Audiology and Speech Pathology - Research Publications
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ItemNo Preview AvailableStuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40(OXFORD UNIV PRESS, 2023-12-01)Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.
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ItemUsing machine-learning methods to identify early-life predictors of 11-year language outcome(WILEY, 2023-08)BACKGROUND: Language is foundational for neurodevelopment and quality of life, but an estimated 10% of children have a language disorder at age 5. Many children shift between classifications of typical and low language if assessed at multiple times in the early years, making it difficult to identify which children will have persisting difficulties and benefit most from support. This study aims to identify a parsimonious set of preschool indicators that predict language outcomes in late childhood, using data from the population-based Early Language in Victoria Study (n = 839). METHODS: Parents completed surveys about their children at ages 8, 12, 24, and 36 months. At 11 years, children were assessed using the Clinical Evaluation of Language Fundamentals 4th Edition (CELF-4). We used random forests to identify which of the 1990 parent-reported questions best predict children's 11-year language outcome (CELF-4 score ≤81 representing low language) and used SuperLearner to estimate the accuracy of the constrained sets of questions. RESULTS: At 24 months, seven predictors relating to vocabulary, symbolic play, pragmatics and behavior yielded 73% sensitivity (95% CI: 57, 85) and 77% specificity (95% CI: 74, 80) for predicting low language at 11 years. [Corrections made on 5 May 2023, after first online publication: In the preceding sentence 'motor skills' has been corrected to 'behavior' in this version.] At 36 months, 7 predictors relating to morphosyntax, vocabulary, parent-child interactions, and parental stress yielded 75% sensitivity (95% CI: 58, 88) and 85% specificity (95% CI: 81, 87). Measures at 8 and 12 months yielded unsatisfactory accuracy. CONCLUSIONS: We identified two short sets of questions that predict language outcomes at age 11 with fair accuracy. Future research should seek to replicate results in a separate cohort.
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ItemHypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities(SPRINGERNATURE, 2022-11-29)Reading Disability (RD) is often characterized by difficulties in the phonology of the language. While the molecular mechanisms underlying it are largely undetermined, loci are being revealed by genome-wide association studies (GWAS). In a previous GWAS for word reading (Price, 2020), we observed that top single-nucleotide polymorphisms (SNPs) were located near to or in genes involved in neuronal migration/axon guidance (NM/AG) or loci implicated in autism spectrum disorder (ASD). A prominent theory of RD etiology posits that it involves disturbed neuronal migration, while potential links between RD-ASD have not been extensively investigated. To improve power to identify associated loci, we up-weighted variants involved in NM/AG or ASD, separately, and performed a new Hypothesis-Driven (HD)-GWAS. The approach was applied to a Toronto RD sample and a meta-analysis of the GenLang Consortium. For the Toronto sample (n = 624), no SNPs reached significance; however, by gene-set analysis, the joint contribution of ASD-related genes passed the threshold (p~1.45 × 10-2, threshold = 2.5 × 10-2). For the GenLang Cohort (n = 26,558), SNPs in DOCK7 and CDH4 showed significant association for the NM/AG hypothesis (sFDR q = 1.02 × 10-2). To make the GenLang dataset more similar to Toronto, we repeated the analysis restricting to samples selected for reading/language deficits (n = 4152). In this GenLang selected subset, we found significant association for a locus intergenic between BTG3-C21orf91 for both hypotheses (sFDR q < 9.00 × 10-4). This study contributes candidate loci to the genetics of word reading. Data also suggest that, although different variants may be involved, alleles implicated in ASD risk may be found in the same genes as those implicated in word reading. This finding is limited to the Toronto sample suggesting that ascertainment influences genetic associations.
