DAF, the rate of stuttering-like disfluencies and speech errors increased significantly, while articulation rate decreased significantly in AWS. In Experiment 2, AWS exhibited higher kinematic variability than AWNS across the feedback conditions. Under 25-ms DAF, the spatiotemporal index of AWS decreased significantly compared to the other feedback conditions. AWS showed lower overall percent determinism than AWNS, but their percent determinism increased under 50-ms DAF to approximate that of AWNS. Conclusions Auditory feedback manipulations can alter speech fluency and kinematic variability in AWS. Longer latency auditory feedback delays induce speech disruptions, while subtle auditory feedback manipulations potentially benefit speech motor control. Both AWS and AWNS are susceptible to auditory feedback during speech production, but AWS appear to exhibit a distinct continuum of sensitivity.

Identifying developmental stuttering and associated comorbidities in electronic health records and creating a phenome risk classifier.

PURPOSE: This study aimed to identify cases of developmental stuttering and associated comorbidities in de-identified electronic health records (EHRs) at Vanderbilt University Medical Center, and, in turn, build and test a stuttering prediction model. METHODS: A multi-step process including a keyword search of medical notes, a text-mining algorithm, and manual review was employed to identify stuttering cases in the EHR. Confirmed cases were compared to matched controls in a phenotype code (phecode) enrichment analysis to reveal conditions associated with stuttering (i.e., comorbidities). These associated phenotypes were used as proxy variables to phenotypically predict stuttering in subjects within the EHR that were not otherwise identifiable using the multi-step identification process described above. RESULTS: The multi-step process resulted in the manually reviewed identification of 1,143 stuttering cases in the EHR. Highly enriched phecodes included codes related to childhood onset fluency disorder, adult-onset fluency disorder, hearing loss, sleep disorders, atopy, a multitude of codes for infections, neurological deficits, and body weight. These phecodes were used as variables to create a phenome risk classifier (PheRC) prediction model to identify additional high likelihood stuttering cases. The PheRC prediction model resulted in a positive predictive value of 83 %. CONCLUSIONS: This study demonstrates the feasibility of using EHRs in the study of stuttering and found phenotypic associations. The creation of the PheRC has the potential to enable future studies of stuttering using existing EHR data, including investigations into the genetic etiology.

The Role of Effortful Control in Stuttering Severity in Children: Replication Study.

Background In 2014, Kraft et al. assessed the temperament, home environment, and significant life events of 69 North American children who stutter to examine the combined and compounded effects of these individualized factors on mediating overt stuttering severity. The temperament domain of effortful control was singularly found to be significantly predictive of stuttering severity. Purpose Because of the clinical significance of the initial study's findings, a replication study with a different, larger cohort of children who stutter was warranted to validate the reported outcomes. Method The current study assesses 98 children who stutter, ages 2;4 to 12;6 (years; months, M = 6;7), recruited from Perth, Australia. Results The results support the previous findings of Kraft, Ambrose, and Chon (2014) , with effortful control remaining the sole significant contributor to variability in stuttering severity, as rated by both parents and clinicians. Conclusion These cumulative and consistent outcomes support the need to develop targeted intervention strategies that specifically strengthen aspects of effortful control as a means to support positive therapeutic change in children who stutter.

Stuttering as a trait or state - an ALE meta-analysis of neuroimaging studies.

Stuttering is a speech disorder characterised by repetitions, prolongations and blocks that disrupt the forward movement of speech. An earlier meta-analysis of brain imaging studies of stuttering (Brown et al., 2005) revealed a general trend towards rightward lateralization of brain activations and hyperactivity in the larynx motor cortex bilaterally. The present study sought not only to update that meta-analysis with recent work but to introduce an important distinction not present in the first study, namely the difference between 'trait' and 'state' stuttering. The analysis of trait stuttering compares people who stutter (PWS) with people who do not stutter when behaviour is controlled for, i.e., when speech is fluent in both groups. In contrast, the analysis of state stuttering examines PWS during episodes of stuttered speech compared with episodes of fluent speech. Seventeen studies were analysed using activation likelihood estimation. Trait stuttering was characterised by the well-known rightward shift in lateralization for language and speech areas. State stuttering revealed a more diverse pattern. Abnormal activation of larynx and lip motor cortex was common to the two analyses. State stuttering was associated with overactivation in the right hemisphere larynx and lip motor cortex. Trait stuttering was associated with overactivation of lip motor cortex in the right hemisphere but underactivation of larynx motor cortex in the left hemisphere. These results support a large literature highlighting laryngeal and lip involvement in the symptomatology of stuttering, and disambiguate two possible sources of activation in neuroimaging studies of persistent developmental stuttering.

PlexinA polymorphisms mediate the developmental trajectory of human corpus callosum microstructure.

