Publications

Abstract

Readers and listeners actively predict upcoming words during language processing. These predictions might serve to support the unification of incoming words into sentence context and thus rely on interactions between areas in the language network. In the current magnetoencephalography study, participants read sentences that varied in contextual constraints so that the predictability of the sentence-final words was either high or low. Before the sentence-final words, we observed stronger alpha power suppression for the highly compared with low constraining sentences in the left inferior frontal cortex, left posterior temporal region, and visual word form area. Importantly, the temporal and visual word form area alpha power correlated negatively with left frontal gamma power for the highly constraining sentences. We suggest that the correlation between alpha power decrease in temporal language areas and left prefrontal gamma power reflects the initiation of an anticipatory unification process in the language network.

Abstract

Using magnetoencephalography, the current study examined gamma activity associated with language prediction. Participants read high- and low-constraining sentences in which the final word of the sentence was either expected or unexpected. Although no consistent gamma power difference induced by the sentence-final words was found between the expected and unexpected conditions, the correlation of gamma power during the prediction and activation intervals of the sentence-final words was larger when the presented words matched with the prediction compared with when the prediction was violated or when no prediction was available. This suggests that gamma magnitude relates to the match between predicted and perceived words. Moreover, the expected words induced activity with a slower gamma frequency compared with that induced by unexpected words. Overall, the current study establishes that prediction is related to gamma power correlations and a slowing of the gamma frequency.

Abstract

The blocked cyclic naming paradigm has been increasingly employed to investigate the mechanisms underlying spoken word production. Semantic homogeneity typically elicits longer naming latencies than heterogeneity; however, it is debated whether competitive lexical selection or incremental learning underlies this effect. The current study manipulated both semantic and phonological homogeneity and used behavioural and electrophysiological measurements to provide evidence that can distinguish between the two accounts. Results show that naming latencies are longer in semantically homogeneous blocks, but shorter in phonologically homogeneous blocks, relative to heterogeneity. The semantic factor significantly modulates electrophysiological waveforms from 200 ms and the phonological factor from 350 ms after picture presentation. A positive component was demonstrated in both manipulations, possibly reflecting a task-related top-down bias in performing blocked cyclic naming. These results provide novel insights into the neural correlates of blocked cyclic naming and further contribute to the understanding of spoken word production.

Abstract

Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome-sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1-2% of the human genome. With the advent of whole-genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and non-coding) to fill in the missing heritability of complex disorders. These new technologies bring new challenges, as the number of non-coding variants identified per individual can be overwhelming, making it prudent to focus on non-coding regions of known function, for which the effects of variation can be predicted and directly tested to assess pathogenicity. The 3’UTRome is a region of the non-coding genome that perfectly fulfils these criteria and is of high interest when searching for pathogenic variation related to complex neurodevelopmental disorders. Herein, we review the regulatory roles of the 3’UTRome as binding sites for microRNAs, RNA binding proteins or during alternative polyadenylation. We detail existing evidence that these regions contribute to neurodevelopmental disorders and outline strategies for identification and validation of novel putatively pathogenic variation in these regions. This evidence suggests that studying the 3’UTRome will lead to the identification of new risk factors, new candidate disease genes and a better understanding of the molecular mechanisms contributing to NDDs.

Abstract

Distributional vowel training for adults has been reported as “effective” for Spanish and Bulgarian learners of Dutch vowels, in studies using a behavioural task. A recent study did not yield a similar clear learning effect for Dutch learners of the English vowel contrast /æ/~/ε/, as measured with event-related potentials (ERPs). The present study aimed to examine the possibility that the latter result was related to the method. As in the ERP study, we tested whether distributional training improved Dutch adult learners’ perception of English /æ/~/ε/. However, we measured behaviour instead of ERPs, in a design identical to that used in the previous studies with Spanish learners. The results do not support an effect of distributional training and thus “replicate” the ERP study. We conclude that it remains unclear whether distributional vowel training is effective for Dutch adults.

