Approaches to Measuring Language Lateralisation: An Exploratory Study Comparing Two fMRI Methods and Functional Transcranial Doppler Ultrasound.

In this exploratory study we compare and contrast two methods for deriving a laterality index (LI) from functional magnetic resonance imaging (fMRI) data: the weighted bootstrapped mean from the LI Toolbox (toolbox method), and a novel method that uses subtraction of activations from homologous regions in left and right hemispheres to give an array of difference scores (mirror method). Data came from 31 individuals who had been selected to include a high proportion of people with atypical laterality when tested with functional transcranial Doppler ultrasound (fTCD). On two tasks, word generation and semantic matching, the mirror method generally gave better agreement with fTCD laterality than the toolbox method, both for individual regions of interest, and for a large region corresponding to the middle cerebral artery. LI estimates from this method had much smaller confidence intervals (CIs) than those from the toolbox method; with the mirror method, most participants were reliably lateralised to left or right, whereas with the toolbox method, a higher proportion were categorised as bilateral (i.e., the CI for the LI spanned zero). Reasons for discrepancies between fMRI methods are discussed: one issue is that the toolbox method averages the LI across a wide range of thresholds. Furthermore, examination of task-related t-statistic maps from the two hemispheres showed that language lateralisation is evident in regions characterised by deactivation, and so key information may be lost by ignoring voxel activations below zero, as is done with conventional estimates of the LI.

How reliable is assessment of children's sentence comprehension using a self-directed app? A comparison of supported versus independent use.

This study reports on the feasibility of using the Test of Complex Syntax- Electronic (TECS-E), as a self-directed app, to measure sentence comprehension in children aged 4 to 5 ½ years old; how testing apps might be adapted for effective independent use; and agreement levels between face-to-face supported computerized and independent computerized testing with this cohort. A pilot phase was completed with 4 to 4;06-year-old children, to determine the appropriate functional app features required to facilitate independent test completion. Following the integration of identified features, children completed the app independently or with adult support (4-4;05 (n = 22) 4;06-4;11 months (n = 55) and 5 to 5;05 (n = 113)) and test re-test reliability was examined. Independent test completion posed problems for children under 5 years but for those over 5, TECS-E is a reliable method to assess children's understanding of complex sentences, when used independently.

Laterality indices consensus initiative (LICI): A Delphi expert survey report on recommendations to record, assess, and report asymmetry in human behavioural and brain research.

Laterality indices (LIs) quantify the left-right asymmetry of brain and behavioural variables and provide a measure that is statistically convenient and seemingly easy to interpret. Substantial variability in how structural and functional asymmetries are recorded, calculated, and reported, however, suggest little agreement on the conditions required for its valid assessment. The present study aimed for consensus on general aspects in this context of laterality research, and more specifically within a particular method or technique (i.e., dichotic listening, visual half-field technique, performance asymmetries, preference bias reports, electrophysiological recording, functional MRI, structural MRI, and functional transcranial Doppler sonography). Experts in laterality research were invited to participate in an online Delphi survey to evaluate consensus and stimulate discussion. In Round 0, 106 experts generated 453 statements on what they considered good practice in their field of expertise. Statements were organised into a 295-statement survey that the experts then were asked, in Round 1, to independently assess for importance and support, which further reduced the survey to 241 statements that were presented again to the experts in Round 2. Based on the Round 2 input, we present a set of critically reviewed key recommendations to record, assess, and report laterality research for various methods.

Language and reading impairments are associated with increased prevalence of non-right-handedness.

Handedness has been studied for association with language-related disorders because of its link with language hemispheric dominance. No clear pattern has emerged, possibly because of small samples, publication bias, and heterogeneous criteria across studies. Non-right-handedness (NRH) frequency was assessed in N = 2503 cases with reading and/or language impairment and N = 4316 sex-matched controls identified from 10 distinct cohorts (age range 6-19 years old; European ethnicity) using a priori set criteria. A meta-analysis (Ncases  = 1994) showed elevated NRH % in individuals with language/reading impairment compared with controls (OR = 1.21, CI = 1.06-1.39, p = .01). The association between reading/language impairments and NRH could result from shared pathways underlying brain lateralization, handedness, and cognitive functions.