PlexinA is a neuronal receptor protein that facilitates axon guidance during embryogenesis. This gene is associated with several neurological disorders including Alzheimer's disease, Parkinson's disease and autism. However, the effect of variants of PlexinA on brain structure remains unclear. We demonstrate that single-nucleotide polymorphisms within the intron and 3'-untranslated region segments of several human PlexinA genes alter the post-natal developmental trajectory of corpus callosum microstructure. This is the first demonstration that PLXNA mediation of neuroanatomical traits can be detected in humans using in vivo neuroimaging techniques. This result should encourage future research that targets specific disease-related polymorphisms and their relevant neural pathways.

Individual variability in delayed auditory feedback effects on speech fluency and rate in normally fluent adults.

PURPOSE: Delayed auditory feedback (DAF) is known to induce stuttering-like disfluencies (SLDs) and cause speech rate reductions in normally fluent adults, but the reason for speech disruptions is not fully known, and individual variation has not been well characterized. Studying individual variation in susceptibility to DAF may identify factors that predispose an individual to be more or less dependent on auditory feedback. METHOD: Participants were 62 normally fluent adults. Each participant performed a spontaneous speech task in 250-ms DAF and amplified nondelayed auditory feedback (NAF) conditions. SLDs, other disfluencies (ODs), speech errors (SEs), and articulation rate (AR) were measured under each condition. RESULTS: In the DAF condition, SLDs and SEs significantly increased, and AR decreased. Sex had a limited effect in that men exhibited higher rates of ODs and faster AR than women. More important, parametric cluster analysis identified that 2- and 3-subgroup solutions reveal important variation that differentiates tendencies toward disfluency changes and rate reduction under DAF, which are theoretically and empirically preferred to a single-group solution. CONCLUSION: Individual variability in response to DAF may be accounted for by subgroups of individuals. This suggests that certain normally fluent individuals could be more dependent on intact feedback to maintain fluency.

Genetic bases of stuttering: the state of the art, 2011.

OBJECTIVE: The literature on the genetics of stuttering is reviewed with special reference to the historical development from psychosocial explanations leading up to current biological research of gene identification. SUMMARY: A gradual progression has been made from the early crude methods of counting percentages of stuttering probands who have relatives who stutter to recent studies using entire genomes of DNA collected from each participant. Despite the shortcomings of some early studies, investigators have accumulated a substantial body of data showing a large presence of familial stuttering. This encouraged more refined research in the form of twin studies. Concordance rates among twins were sufficiently high to lend additional support to the genetic perspective of stuttering. More sophisticated aggregation studies and segregation analyses followed, producing data that matched recognized genetic models, providing the final 'go ahead' to proceed from the behavior/statistical genetics into the sphere of biological genetics. Recent linkage and association studies have begun to reveal contributing genes to the disorder. CONCLUSION: No definitive findings have been made regarding which transmission model, chromosomes, genes, or sex factors are involved in the expression of stuttering in the population at large. Future research and clinical implications are discussed.

Functional brain activation differences in stuttering identified with a rapid fMRI sequence.

UNLABELLED: The purpose of this study was to investigate whether brain activity related to the presence of stuttering can be identified with rapid functional MRI (fMRI) sequences that involved overt and covert speech processing tasks. The long-term goal is to develop sensitive fMRI approaches with developmentally appropriate tasks to identify deviant speech motor and auditory brain activity in children who stutter closer to the age at which recovery from stuttering is documented. Rapid sequences may be preferred for individuals or populations who do not tolerate long scanning sessions. In this report, we document the application of a picture naming and phoneme monitoring task in 3 min fMRI sequences with adults who stutter (AWS). If relevant brain differences are found in AWS with these approaches that conform to previous reports, then these approaches can be extended to younger populations. Pairwise contrasts of brain BOLD activity between AWS and normally fluent adults indicated the AWS showed higher BOLD activity in the right inferior frontal gyrus (IFG), right temporal lobe and sensorimotor cortices during picture naming and higher activity in the right IFG during phoneme monitoring. The right lateralized pattern of BOLD activity together with higher activity in sensorimotor cortices is consistent with previous reports, which indicates rapid fMRI sequences can be considered for investigating stuttering in younger participants. EDUCATIONAL OBJECTIVES: The reader will learn about and be able to describe the: (1) use of functional MRI to study persistent developmental stuttering; (2) differences in brain activation between persons who stutter and normally fluent speakers; and (3) potential benefit of time efficient fMRI sequences combined with a range of speech processing tasks for investigating stuttering in younger populations.

Corpus callosum differences associated with persistent stuttering in adults.

Recent studies have implicated anatomical differences in speech-relevant brain regions of adults who stutter (AWS) compared to normally fluent adults (NFA). The present study focused on the region of the corpus callosum (CC) which is involved in interhemispheric processing between the left and right cerebral hemispheres. Two-dimensional segmentation of area and voxel-based morphometry were used to evaluate the corpus callosum. Results revealed that the rostrum and anterior midbody of the CC were larger in AWS than NFA. In addition, the overall callosa area was larger in AWS than NFA. The group comparison of white matter volume showed a cluster of increased white matter volume predominantly encompassing the rostrum across the midline portion in AWS. These results potentially reflect anatomical changes associated with differences in the hemispheric distribution of language processes that have been reported previously in AWS.