Abstract

Words which are expected to contain the same surface string of segments may, under identical prosodic circumstances, sometimes be realized with slight differences in duration. Some researchers have attributed such effects to differences in the words’ underlying forms (incomplete neutralization), while others have suggested orthographic influence and extremely careful speech as the cause. In this paper, we demonstrate such sub-phonemic durational differences in Dutch, a language which some past research has found not to have such effects. Past literature has also shown that listeners can often make use of incomplete neutralization to distinguish apparent homophones. We extend perceptual investigations of this topic, and show that listeners can perceive even durational differences which are not consistently observed in production. We further show that a difference which is primarily orthographic rather than underlying can also create such durational differences. We conclude that a wide variety of factors, in addition to underlying form, can induce speakers to produce slight durational differences which listeners can also use in perception.

Abstract

Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

Abstract

Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood.
Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Raine) Study. Genome-wide significant loci were examined in a further 3918 individuals (48 530 measurements) from Northern Finland. Linear mixed effects models with smoothing splines were used in each cohort for longitudinal modelling of BMI.
Results: A novel SNP, downstream from the FAM120AOS gene on chromosome 9, was detected in the meta-analysis of ALSPAC and Raine. This association was driven by a difference in BMI at 8 years (T allele of rs944990 increased BMI; PSNP = 1.52 × 10−8), with a modest association with change in BMI over time (PWald(Change) = 0.006). Three known adult BMI-associated loci (FTO, MC4R and ADCY3) and one childhood obesity locus (OLFM4) reached genome-wide significance (PWald < 1.13 × 10−8) with BMI at 8 years and/or change over time.
Conclusions: This GWAS of BMI trajectories over childhood identified a novel locus that warrants further investigation. We also observed genome-wide significance with previously established obesity loci, making the novel observation that these loci affected both the level and the rate of change in BMI. We have demonstrated that the use of repeated measures data can increase power to allow detection of genetic loci with smaller sample sizes.

Abstract

Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993–1996 and 2002–2005 and from UK in 1991–1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10−14 for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10−6 >} P {> 5 × 10−8). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.

Abstract

This article presents electrophysiological data on on-line syntactic processing during auditory sentence comprehension in patients with Broca's aphasia. Event-related brain potentials (ERPs) were recorded from the scalp while subjects listened to sentences that were either syntactically correct or contained violations of subject-verb agreement. Three groups of subjects were tested: Broca patients (n = 10), nonaphasic patients with a right-hemisphere (RH) lesion (n = 5), and healthy agedmatched controls (n = 12). The healthy, control subjects showed a P600/SPS effect as response to the agreement violations. The nonaphasic patients with an RH lesion showed essentially the same pattern. The overall group of Broca patients did not show this sensitivity. However, the sensitivity was modulated by the severity of the syntactic comprehension impairment. The largest deviation from the standard P600/SPS effect was found in the patients with the relatively more severe syntactic comprehension impairment. In addition, ERPs to tones in a classical tone oddball paradigm were also recorded. Similar to the normal control subjects and RH patients, the group of Broca patients showed a P300 effect in the tone oddball condition. This indicates that aphasia in itself does not lead to a general reduction in all cognitive ERP effects. It was concluded that deviations from the standard P600/SPS effect in the Broca patients reflected difficulties with on-line maintaining of number information across clausal boundaries for establishing subject-verb agreement.

Abstract

The establishment of a reliable model for the study of Purkinje cells in vitro is of particular importance, given their central role in cerebellar function and pathology. Recent advances in induced pluripotent stem cell (iPSC) technology offer the opportunity to generate multiple neuronal subtypes for study in vitro. However, to date, only a handful of studies have generated Purkinje cells from human pluripotent stem cells, with most of these protocols proving challenging to reproduce. Here, we describe a simplified method for the reproducible generation of Purkinje cells from human iPSCs. After 21 days of treatment with factors selected to mimic the self-inductive properties of the isthmic organiser—insulin, fibroblast growth factor 2 (FGF2), and the transforming growth factor β (TGFβ)-receptor blocker SB431542—hiPSCs could be induced to form En1-positive cerebellar progenitors at efficiencies of up to 90%. By day 35 of differentiation, subpopulations of cells representative of the two cerebellar germinal zones, the rhombic lip (Atoh1-positive) and ventricular zone (Ptf1a-positive), could be identified, with the latter giving rise to cells positive for Purkinje cell progenitor-specific markers, including Lhx5, Kirrel2, Olig2 and Skor2. Further maturation was observed following dissociation and co-culture of these cerebellar progenitors with mouse cerebellar cells, with 10% of human cells staining positive for the Purkinje cell marker calbindin by day 70 of differentiation. This protocol, which incorporates modifications designed to enhance cell survival and maturation and improve the ease of handling, should serve to make existing models more accessible, in order to enable future advances in the field.