Generalized models for quantifying laterality using functional transcranial Doppler ultrasound.

We consider how analysis of brain lateralization using functional transcranial Doppler ultrasound (fTCD) data can be brought in line with modern statistical methods typically used in functional magnetic resonance imaging (fMRI). Conventionally, a laterality index is computed in fTCD from the difference between the averages of each hemisphere's signal within a period of interest (POI) over a series of trials. We demonstrate use of generalized linear models (GLMs) and generalized additive models (GAM) to analyze data from individual participants in three published studies (N = 154, 73 and 31), and compare this with results from the conventional POI averaging approach, and with laterality assessed using fMRI (N = 31). The GLM approach was based on classic fMRI analysis that includes a hemodynamic response function as a predictor; the GAM approach estimated the response function from the data, including a term for time relative to epoch start (simple GAM), plus a categorical index corresponding to individual epochs (complex GAM). Individual estimates of the fTCD laterality index are similar across all methods, but error of measurement is lowest using complex GAM. Reliable identification of cases of bilateral language appears to be more accurate with complex GAM. We also show that the GAM-based approach can be used to efficiently analyze more complex designs that incorporate interactions between tasks.

Testing the relationship between lateralization on sequence-based motor tasks and language laterality using an online battery.

ABSTRACTStudies have highlighted an association between motor laterality and speech production laterality. It is thought that common demands for sequential processing may underlie this association. However, most studies in this area have relied on relatively small samples and have infrequently explored the reliability of the tools used to assess lateralization. We, therefore, established the validity and reliability of an online battery measuring sequence-based motor laterality and language laterality before exploring the associations between laterality indices on language and motor tasks. The online battery was completed by 621 participants, 52 of whom returned to complete the battery a second time. The three motor tasks included in the battery showed good between-session reliability (r ≥ .78) and were lateralized in concordance with hand preference. The novel measure of speech production laterality was left lateralized at population level as predicted, but reliability was less satisfactory (r = .62). We found no evidence of an association between sequence-based motor laterality and language laterality. Those with a left-hand preference were more strongly lateralized on motor tasks requiring midline crossing; this effect was not observed in right-handers. We conclude that there is little evidence of the co-lateralization of language and sequence-based motor skill on this battery.

Does the autism phenotype differ when selecting groups by neurodevelopmental versus genetic diagnosis? An observational study comparing autism and sex chromosome trisomy.

Background: Autism is diagnosed on the basis of social and non-social behavioural features that are assumed to cluster together, and assumed to be distinct from other aspects of development, such as language ability. It is unclear, however, if these assumptions are valid. This study presents a novel approach to answering this question by investigating whether correlations between autism features are similar for groups selected on behavioural versus genetic diagnosis. Methods: The autism phenotype was assessed by diagnostic interview in young people aged 7 to 14 diagnosed with autism ( N=61) or sex chromosome trisomy (SCT; N=49). Data were analysed by confirmatory factor analysis and MANOVA. Results: Autism features showed a similar factor structure and were distinct from language ability in both groups. However, the SCT group was more likely to show clinically-significant difficulties in just some aspects of autism and a lower level of non-social autism features for their social-communication disabilities. Conclusions: We suggest the group differences emerged because autism diagnostic criteria do not map exactly on the autism phenotype as it manifests "naturally". Conventional diagnostic criteria for autism miss those with uneven profiles of difficulty and those with relatively low levels of restricted and repetitive behaviours and interests.

Inconsistent language lateralisation - Testing the dissociable language laterality hypothesis using behaviour and lateralised cerebral blood flow.