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ItemGenome-wide analyses of individual differences in quantitatively assessed reading- and language-related skills in up to 34,000 people(NATL ACAD SCIENCES, 2022-08-18)The use of spoken and written language is a fundamental human capacity. Individual differences in reading- and language-related skills are influenced by genetic variation, with twin-based heritability estimates of 30 to 80% depending on the trait. The genetic architecture is complex, heterogeneous, and multifactorial, but investigations of contributions of single-nucleotide polymorphisms (SNPs) were thus far underpowered. We present a multicohort genome-wide association study (GWAS) of five traits assessed individually using psychometric measures (word reading, nonword reading, spelling, phoneme awareness, and nonword repetition) in samples of 13,633 to 33,959 participants aged 5 to 26 y. We identified genome-wide significant association with word reading (rs11208009, P = 1.098 × 10-8) at a locus that has not been associated with intelligence or educational attainment. All five reading-/language-related traits showed robust SNP heritability, accounting for 13 to 26% of trait variability. Genomic structural equation modeling revealed a shared genetic factor explaining most of the variation in word/nonword reading, spelling, and phoneme awareness, which only partially overlapped with genetic variation contributing to nonword repetition, intelligence, and educational attainment. A multivariate GWAS of word/nonword reading, spelling, and phoneme awareness maximized power for follow-up investigation. Genetic correlation analysis with neuroimaging traits identified an association with the surface area of the banks of the left superior temporal sulcus, a brain region linked to the processing of spoken and written language. Heritability was enriched for genomic elements regulating gene expression in the fetal brain and in chromosomal regions that are depleted of Neanderthal variants. Together, these results provide avenues for deciphering the biological underpinnings of uniquely human traits.
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ItemAtypical development of Broca's area in a large family with inherited stuttering(OXFORD UNIV PRESS, 2022-04-29)Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9-63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca's area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca's area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.
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ItemSelf-reported impact of developmental stuttering across the lifespan(WILEY, 2022-10)AIM: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. METHOD: Participants aged 7 years and older with a history of developmental stuttering were recruited. Self-reported phenotypic data were collected online including stuttering symptomatology, co-occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. RESULTS: A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months; range = 18-93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years; range = 7-17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype; 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). INTERPRETATION: The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. WHAT THIS PAPER ADDS: Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.
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ItemAssociations between expressive and receptive language and internalizing and externalizing behaviours in a community-based prospective study of slow-to-talk toddlers(WILEY, 2017-11)BACKGROUND: Evidence suggests that language and social, emotional and behavioural (SEB) difficulties are associated in children and adolescents. When these associations emerge and whether they differ by language or SEB difficulty profile is unclear. This knowledge is crucial to guide prevention and intervention programmes for children with language and SEB difficulties. AIMS: To determine whether receptive and expressive language skills are associated with internalizing and externalizing behaviours in slow-to-talk toddlers. METHODS & PROCEDURES: In a community-based prospective study of 200 slow-to-talk children, language was measured at 24 and 36 months using Preschool Language Scale 4th Edition and at 48 months using Clinical Evaluation of Language Fundamentals-Preschool 2nd Edition. Internalizing and externalizing behaviours were measured by parent report at each age. Longitudinal data were analysed using repeated-measures regression, with up to three observations per child. Robust standard errors were used to account for non-independence of measures within participants. The shape of the associations were examined by fitting quadratic and cubic terms. The effects of confounders on the associations were examined. OUTCOMES & RESULTS: Receptive language had a negative linear association with internalizing behaviours after adjusting for confounders (β = -0.16, 95% [CI = -0.26, -0.07], p = .001); and a negative curved association with externalizing behaviours after adjusting for biological confounders (βquadratic = 0.08 [0.01, 0.15], p = .03, βcubic = -0.04 [-0.07, -0.02], p = .001), attenuating after adjusting for environmental confounders (βquadratic = 0.06 [-0.01, 0.13], p = .09, βcubic = -0.03 [-0.06, -0.003], p = .03). The curvature suggests that the negative association with externalizing behaviours only existed for children with either very low or very high receptive language scores. After controlling for confounders, there was no evidence that expressive language scores were associated with internalizing (β = -0.08, 95% [CI = -0.17, 0.01], p = .10) or externalizing behaviours (β = 0.03, 95% [CI = -0.09, 0.18], p = .61). Tests of interaction revealed no evidence of a differential association by age. CONCLUSIONS & IMPLICATIONS: In 24-48-month-old slow-to-talk children, lower receptive language scores were associated with higher internalizing behaviours. The magnitude of the association was small. For children with very poor receptive language scores, lower receptive language skills were associated with higher externalizing behaviours. Young children with low receptive language abilities may be at risk of internalizing difficulties; those with very low receptive language skills may be at particular risk of externalizing difficulties. This has clinical implications for interventions for young children with receptive language difficulties.
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ItemNo Preview AvailableArticulation or phonology? Evidence from longitudinal error data(TAYLOR & FRANCIS INC, 2018)Children's speech difficulties can be motor (phone misarticulation) or linguistic (impaired knowledge of phonological contrasts and constraints). These two difficulties sometimes co-occur. This paper reports longitudinal data from the Early Language in Victoria Study (ELVS) at 4 and 7 years of age. Of 1494 participants, 93 made non-age appropriate speech errors on standardised assessments at 4 years, and were able to be reassessed at 7 years. At 4 years, 85% of these children only made phonological errors, 14% made both articulation and phonological errors and one child only made articulation errors (a lateral lisp). In total, 8 of 13 children making both articulation and phonological errors at 4 years had resolved by 7 years. Unexpectedly, eight children who had demonstrated articulation of fricatives at 4 years, acquired distorted production of ≥ 50% of occurrences of/s, z/ by 7 years. In total, then, 22 children (24% of children with speech difficulties) made articulatory errors at one or both assessments. Case data for all children are presented. Theoretical and clinical implications are considered.
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ItemAtypical Callosal Morphology in Children with Speech Sound Disorder(PERGAMON-ELSEVIER SCIENCE LTD, 2017-12-26)Speech sound disorder (SSD) is common, yet its neurobiology is poorly understood. Recent studies indicate atypical structural and functional anomalies either in one hemisphere or both hemispheres, which might be accompanied by alterations in inter-hemispheric connectivity. Indeed, abnormalities of the corpus callosum - the main fiber tract connecting the two hemispheres - have been linked to speech and language deficits in associated disorders, such as stuttering, dyslexia, aphasia, etc. However, there is a dearth of studies examining the corpus callosum in SSD. Here, we investigated whether a sample of 18 children with SSD differed in callosal morphology from 18 typically developing children carefully matched for age. Significantly reduced dimensions of the corpus callosum, particularly in the callosal anterior third, were observed in children with SSD. These findings indicating pronounced callosal aberrations in SSD make an important contribution to an understudied field of research and may suggest that SSD is accompanied by atypical lateralization of speech and language function.
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ItemExploring the speech and language of individuals with non-syndromic submucous cleft palate: a preliminary report(WILEY, 2019-09)BACKGROUND: Submucous cleft palate (SMCP) has a heterogeneous presentation and is often identified late or misdiagnosed. Diagnosis is prompted by speech, resonance or feeding symptoms associated with velopharyngeal insufficiency. However, the broader impacts of SMCP on communication have rarely been examined and therefore are poorly understood. AIM: To describe the communicative profile of individuals with non-syndromic SMCP by examining speech, language and pragmatics (social language). METHODS & PROCEDURES: Fifteen participants with SMCP aged 5;1-12;8, without a genetic diagnosis, participated in the study. Participants completed standardized assessments examining language, resonance, speech and non-verbal intellect. Parents also completed the Children's Communication Checklist (CCC-2), which provided a measure of overall communicative ability, including pragmatic skills. Formal language outcomes were compared with two cohorts: 36 individuals with overt non-syndromic clefts and 129 individuals with no history of clefting. OUTCOMES & RESULTS: Speech intelligibility was reduced secondary to hypernasality, disordered articulation and/or impaired phonology (n = 7) in children with SMCP. Poorer overall language outcomes were observed for children with SMCP compared with both those with overt clefts and no history of clefting (p < 0.001). Language scores for children with SMCP ranged from impaired (n = 6) to above the standardized mean (n = 4). Receptive and expressive language performance were independently correlated with non-verbal IQ (p < 0.01). Those with severe language impairment (n = 4) also had borderline or impaired non-verbal IQ. Parents reported that speech and semantics were the most affected sub-domains of communication, while scores were the highest for the initiation domain. Speech and language skills were correlated strongly with pragmatics (r = 0.877, p < 0.01). CONCLUSIONS & IMPLICATIONS: Overall, performance was variable within the SMCP group across speech, language and pragmatic assessments. In addition to well-documented speech difficulties, children with SMCP may have language or pragmatic impairments, suggesting that further neurodevelopmental influences may be at play. As such, for individuals with SMCP, additional clinical screening of language and pragmatic abilities may be required to ensure accurate diagnosis and guide both cleft and non-cleft related therapy programmes.