Abstract

Induced pluripotent stem cell (iPSC) technology has emerged as an important tool in understanding, and potentially reversing, disease pathology. This is particularly true in the case of neurodegenerative diseases, in which the affected cell types are not readily accessible for study. Since the first descriptions of iPSC-based disease modelling, considerable advances have been made in understanding the aetiology and progression of a diverse array of neurodegenerative conditions, including Parkinson's disease and Alzheimer's disease. To date, however, relatively few studies have succeeded in using iPSCs to model the neurodegeneration observed in cerebellar ataxia. Given the distinct neurodevelopmental phenotypes associated with certain types of ataxia, iPSC-based models are likely to provide significant insights, not only into disease progression, but also to the development of early-intervention therapies. In this review, we describe the existing iPSC-based disease models of this heterogeneous group of conditions and explore the challenges associated with generating cerebellar neurons from iPSCs, which have thus far hindered the expansion of this research.

Abstract

This study investigated the perception of American English phonemes by native listeners. Listeners identified either the consonant or the vowel in all possible English CV and VC syllables. The syllables were embedded in multispeaker babble at three signal-to-noise ratios (0 dB, 8 dB, and 16 dB). Effects of syllable position, signal-to-noise ratio, and articulatory features on vowel and consonant identification are discussed. The results constitute the largest source of data that is currently available on phoneme confusion patterns of American English phonemes by native listeners.

Abstract

This study investigated the perception of American English phonemes by native listeners. Listeners identified either the consonant or the vowel in all possible English CV and VC syllables. The syllables were embedded in multispeaker babble at three signalto-noise ratios (0 dB, 8 dB, and 16 dB). Effects of syllable position, signal-to-noise ratio, and articulatory features on vowel and consonant identification are discussed. The results constitute the largest source of data that is currently available on phoneme confusion patterns of American English phonemes by native listeners.

Abstract

Four eye-tracking experiments examined lexical competition in non-native spoken-word recognition. Dutch listeners hearing English fixated longer on distractor pictures with names containing vowels that Dutch listeners are likely to confuse with vowels in a target picture name (pencil, given target panda) than on less confusable distractors (beetle, given target bottle). English listeners showed no such viewing time difference. The confusability was asymmetric: given pencil as target, panda did not distract more than distinct competitors. Distractors with Dutch names phonologically related to English target names (deksel, ‘lid,’ given target desk) also received longer fixations than distractors with phonologically unrelated names. Again, English listeners showed no differential effect. With the materials translated into Dutch, Dutch listeners showed no activation of the English words (desk, given target deksel). The results motivate two conclusions: native phonemic categories capture second-language input even when stored representations maintain a second-language distinction; and lexical competition is greater for non-native than for native listeners.

Abstract

The extreme case of perceptual similarity is indiscriminability, as when two second‐language phonemes map to a single native category. An example is the English had‐head vowel contrast for Dutch listeners; Dutch has just one such central vowel, transcribed [E]. We examine whether the failure to discriminate in phonetic categorization implies indiscriminability in other—e.g., lexical—processing. Eyetracking experiments show that Dutch‐native listeners instructed in English to ‘‘click on the panda’’ look (significantly more than native listeners) at a pictured pencil, suggesting that pan‐ activates their lexical representation of pencil. The reverse, however, is not the case: ‘‘click on the pencil’’ does not induce looks to a panda, suggesting that pen‐ does not activate panda in the lexicon. Thus prelexically undiscriminated second‐language distinctions can nevertheless be maintained in stored lexical representations. The problem of mapping a resulting unitary input to two distinct categories in lexical representations is solved by allowing input to activate only one second‐language category. For Dutch listeners to English, this is English [E], as a result of which no vowels in the signal ever map to words containing [ae]. We suggest that the choice of category is here motivated by a more abstract, phonemic, metric of similarity.

Abstract

Two eye-tracking experiments examined linguistic gender effects in non-native spoken-word recognition. French participants, who knew German well, followed spoken instructions in German to click on pictures on a computer screen (e.g., Wo befindet sich die Perle, “where is the pearl”) while their eye movements were monitored. The name of the target picture was preceded by a gender-marked article in the instructions. When a target and a competitor picture (with phonologically similar names) were of the same gender in both German and French, French participants fixated competitor pictures more than unrelated pictures. However, when target and competitor were of the same gender in German but of different gender in French, early fixations to the competitor picture were reduced. Competitor activation in the non-native language was seemingly constrained by native gender information. German listeners showed no such viewing time difference. The results speak against a form-based account of the linguistic gender effect. They rather support the notion that the effect originates from the grammatical level of language processing.

Abstract

In this paper, we present empirical data from a corpus study on the linear order of subjects and objects in German main clauses. The aim was to establish the validity of three well-known ordering constraints: given complements tend to occur before new complements, definite before indefinite, and pronoun before full noun phrase complements. Frequencies of occurrences were derived for subject-first and object-first sentences from the German Negra corpus. While all three constraints held on subject-first sentences, results for object-first sentences varied. Our findings suggest an influence of grammatical functions on the ordering of verb complements.

Abstract

Reports of an advantage of bilingualism on brain structure in young adult participants
are inconsistent. Abutalebi et al. (2012) reported more efficient monitoring of conflict during the
Flanker task in young bilinguals compared to young monolingual speakers. The present study
compared young adult (mean age = 24) Cantonese-English bilinguals in Hong Kong and young
adult monolingual speakers. We expected (a) differences in metabolites in neural tissue to result
from bilingual experience, as measured by 1H-MRS at 3T, (b) correlations between metabolic
levels and Flanker conflict and interference effects (c) different associations in bilingual and
monolingual speakers. We found evidence of metabolic differences in the ACC due to bilingualism,
specifically in metabolites Cho, Cr, Glx and NAA. However, we found no significant correlations
between metabolic levels and conflict and interference effects and no significant evidence of
differential relationships between bilingual and monolingual speakers. Furthermore, we found no
evidence of significant differences in the mean size of conflict and interference effects between
groups i.e. no bilingual advantage. Lower levels of Cho, Cr, Glx and NAA in bilingual adults
compared to monolingual adults suggest that the brains of bilinguals develop greater adaptive
control during conflict monitoring because of their extensive bilingual experience.

Abstract

Three experiments were designed to examine the effect on picture naming of the prior production of a word related in phonological form. In Experiment 1, the latency to produce Dutch words in response to pictures (e.g., hoed , hat) was longer following the production of a form-related word (e.g., hond , dog) in response to a definition on a preceding trial, than when the preceding definition elicited an unrelated word (e.g., kerk , church). Experiment 2 demonstrated that the inhibitory effect disappears when one unrelated word is produced intervening prime and target productions (e.g., hond-kerk-hoed ). The size of the inhibitory effect was not significantly affected by the frequency of the prime words or the target picture names. In Experiment 3, facilitation was observed for word pairs that shared offset segments (e.g., kurk-jurk , cork-dress), whereas inhibition was observed for shared onset segments (e.g., bloed-bloem , blood-flower). However, no priming was observed for prime and target words with shared phonemes but no mismatching segments (e.g., oom-boom , uncle-tree; hex-hexs , fence-witch). These findings are consistent with a process of phoneme competition during phonological encoding.

Abstract

In this paper, we report an experiment on the naming of household containers in Dutch and Icelandic carried out as part of the Evolution of Semantic Systems project (EoSS; Majid et al., 2011). This naming experiment allows us to support and elaborate on a hypothesis by Malt et al. (2003) that productive morphology in the naming domain can have an influence on boundary placement within the extensional space. Specifically, we demonstrate that the Dutch diminutive -(t)je favours a cut between small items versus others, whereas Icelandic, which does not use the diminutive in this domain, favours a cut between large items and others. This is not a typological effect, as Dutch and Icelandic are both Germanic languages and both have diminutive morphology available in principle. We find no evidence that the diminutive produces a proliferation of terms and/or fine-grained nesting within the extensional domain. Rather, the Dutch diminutive favours a more even distribution of terms across the space whereas Icelandic favours broad inclusive terms with a number of narrower specialist terms. Further, the extensional space defined by the diminutive is not associated with its own clear prototypical exemplar. Using evidence from compounding and modification, we also consider which semantic features are prominent in differentiating categories within the domain. By far the most prominent in both languages is the inferred contents of the container. Other than contents, however, the languages differ in the range and prominence of features such as intended usage or material of composition. Our results demonstrate that in order to understand the processes that produce semantic divisions of basic object classes, we should consider fine-grained analyses of closely related languages alongside analyses of typologically different languages.

Abstract

Background

The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache.
Methods

Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis.
Results

None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways.
Conclusion

In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease

Abstract

Researchers have suggested that the vocabularies of languages are oriented towards the communicative needs of language users. Here, we provide evidence demonstrating that the higher frequency of visual words in a large variety of English corpora is reflected in greater lexical differentiation—a greater number of unique words—for the visual domain in the English lexicon. In comparison, sensory modalities that are less frequently talked about, particularly taste and smell, show less lexical differentiation. In addition, we show that even though sensory language can be expected to change across historical time and between contexts of use (e.g., spoken language versus fiction), the pattern of visual dominance is a stable property of the English language. Thus, we show that across the board, precisely those semantic domains that are more frequently talked about are also more lexically differentiated, for perceptual experiences. This correlation between type and token frequencies suggests that the sensory lexicon of English is geared towards communicative efficiency.

Abstract

Impaired emotion regulation may underlie exaggerated emotional reactivity in patients with obsessive compulsive disorder (OCD), yet instructed emotion regulation has never been studied in the disorder. METHOD: This study aimed to assess the neural correlates of emotion processing and regulation in 43 medication-free OCD patients and 38 matched healthy controls, and additionally test if these can be modulated by stimulatory (patients) and inhibitory (controls) repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (dlPFC). Participants performed an emotion regulation task during functional magnetic resonance imaging before and after a single session of randomly assigned real or sham rTMS. Effect of group and rTMS were assessed on self-reported distress ratings and brain activity in frontal-limbic regions of interest. RESULTS: Patients had higher distress ratings than controls during emotion provocation, but similar rates of distress reduction after voluntary emotion regulation. OCD patients compared with controls showed altered amygdala responsiveness during symptom provocation and diminished left dlPFC activity and frontal-amygdala connectivity during emotion regulation. Real v. sham dlPFC stimulation differentially modulated frontal-amygdala connectivity during emotion regulation in OCD patients. CONCLUSIONS: We propose that the increased emotional reactivity in OCD may be due to a deficit in emotion regulation caused by a failure of cognitive control exerted by the dorsal frontal cortex. Modulatory rTMS over the left dlPFC may influence automatic emotion regulation capabilities by influencing frontal-limbic connectivity.

Abstract

In three cross-modal priming experiments we asked whether adaptation to a foreign-accented speaker is automatic, and whether adaptation can be seen after a long delay between initial exposure and test. Dutch listeners were exposed to a Hebrew-accented Dutch speaker with two types of Dutch words: those that contained [ɪ] (globally accented words), and those in which the Dutch [i] was shortened to [ɪ] (specific accent marker words). Experiment 1, which served as a baseline, showed that native Dutch participants showed facilitatory priming for globally accented, but not specific accent, words. In experiment 2, participants performed a 3.5-minute phoneme monitoring task, and were tested on their comprehension of the accented speaker 24 hours later using the same cross-modal priming task as in experiment 1. During the phoneme monitoring task, listeners were asked to detect a consonant that was not strongly accented. In experiment 3, the delay between exposure and test was extended to 1 week. Listeners in experiments 2 and 3 showed facilitatory priming for both globally accented and specific accent marker words. Together, these results show that adaptation to a foreign-accented speaker can be rapid and automatic, and can be observed after a prolonged delay in testing.

Abstract

To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E−8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E−07), TOX (rs7823467, P = 3.47E−07) and LINC00340 (rs12212674, P = 1.49E−06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = −0.59, P = 2.10E−04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.

Abstract

In het onderwijs wordt aangenomen dat hardop en stillezen dezelfde processen zijn. In dit onderzoek wordt gekeken naar het verschil tussen hardop en stillezen wat betreft leessnelheid en tekstbegrip bij 90 kinderen uit groep 4. Ook wordt de invloed van de cognitieve vaardigheden fonologisch bewustzijn, benoemsnelheid en visuele aandachtsspanne op de verschillende leesmodi onderzocht. De participanten lazen stil sneller, maar begrepen de tekst beter hardop. De cognitieve vaardigheden correleerden met hardop en stillezen wat betreft leessnelheid, maar hingen in beide leesmodi niet samen met tekstbegrip. Hoewel hardop en stillezen samenhangen, onderstrepen deze bevindingen dat het verschillende leesmodi zijn.

Abstract

Spinocerebellar ataxia type 14 (SCA14) is a subtype of the autosomal dominant cerebellar ataxias that is characterized by slowly progressive cerebellar dysfunction and neurodegeneration. SCA14 is caused by mutations in the PRKCG gene, encoding protein kinase C gamma (PKCγ). Despite the identification of 40 distinct disease-causing mutations in PRKCG, the pathological mechanisms underlying SCA14 remain poorly understood. Here we report the molecular neuropathology of SCA14 in post-mortem cerebellum and in human patient-derived induced pluripotent stem cells (iPSCs) carrying two distinct SCA14 mutations in the C1 domain of PKCγ, H36R and H101Q. We show that endogenous expression of these mutations results in the cytoplasmic mislocalization and aggregation of PKCγ in both patient iPSCs and cerebellum. PKCγ aggregates were not efficiently targeted for degradation. Moreover, mutant PKCγ was found to be hyper-activated, resulting in increased substrate phosphorylation. Together, our findings demonstrate that a combination of both, loss-of-function and gain-of-function mechanisms are likely to underlie the pathogenesis of SCA14, caused by mutations in the C1 domain of PKCγ. Importantly, SCA14 patient iPSCs were found to accurately recapitulate pathological features observed in post-mortem SCA14 cerebellum, underscoring their potential as relevant disease models and their promise as future drug discovery tools.

Abstract

Diffusion tensor imaging (DTI) and a longitudinal language learning approach were applied to investigate the relationship between the achieved second language (L2) proficiency during L2 learning and the reorganization of structural connectivity between core language areas. Language proficiency tests and DTI scans were obtained from German students before and after they completed an intensive 6-week course of the Dutch language. In the initial learning stage, with increasing L2 proficiency, the hemispheric dominance of the BA6-temporal pathway (mainly along the arcuate fasciculus) shifted from the left to the right hemisphere. With further increased proficiency, however, lateralization dominance was again found in the left BA6-temporal pathway. This result is consistent with reports in the literature that imply a stronger involvement of the right hemisphere in L2-processing especially for less proficient L2-speakers. This is the first time that a L2-proficiency-dependent laterality shift in structural connectivity of language pathways during L2 acquisition has been observed to shift from left to right, and back to left hemisphere dominance with increasing L2-proficiency. We additionally find that changes in fractional anisotropy values after the course are related to the time elapsed between the two scans. The results suggest that structural connectivity in (at least part of) the perisylvian language network may be subject to fast dynamic changes following language learning

Abstract

Electroencephalography (EEG) provides high temporal resolution cognitive information from non-invasive recordings. However, one of the common practices-using a subset of sensors in ERP analysis is hard to provide a holistic and precise dynamic results. Selecting or grouping subsets of sensors may also be subject to selection bias, multiple comparison, and further complicated by individual differences in the group-level analysis. More importantly, changes in neural generators and variations in response magnitude from the same neural sources are difficult to separate, which limit the capacity of testing different aspects of cognitive hypotheses. We introduce EasyEEG, a toolbox that includes several multivariate analysis methods to directly test cognitive hypotheses based on topographic responses that include data from all sensors. These multivariate methods can investigate effects in the dimensions of response magnitude and topographic patterns separately using data in the sensor space, therefore enable assessing neural response dynamics. The concise workflow and the modular design provide user-friendly and programmer-friendly features. Users of all levels can benefit from the open-sourced, free EasyEEG to obtain a straightforward solution for efficient processing of EEG data and a complete pipeline from raw data to final results for publication.

Abstract

This article provides a first overview of some striking grammatical structures in Türk Idotscedilaret Dili (Turkish Sign Language, TID), the sign language used by the Deaf community in Turkey. The data are described with a typological perspective in mind, focusing on aspects of TID grammar that are typologically unusual across sign languages. After giving an overview of the historical, sociolinguistic and educational background of TID and the language community using this sign language, five domains of TID grammar are investigated in detail. These include a movement derivation signalling completive aspect, three types of nonmanual negation — headshake, backward head tilt, and puffed cheeks — and their distribution, cliticization of the negator NOT to a preceding predicate host sign, an honorific whole-entity classifier used to refer to humans, and a question particle, its history and current status in the language. A final evaluation points out the significance of these data for sign language research and looks at perspectives for a deeper understanding of the language and its history.

Abstract

This article reports on results from a broad crosslinguistic study based on data from thirty-five signed languages around the world. The study is the first of its kind, and the typological generalizations presented here cover the domain of interrogative structures as they appear across a wide range of geographically and genetically distinct signed languages. Manual and nonmanual ways of marking basic types of questions in signed languages are investigated. As a result, it becomes clear that the range of crosslinguistic variation is extensive for some subparameters, such as the structure of question-word paradigms, while other parameters, such as the use of nonmanual expressions in questions, show more similarities across signed languages. Finally, it is instructive to compare the findings from signed language typology to relevant data from spoken languages at a more abstract, crossmodality level.

Abstract

This article presents a typology of negative constructions across a substantial number of sign languages from around the globe. After situating the topic within the wider context of linguistic typology, the main negation strategies found across sign languages are described. Nonmanual negation includes the use of head movements and facial expressions for negation and is of great importance in sign languages as well as particularly interesting from a typological point of view. As far as manual signs are concerned, independent negative particles represent the dominant strategy, but there are also instances of irregular negation in most sign languages. Irregular negatives may take the form of suppletion, cliticisation, affixing, or internal modification of a sign. The results of the study lead to interesting generalisations about similarities and differences between negatives in signed and spoken languages.

Abstract

In the word-learning domain, both adults and young children are able to find the correct referent of a word from highly ambiguous contexts that involve many words and objects by computing distributional statistics across the co-occurrences of words and referents at multiple naming moments (Yu & Smith, 2007; Smith & Yu, 2008). However, there is still debate regarding how learners accumulate distributional information to learn object labels in natural learning environments, and what underlying learning mechanism learners are most likely to adopt. Using the Human Simulation Paradigm (Gillette, Gleitman, Gleitman & Lederer, 1999), we found that participants’ learning performance gradually improved and that their ability to remember and carry over partial knowledge from past learning instances facilitated subsequent learning. These results support the statistical learning model that word learning is a continuous process.

Abstract

Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss-of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification.

Abstract

Face-selective regions (FSRs) are among the most widely studied functional regions in the human brain. However, individual variability of the FSRs has not been well quantified. Here we use functional magnetic resonance imaging (fMRI) to localize the FSRs and quantify their spatial and functional variabilities in 202 healthy adults. The occipital face area (OFA), posterior and anterior fusiform face areas (pFFA and aFFA), posterior continuation of the superior temporal sulcus (pcSTS), and posterior and anterior STS (pSTS and aSTS) were delineated for each individual with a semi-automated procedure. A probabilistic atlas was constructed to characterize their interindividual variability, revealing that the FSRs were highly variable in location and extent across subjects. The variability of FSRs was further quantified on both functional (i.e., face selectivity) and spatial (i.e., volume, location of peak activation, and anatomical location) features. Considerable interindividual variability and rightward asymmetry were found in all FSRs on these features. Taken together, our work presents the first effort to characterize comprehensively the variability of FSRs in a large sample of healthy subjects, and invites future work on the origin of the variability and its relation to individual differences in behavioral performance. Moreover, the probabilistic functional atlas will provide an adequate spatial reference for mapping the face network.

Abstract

Although bilingual speakers are very good at selectively using one language rather than another, sometimes language selection errors occur. To investigate how bilinguals monitor their speech errors and control their languages in use, we recorded event-related potentials (ERPs) in unbalanced Dutch-English bilingual speakers in a cued language-switching task. We tested the conflict-based monitoring model of Nozari and colleagues by investigating the error-related negativity (ERN) and comparing the effects of the two switching directions (i.e., to the first language, L1 vs. to the second language, L2). Results show that the speakers made more language selection errors when switching from their L2 to the L1 than vice versa. In the EEG, we observed a robust ERN effect following language selection errors compared to correct responses, reflecting monitoring of speech errors. Most interestingly, the ERN effect was enlarged when the speakers were switching to their L2 (less conflict) compared to switching to the L1 (more conflict). Our findings do not support the conflict-based monitoring model. We discuss an alternative account in terms of error prediction and reinforcement learning.

Abstract

Although bilingual speakers are very good at selectively using one language rather than another, sometimes language selection errors occur. We examined the relative contribution of top-down cognitive control and bottom-up language priming to these errors. Unbalanced Dutch-English bilinguals named pictures and were cued to switch between languages under time pressure. We also manipulated the number of same-language trials before a switch (long vs. short runs). Results show that speakers made more language selection errors when switching from their second language (L2) to the first language (L1) than vice versa. Furthermore, they made more errors when switching to the L1 after a short compared to a long run of L2 trials. In the reverse switching direction (L1 to L2), run length had no effect. These findings are most compatible with an account of language selection errors that assigns a strong role to top-down processes of cognitive control.

Abstract

It is undisputed that presenting a rhythmic stimulus leads to a measurable brain response that follows the rhythmic structure of this stimulus. What is still debated, however, is the question whether this brain response exclusively reflects a regular repetition of evoked responses, or whether it also includes entrained oscillatory activity. Here we systematically present evidence in favor of an involvement of entrained neural oscillations in the processing of rhythmic input while critically pointing out which questions still need to be addressed before this evidence could be considered conclusive. In this context, we also explicitly discuss the potential functional role of such entrained oscillations, suggesting that these stimulus-aligned oscillations reflect, and serve as, predictive processes, an idea often only implicitly assumed in the literature.

Abstract

Neural correlates of lexical stress were studied using the mismatch negativity (MMN) component in event-related potentials. The MMN responses were expected to reveal the encoding of stress information into long-term memory and the contributions of prosodic features such as fundamental frequency (F0) and intensity toward lexical access. In a passive oddball paradigm, neural responses to changes in F0, intensity, and in both features together were recorded for words and pseudowords. The findings showed significant differences not only between words and pseudowords but also between prosodic features. Early processing of prosodic information in words was indexed by an intensity-related MMN and an F0-related P200. These effects were stable at right-anterior and mid-anterior regions. At a later latency, MMN responses were recorded for both words and pseudowords at the mid-anterior and posterior regions. The P200 effect observed for F0 at the early latency for words developed into an MMN response. Intensity elicited smaller MMN for pseudowords than for words. Moreover, a larger brain area was recruited for the processing of words than for the processing of pseudowords. These findings suggest earlier and higher sensitivity to prosodic changes in words than in pseudowords, reflecting a language-related process. The present study, therefore, not only establishes neural correlates of lexical stress but also confirms the presence of long-term memory traces for prosodic information in the brain.

Abstract

This study investigates the morphological and morphosyntactic characteristics of hand configurations in signs, particularly in Nederlandse Gebarentaal (NGT). The literature on sign languages in general acknowledges that hand configurations can function as morphemes, more specifically as classifiers , in a subset of signs: verbs expressing the motion, location, and existence of referents (VELMs). These verbs are considered the output of productive sign formation processes. In contrast, other signs in which similar hand configurations appear ( iconic or motivated signs) have been considered to be lexicalized signs, not involving productive processes. This research report shows that meaningful hand configurations have (at least) two very different functions in the grammar of NGT (and presumably in other sign languages, too). First, they are agreement markers on VELMs, and hence are functional elements. Second, they are roots in motivated signs, and thus lexical elements. The latter signs are analysed as root compounds and are formed from various roots by productive processes. The similarities in surface form and differences in morphosyntactic characteristics observed in comparison of VELMs and root compounds are attributed to their different structures and to the sign language interface between grammar and phonetic form

Abstract

Although in many respects sign languages have a similar structure to that of spoken languages, the different modalities in which both types of languages are expressed cause differences in structure as well. One of the most striking differences between spoken and sign languages is the influence of the interface between grammar and PF on the surface form of utterances. Spoken language words and phrases are in general characterized by sequential strings of sounds, morphemes and words, while in sign languages we find that many phonemes, morphemes, and even words are expressed simultaneously. A linguistic model should be able to account for the structures that occur in both spoken and sign languages. In this paper, I will discuss the morphological/ morphosyntactic structure of signs in Nederlandse Gebarentaal (Sign Language of the Netherlands, henceforth NGT), with special focus on the components ‘place of articulation’ and ‘handshape’. I will focus on their multiple functions in the grammar of NGT and argue that the framework of Distributed Morphology (DM), which accounts for word formation in spoken languages, is also suited to account for the formation of structures in sign languages. First I will introduce the phonological and morphological structure of NGT signs. Then, I will briefly outline the major characteristics of the DM framework. Finally, I will account for signs that have the same surface form but have a different morphological structure by means of that framework.