BACKGROUND: Most people have strong left-brain lateralisation for language, with a minority showing right- or bilateral language representation. On some receptive language tasks, however, lateralisation appears to be reduced or absent. This contrasting pattern raises the question of whether and how language laterality may fractionate within individuals. Building on our prior work, we postulated (a) that there can be dissociations in lateralisation of different components of language, and (b) these would be more common in left-handers. A subsidiary hypothesis was that laterality indices will cluster according to two underlying factors corresponding to whether they involve generation of words or sentences, versus receptive language. METHODS: We tested these predictions in two stages: At Step 1 an online laterality battery (Dichotic listening, Rhyme Decision and Word Comprehension) was given to 621 individuals (56% left-handers); At Step 2, functional transcranial Doppler ultrasound (fTCD) was used with 230 of these individuals (51% left-handers). 108 left-handers and 101 right-handers gave useable data on a battery of three language generation and three receptive language tasks. RESULTS: Neither the online nor fTCD measures supported the notion of a single language laterality factor. In general, for both online and fTCD measures, tests of language generation were left-lateralised. In contrast, the receptive tasks were at best weakly left-lateralised or, in the case of Word Comprehension, slightly right-lateralised. The online measures were only weakly correlated, if at all, with fTCD measures. Most of the fTCD measures had split-half reliabilities of at least .7, and showed a distinctive pattern of intercorrelation, supporting a modified two-factor model in which Phonological Decision (generation) and Sentence Decision (reception) loaded on both factors. The same factor structure fitted data from left- and right-handers, but mean scores on the two factors were lower (less left-lateralised) in left-handers. CONCLUSIONS: There are at least two factors influencing language lateralization in individuals, but they do not correspond neatly to language generation and comprehension. Future fMRI studies could help clarify how far they reflect activity in specific brain regions.

Stage 2 registered report: investigating a preference for certainty in conversation among autistic adults.

Social communication difficulties are a diagnostic feature in autism. These difficulties are sometimes attributed, at least in part, to impaired ability in making inferences about what other people mean. In this registered report, we tested a competing hypothesis that the communication profile of adults on the autism spectrum can be more strongly characterised by reduced confidence in making inferences in the face of uncertain information. We tested this hypothesis by comparing the performance of 102 autistic and 109 non-autistic adults on a test of implied meaning, using a test of grammaticality judgements as a control task. We hypothesised that autistic adults would report substantially lower confidence, allowing for differences in accuracy, than non-autistic adults on the test of implied meaning compared to the grammaticality test. However, our results did not suggest this. Instead, we found that accuracy and confidence were both reduced to a similar extent on the test of implied meaning in the autistic group compared to the control group, although these were only subtle differences. This pattern of results was specific to inference-making, as the autistic and non-autistic groups did not differ on the grammar test. This supports the idea that specific differences in pragmatic language processing can exist in autism in the absence of core language problems. Importantly, this pattern of results (differences on the test of implied meaning and no differences on the grammar test) was reversed in a group with self-reported reading difficulties, indicating that the differences in inference-making were specific to the autistic group. Lastly, we found relationships between Intolerance of Uncertainty, performance on the test of implied meaning, and self-reported social communication challenges. This supports the idea that discomfort with uncertainty plays a role in the pragmatic language and communication challenges in autism.

Correction: A survey of biomedical journals to detect editorial bias and nepotistic behavior.

[This corrects the article DOI: 10.1371/journal.pbio.3001133.].

A novel online assessment of pragmatic and core language skills: An attempt to tease apart language domains in children.

It remains unclear whether pragmatic language skills and core language skills (grammar and vocabulary) are distinct language domains. The present work aimed to tease apart these domains using a novel online assessment battery administered to almost 400 children aged 7 to 13 years. Confirmatory factor analysis indicated that pragmatic and core language domains could be measured separately, but that both domains were highly related (r = .79). However, zero-order correlations between pragmatic tests were quite small, indicating that task-specific skills played an important role in performance, and follow-up exploratory factor analysis suggested that pragmatics might be best understood as a family of skills rather than a domain. This means that these different pragmatic skills may have different cognitive underpinnings and also need to be assessed separately. However, our overall results supported the idea that pragmatic and core aspects of language are closely related during development, with one area scaffolding development in the other.

A survey of biomedical journals to detect editorial bias and nepotistic behavior.

Alongside the growing concerns regarding predatory journal growth, other questionable editorial practices have gained visibility recently. Among them, we explored the usefulness of the Percentage of Papers by the Most Prolific author (PPMP) and the Gini index (level of inequality in the distribution of authorship among authors) as tools to identify journals that may show favoritism in accepting articles by specific authors. We examined whether the PPMP, complemented by the Gini index, could be useful for identifying cases of potential editorial bias, using all articles in a sample of 5,468 biomedical journals indexed in the National Library of Medicine. For articles published between 2015 and 2019, the median PPMP was 2.9%, and 5% of journal exhibited a PPMP of 10.6% or more. Among the journals with the highest PPMP or Gini index values, where a few authors were responsible for a disproportionate number of publications, a random sample was manually examined, revealing that the most prolific author was part of the editorial board in 60 cases (61%). The papers by the most prolific authors were more likely to be accepted for publication within 3 weeks of their submission. Results of analysis on a subset of articles, excluding nonresearch articles, were consistent with those of the principal analysis. In most journals, publications are distributed across a large number of authors. Our results reveal a subset of journals where a few authors, often members of the editorial board, were responsible for a disproportionate number of publications. To enhance trust in their practices, journals need to be transparent about their editorial and peer review practices.

Assessing the reliability of an online behavioural laterality battery: A pre-registered study.

Studies of cerebral lateralization often involve participants completing a series of perceptual tasks under laboratory conditions. This has constrained the number of participants recruited in such studies. Online testing can allow for much larger sample sizes but limits the amount of experimental control that is feasible. Here we considered whether online testing could give valid and reliable results on four tasks: a rhyme decision visual half-field task, a dichotic listening task, a chimeric faces task, and a finger tapping task. We recruited 392 participants, oversampling left-handers, who completed the battery twice. Three of the tasks showed evidence of both validity and reliability, insofar as they showed hemispheric advantages in the expected direction and test-retest reliability of at least r = .75. The reliability of the rhyme decision task was less satisfactory (r = .62). We also confirmed a prediction that extreme left-handers were more likely to depart from typical lateralization. Lateralization across the two language tasks (dichotic listening and rhyme judgement) was weakly correlated, but unrelated to lateralization on the chimeric faces task. We conclude that three of the tasks, dichotic listening, chimeric faces and finger tapping, show considerable promise for online evaluation of cerebral lateralization.

Using multiple outcomes in intervention studies: improving power while controlling type I errors.

Background The CONSORT guidelines for clinical trials recommend use of a single primary outcome, to guard against the raised risk of false positive findings when multiple measures are considered. It is, however, possible to include a suite of multiple outcomes in an intervention study, while controlling the familywise error rate, if the criterion for rejecting the null hypothesis specifies that N or more of the outcomes reach an agreed level of statistical significance, where N depends on the total number of outcome measures included in the study, and the correlation between them. Methods Simulations were run, using a conventional null-hypothesis significance testing approach with alpha set at .05, to explore the case when between 2 and 12 outcome measures are included to compare two groups, with average correlation between measures ranging from zero to .8, and true effect size ranging from 0 to .7. In step 1, a table is created giving the minimum N significant outcomes (MinNSig) that is required for a given set of outcome measures to control the familywise error rate at 5%. In step 2, data are simulated using MinNSig values for each set of correlated outcomes and the resulting proportion of significant results is computed for different sample sizes,correlations, and effect sizes. Results The Adjust NVar approach can achieve a more efficient trade-off between power and type I error rate than use of a single outcome when there are three or more moderately intercorrelated outcome variables. Conclusions Where it is feasible to have a suite of moderately correlated outcome measures, then this might be a more efficient approach than reliance on a single primary outcome measure in an intervention study. In effect, it builds in an internal replication to the study. This approach can also be used to evaluate published intervention studies.

Functional organisation for verb generation in children with developmental language disorder.

Developmental language disorder (DLD) is characterised by difficulties in learning one's native language for no apparent reason. These language difficulties occur in 7% of children and are known to limit future academic and social achievement. Our understanding of the brain abnormalities associated with DLD is limited. Here, we used a simple four-minute verb generation task (children saw a picture of an object and were instructed to say an action that goes with that object) to test children between the ages of 10-15 years (DLD N = 50, typically developing N = 67). We also tested 26 children with poor language ability who did not meet our criteria for DLD. Contrary to our registered predictions, we found that children with DLD did not have (i) reduced activity in language relevant regions such as the left inferior frontal cortex; (ii) dysfunctional striatal activity during overt production; or (iii) a reduction in left-lateralised activity in frontal cortex. Indeed, performance of this simple language task evoked activity in children with DLD in the same regions and to a similar level as in typically developing children. Consistent with previous reports, we found sub-threshold group differences in the left inferior frontal gyrus and caudate nuclei, but only when analysis was limited to a subsample of the DLD group (N = 14) who had the poorest performance on the task. Additionally, we used a two-factor model to capture variation in all children studied (N = 143) on a range of neuropsychological tests and found that these language and verbal memory factors correlated with activity in different brain regions. Our findings indicate a lack of support for some neurological models of atypical language learning, such as the procedural deficit hypothesis or the atypical lateralization hypothesis, at least when using simple language tasks that children can perform. These results also emphasise the importance of controlling for and monitoring task performance.

"Second guessing yourself all the time about what they really mean ": Cognitive differences between autistic and non-autistic adults in understanding implied meaning.

This study investigated cognitive differences between autistic and non-autistic people in understanding implied meaning in conversation using a novel computerized test, the Implicature Comprehension Test. Controlling for core language ability, autistic participants (N = 66) were over twice as likely to endorse a non-normative interpretation of an implied meaning and over five times as likely to select "do not know" when asked about the presence of an implied meaning, compared to non-autistic participants (N = 118). A further experiment suggested that the selection of "do not know" reflected a cognitive preference for certainty and explicit communication, and that the normative inference could often be made when the test format was more constrained. Our research supports the hypothesis that autistic individuals can find it challenging to process language in its pragmatic context, and that cognitive preferences play a role in this. LAY SUMMARY: We investigated differences between autistic and non-autistic people in understanding implied meanings in conversation. We found that autistic people were more likely to select a different interpretation of implied meanings compared to other people, and also much more likely to avoid processing implied meanings when the task allowed this. Our research supports the view that autistic people can find it challenging to process indirect meanings, and that they tend to prefer explicit forms of communication.

Profile of language abilities in a sample of adults with developmental disorders.

This study investigated the profile of language abilities in a sample of high-achieving English speaking adults with developmental disorders. Ninety-seven adult participants were recruited: 49 with a dyslexia diagnosis (dyslexic group), 16 with a diagnosis of a different developmental disorder including dyspraxia, autism and SpLD (non-dyslexic developmental disorder group) and 32 with no diagnosis (non-disordered group). Dyslexic and non-dyslexic developmental disorder groups demonstrated similar impairments across measures of word reading, working memory, processing speed and oral language. Dyslexic participants showed the usual pattern of impaired phonological skills but spared non-verbal intelligence and vocabulary. There were also some suggestions of impaired structural oral language skills in this group. A data-driven clustering analysis found that diagnosis was not a reliable predictor of similarity between cases, with diagnostic categories split between data-driven clusters. Overall, the findings indicate that high-achieving adults with developmental disorders do demonstrate impairments that are likely to affect success in higher education, but that support needs should be assessed on a case-by-case basis, rather than according to diagnostic label.

Registered report: investigating a preference for certainty in conversation among autistic adults compared to dyslexic adults and the general population.

Social communication difficulties are a diagnostic feature in autism. These difficulties are sometimes attributed, at least in part, to impaired ability in making inferences about what other people mean. In this registered report, we test a competing hypothesis that the communication profile of adults on the autism spectrum can be more strongly characterised by reduced confidence in making inferences in the face of uncertain information. We will test this hypothesis by comparing the performance of 100 autistic and 100 non-autistic adults on a test of implied meaning, using a test of grammaticality judgements as a control task. We hypothesise that autistic adults will report substantially lower confidence, allowing for differences in accuracy, than non-autistic adults on the test of implied meaning compared to the grammaticality test. In addition, we hypothesise that reduced confidence in drawing inferences will relate to the cognitive trait Intolerance of Uncertainty and self-reported social communication challenges. Finally, we will conduct exploratory analysis to assess the specificity of the communication profile of the autistic adults by comparing their performance to that of dyslexic adults, who might also be expected to experience challenges with language and communication.

Copy number variation burden does not predict severity of neurodevelopmental phenotype in children with a sex chromosome trisomy.

Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)-stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss-of-function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within-group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems.