Publications

Abstract

TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13–1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts. © 2017 The Author(s)

Abstract

Over 25 genes are known to affect the risk of developing Alzheimer disease (AD), the most common neurodegenerative dementia. However, mechanistic insights and improved disease management remains limited, due to difficulties in determining the functional consequences of genetic associations. Transcriptomics is increasingly being used to corroborate or enhance interpretation of genetic discoveries. These approaches, which include second and third generation sequencing, single-cell sequencing, and bioinformatics, reveal allele-specific events connecting AD risk genes to expression profiles, and provide converging evidence of pathophysiological pathways underlying AD. Simultaneously, they highlight brain region- and cell-type-specific expression patterns, and alternative splicing events that affect the straightforward relation between a genetic variant and AD, re-emphasizing the need for an integrated approach of genetics and transcriptomics in understanding AD. © 2018 The Authors

Abstract

Background

The number of words children produce (expressive vocabulary) and understand (receptive vocabulary) changes rapidly during early development, partially due to genetic factors. Here, we performed a meta–genome-wide association study of vocabulary acquisition and investigated polygenic overlap with literacy, cognition, developmental phenotypes, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD).

Methods

We studied 37,913 parent-reported vocabulary size measures (English, Dutch, Danish) for 17,298 children of European descent. Meta-analyses were performed for early-phase expressive (infancy, 15–18 months), late-phase expressive (toddlerhood, 24–38 months), and late-phase receptive (toddlerhood, 24–38 months) vocabulary. Subsequently, we estimated single nucleotide polymorphism–based heritability (SNP-h2) and genetic correlations (rg) and modeled underlying factor structures with multivariate models.

Results

Early-life vocabulary size was modestly heritable (SNP-h2 = 0.08–0.24). Genetic overlap between infant expressive and toddler receptive vocabulary was negligible (rg = 0.07), although each measure was moderately related to toddler expressive vocabulary (rg = 0.69 and rg = 0.67, respectively), suggesting a multifactorial genetic architecture. Both infant and toddler expressive vocabulary were genetically linked to literacy (e.g., spelling: rg = 0.58 and rg = 0.79, respectively), underlining genetic similarity. However, a genetic association of early-life vocabulary with educational attainment and intelligence emerged only during toddlerhood (e.g., receptive vocabulary and intelligence: rg = 0.36). Increased ADHD risk was genetically associated with larger infant expressive vocabulary (rg = 0.23). Multivariate genetic models in the ALSPAC (Avon Longitudinal Study of Parents and Children) cohort confirmed this finding for ADHD symptoms (e.g., at age 13; rg = 0.54) but showed that the association effect reversed for toddler receptive vocabulary (rg = −0.74), highlighting developmental heterogeneity.

Conclusions

The genetic architecture of early-life vocabulary changes during development, shaping polygenic association patterns with later-life ADHD, literacy, and cognition-related traits.

Abstract

This study examines the influence of orthography on the processing of reduced word forms. For this purpose, we compared the impact of phonological variation with the impact of spelling-sound consistency on the processing of words that may be produced with or without the vowel schwa. Participants learnt novel French words in which the vowel schwa was present or absent in the first syllable. In Experiment 1, the words were consistently produced without schwa or produced in a variable manner (i.e., sometimes produced with and sometimes produced without schwa). In Experiment 2, words were always produced in a consistent manner, but an orthographic exposure phase was included in which words that were produced without schwa were either spelled with or without the letter . Results from naming and eye-tracking tasks suggest that both phonological variation and spelling-sound consistency influence the processing of spoken novel words. However, the influence of phonological variation outweighs the effect of spelling-sound consistency. Our findings therefore suggest that the influence of orthography on the processing of reduced word forms is relatively small.

Abstract

Before infants become mature speakers of their native language, they must acquire a robust word-recognition system which allows them to strike the balance between allowing some variation (mood, voice, accent) and recognizing variability that potentially changes meaning (e.g. cat vs hat). The current meta-analysis quantifies how the latter, termed mispronunciation sensitivity, changes over infants’ first three years, testing competing predictions of mainstream language acquisition theories. Our results show that infants were sensitive to mispronunciations, but accepted them as labels for target objects. Interestingly, and in contrast to predictions of mainstream theories, mispronunciation sensitivity was not modulated by infant age, suggesting that a sufficiently flexible understanding of native language phonology is in place at a young age.

Abstract

We meta‐analyzed the effectiveness of incidental second language word learning from spoken input. Our sample contained 105 effect sizes from 32 primary studies employing meaning‐focused word‐learning activities with 1,964 participants with typical cognitive functioning. The random‐effects meta‐analysis yielded a mean effect size of g = 1.05, reflecting generally large vocabulary gains from spoken input in meaning‐focused activities. A meta‐regression with three substantive and two methodological predictors also revealed that adult participants outperformed children in terms of word learning and that interactive learning tasks were more effective than noninteractive ones. Furthermore, learning scores were higher when measured with recognition than with recall tests. Methodologically, the use of a no‐input control group seemed to protect against an overestimation of learning effects, evidenced by smaller effect sizes. Finally, whether a pretest–posttest design was used did not influence effect sizes. All data and the analysis script are publicly available.

Abstract

Noticing the hole (NTH) occurs when speakers want to say something, but realise they do not know the right word(s). Such awareness of lacking knowledge supposedly facilitates the acquisition of the unknown word(s) from later input (Swain, 1993). We tested this claim by experimentally inducing NTH in a second language (L2) for some participants (experimental), but not others (control). Then, in a price comparison game, all participants were exposed to spoken L2 input containing the to-be-learned words. They were unaware of taking part in an L2 study. Post-tests showed that participants who had noticed holes in their vocabulary had indeed learned more words compared to participants who had not. This held both for the experimental group as well as those participants in the control group who later reported to have noticed holes. Thus, when we become aware of vocabulary holes, the first step to improve our vocabulary is already taken.

Abstract

Metaphors occur frequently in literary texts. Deliberate Metaphor Theory (DMT; e.g., Steen, 2017) proposes that metaphors that serve a communicative function as metaphor are radically different from metaphors that do not have this function. We investigated differences in processing between deliberate and non-deliberate metaphors, compared to non-metaphorical words in literary reading. Using the Deliberate Metaphor Identification Procedure (Reijnierse et al., 2018), we identified metaphors in two literary stories. Then, eye-tracking was used to investigate participants’ (N = 72) reading behavior. Deliberate metaphors were read slower than non-deliberate metaphors, and both metaphor types were read slower than non-metaphorical words. Differences were controlled for several psycholinguistic variables. Differences in reading behavior were related to individual differences in reading experience and absorption and appreciation of the story. These results are in line with predictions from DMT and underline the importance of distinguishing between metaphor types in the experimental study of literary reading.

Abstract

The present study investigated the interplay between selective inhibition (the ability to suppress specific competing responses) and nonselective inhibition (the ability to suppress any inappropriate response) during single word production. To this end, we combined two well-established research paradigms: the picture-word interference task and the stop-signal task. Selective inhibition was assessed by instructing participants to name target pictures (e.g., dog) in the presence of semantically related (e.g., cat) or unrelated (e.g., window) distractor words. Nonselective inhibition was tested by occasionally presenting a visual stop-signal, indicating that participants should withhold their verbal response. The stop-signal was presented early (250 ms) aimed at interrupting the lexical selection stage, and late (325 ms) to influence the word-encoding stage of the speech production process. We found longer naming latencies for pictures with semantically related distractors than with unrelated distractors (semantic interference effect). The results further showed that, at both delays, stopping latencies (i.e., stop-signal RTs) were prolonged for naming pictures with semantically related distractors compared to pictures with unrelated distractors. Taken together, our findings suggest that selective and nonselective inhibition, at least partly, share a common inhibitory mechanism during different stages of the speech production process.

Abstract

Research with nonnative speech spans many different linguistic branches and topics. Most studies include one or a few well-known features of a particular accent. However, due to a lack of empirical studies, little is known about how common these features are among nonnative speakers or how uncommon they are among native speakers. Moreover, it remains to be seen whether findings from such studies generalize to lesser-known features. Here, we demonstrate a quantitative approach to study nonnative accent features using Dutch-accented English as an example. By analyzing the phonetic distances between transcriptions of speech samples, this approach can identify the features that best distinguish nonnative from native speech. In addition, we describe a method to test hypotheses about accent features by checking whether the prevalence of the features overall varies between native and nonnative speakers. Furthermore, we include English speakers from the United States and United Kingdom and native Dutch speakers from Belgium and The Netherlands to address the issue of regional accent variability in both the native and target language. We discuss the results concerning three observed features. Overall, the results provide empirical support for some well-known features of Dutch-accented English, but suggest that others may be infrequent among nonnatives or in fact frequent among natives. In addition, the findings reveal potentially new accent features, and factors that may modulate the expression of known features. Our study demonstrates a fruitful approach to study nonnative accent features that has the potential to expand our understanding of the phenomenon of accent.

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

During early lactation, dairy cows have a negative energy balance since their energy demands exceed their energy intake: in this study, we aimed to investigate the association between diet and plasma metabolomics profiles and how these relate to energy unbalance of course in the early-lactation stage. Holstein-Friesian cows were randomly assigned to a glucogenic (n = 15) or lipogenic (n = 15) diet in early lactation. Blood was collected in week 2 and week 4 after calving. Plasma metabolite profiles were detected using liquid chromatography–mass spectrometry (LC-MS), and a total of 39 metabolites were identified. Two plasma metabolomic profiles were available every week for each cow. Metabolite abundance and metabolite ratios were used for the analysis using the XGboost algorithm to discriminate between diet treatment and lactation week. Using metabolite ratios resulted in better discrimination performance compared with the metabolite abundances in assigning cows to a lipogenic diet or a glucogenic diet. The quality of the discrimination of performance of lipogenic diet and glucogenic diet effects improved from 0.606 to 0.753 and from 0.696 to 0.842 in week 2 and week 4 (as measured by area under the curve, AUC), when the metabolite abundance ratios were used instead of abundances. The top discriminating ratios for diet were the ratio of arginine to tyrosine and the ratio of aspartic acid to valine in week 2 and week 4, respectively. For cows fed the lipogenic diet, choline and the ratio of creatinine to tryptophan were top features to discriminate cows in week 2 vs. week 4. For cows fed the glucogenic diet, methionine and the ratio of 4-hydroxyproline to choline were top features to discriminate dietary effects in week 2 or week 4. This study shows the added value of using metabolite abundance ratios to discriminate between lipogenic and glucogenic diet and lactation weeks in early-lactation cows when using metabolomics data. The application of this research will help to accurately regulate the nutrition of lactating dairy cows and promote sustainable agricultural development.

Abstract

Magnetic resonance spectroscopy (MRS) is the primary method that can measure the levels of metabolites in the brain in vivo. To achieve its potential in clinical usage, the reliability of the measurement requires further articulation. Although there are many studies that investigate the reliability of gamma-aminobutyric acid (GABA), comparatively few studies have investigated the reliability of other brain metabolites, such as glutamate (Glu), N-acetyl-aspartate (NAA), creatine (Cr), phosphocreatine (PCr), or myo-inositol (mI), which all play a significant role in brain development and functions. In addition, previous studies which predominately used only two measurements (two data points) failed to provide the details of the time effect (e.g., time-of-day) on MRS measurement within subjects. Therefore, in this study, MRS data located in the anterior cingulate cortex (ACC) were repeatedly recorded across 1 year leading to at least 25 sessions for each subject with the aim of exploring the variability of other metabolites by using the index coefficient of variability (CV); the smaller the CV, the more reliable the measurements. We found that the metabolites of NAA, tNAA, and tCr showed the smallest CVs (between 1.43% and 4.90%), and the metabolites of Glu, Glx, mI, and tCho showed modest CVs (between 4.26% and 7.89%). Furthermore, we found that the concentration reference of the ratio to water results in smaller CVs compared to the ratio to tCr. In addition, we did not find any time-of-day effect on the MRS measurements. Collectively, the results of this study indicate that the MRS measurement is reasonably reliable in quantifying the levels of metabolites.

Abstract

This study investigates the role of morphology during speech planning in Mandarin Chinese. In a long-lag priming experiment, thirty-two Mandarin Chinese native speakers were asked to name target pictures (e.g., “山” /shan1/ "mountain"). The design involved pictures referring to morpheme-related compound words (e.g., “山羊” /shan1yang2/ "goat") sharing a morpheme with the first (e.g., “山” /shan1/ "mountain") or the second position of the targets (e.g., 脑 /nao3/ “brain” with prime电脑 /dian4nao3/ “computer”), as well as unrelated control items. Behavioral and electrophysiological data were collected. Interestingly, the behavioral results went against earlier findings in Indo-European languages, showing that the target picture naming was not facilitated by morphologically related primes. This suggests no morphological priming for individual constituents in producing Mandarin Chinese disyllabic compound words. However, targets in the morpheme-related word condition did elicit a reduced N400 compared with targets in the morpheme-unrelated condition for the first position overlap in the ERP analyses but not for the second, suggesting automatic activation of the first individual constituent in noun compound production. Implications of these findings are discussed.

Abstract

The question whether compound words are stored in our mental lexicon in a decomposed or full-listing way prompted Janssen and colleagues (2008) to investigate the representation of compounds using word and morpheme frequencies manipulations. Our study replicated their study using a new set of stimuli from a spoken corpus and incorporating EEG data for a more detailed investigation. In the current study, despite ERP analyses revealing no word frequency or morpheme frequency effects across conditions, behavioral outcomes indicated that Mandarin compounds are not sensitive to word frequency. Instead, the response times highlighted a morpheme frequency effect in naming Mandarin compounds, which contrasted with the findings of Janssen and colleagues. These findings challenge the full-listing model and instead support the decompositional model.

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

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

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

Humans excel at extracting structurally-determined meaning from speech despite inherent physical variability. This study explores the brain’s ability to predict and understand spoken language robustly. It investigates the relationship between structural and statistical language knowledge in brain dynamics, focusing on phase and amplitude modulation. Using syntactic features from constituent hierarchies and surface statistics from a transformer model as predictors of forward encoding models, we reconstructed cross-frequency neural dynamics from MEG data during audiobook listening. Our findings challenge a strict separation of linguistic structure and statistics in the brain, with both aiding neural signal reconstruction. Syntactic features have a more temporally spread impact, and both word entropy and the number of closing syntactic constituents are linked to the phase-amplitude coupling of neural dynamics, implying a role in temporal prediction and cortical oscillation alignment during speech processing. Our results indicate that structured and statistical information jointly shape neural dynamics during spoken language comprehension and suggest an integration process via a cross-frequency coupling mechanism

Abstract

Rapid advances over the last decade in DNA sequencing and statistical genetics enable us to investigate the genomic makeup of individuals throughout history. In a recent notable study, Begg et al.1 used Ludwig van Beethoven’s hair strands for genome sequencing and explored genetic predispositions for some of his documented medical issues. Given that it was arguably Beethoven’s skills as a musician and composer that made him an iconic figure in Western culture, we here extend the approach and apply it to musicality. We use this as an example to illustrate the broader challenges of individual-level genetic predictions.

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

Iconic words and signs are characterized by a perceived resemblance between aspects of their form and aspects of their meaning. For example, in English, iconic words include peep and crash, which mimic the sounds they denote, and wiggle and zigzag, which mimic motion. As a semiotic property of words and signs, iconicity has been demonstrated to play a role in word learning, language processing, and language evolution. This paper presents the results of a large-scale norming study for more than 14,000 English words conducted with over 1400 American English speakers. We demonstrate the utility of these ratings by replicating a number of existing findings showing that iconicity ratings are related to age of acquisition, sensory modality, semantic neighborhood density, structural markedness, and playfulness. We discuss possible use cases and limitations of the rating dataset, which is made publicly available.

Abstract

For bilinguals, speaking in a second language (L2) compared to the native language (L1) is usually more difficult. In this study we asked whether the difficulty in L2 production reflects increased demands imposed on domain-general or core language mechanisms. We compared the brain response to speech production in L1 and L2 within two functionally-defined networks in the brain: the Multiple Demand (MD) network and the language network. We found that speech production in L2 was linked to a widespread increase of brain activity in the domain-general MD network. The language network did not show a similarly robust differences in processing speech in the two languages, however, we found increased response to L2 production in the language-specific portion of the left inferior frontal gyrus (IFG). To further explore our results, we have looked at domain-general and language-specific response within the brain structures postulated to form a Bilingual Language Control (BLC) network. Within this network, we found a robust increase in response to L2 in the domain-general, but also in some language-specific voxels including in the left IFG. Our findings show that L2 production strongly engages domain-general mechanisms, but only affects language sensitive portions of the left IFG. These results put constraints on the current model of bilingual language control by precisely disentangling the domain-general and language-specific contributions to the difficulty in speech production in L2.

Abstract

When bilingual speakers switch back to speaking in their native language (L1) after having used their second language (L2), they often experience difficulty in retrieving words in their L1. This phenomenon is referred to as the L2 after-effect. We used the L2 after-effect as a lens to explore the neural bases of bilingual language control mechanisms. Our goal was twofold: first, to explore whether bilingual language control draws on domain-general or language-specific mechanisms; second, to investigate the precise mechanism(s) that drive the L2 after-effect. We used a precision fMRI approach based on functional localizers to measure the extent to which the brain activity that reflects the L2 after-effect overlaps with the language network (Fedorenko et al., 2010) and the domain-general multiple demand network (Duncan, 2010), as well as three task-specific networks that tap into interference resolution, lexical retrieval, and articulation. Forty-two Polish–English bilinguals participated in the study. Our results show that the L2 after-effect reflects increased engagement of domain-general but not language-specific resources. Furthermore, contrary to previously proposed interpretations, we did not find evidence that the effect reflects increased difficulty related to lexical access, articulation, and the resolution of lexical interference. We propose that difficulty of speech production in the picture naming paradigm—manifested as the L2 after-effect—reflects interference at a nonlinguistic level of task schemas or a general increase of cognitive control engagement during speech production in L1 after L2.

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

The language network of the human brain has core components in the inferior frontal cortex and superior/middle temporal cortex, with left-hemisphere dominance in most people. Functional specialization and interconnectivity of these neocortical regions is likely to be reflected in their molecular and cellular profiles. Excitatory connections between cortical regions arise and innervate according to layer-specific patterns. Here we generated a new gene expression dataset from human postmortem cortical tissue samples from core language network regions, using spatial transcriptomics to discriminate gene expression across cortical layers. Integration of these data with existing single-cell expression data identified 56 genes that showed differences in laminar expression profiles between frontal and temporal language cortex together with upregulation in layer II/III and/or layer V/VI excitatory neurons. Based on data from large-scale genome-wide screening in the population, DNA variants within these 56 genes showed set-level associations with inter-individual variation in structural connectivity between left-hemisphere frontal and temporal language cortex, and with predisposition to dyslexia. The axon guidance genes SLIT1 and SLIT2 were consistently implicated. These findings identify region-specific patterns of laminar gene expression as a feature of the brain’s language network.

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

Tokenization significantly influences language models (LMs)’ performance. This paper traces the evolution of tokenizers from word-level to subword-level, analyzing how they balance tokens and types to enhance model adaptability while controlling complexity. Despite subword tokenizers like Byte Pair Encoding (BPE) overcoming many word tokenizer limitations, they encounter difficulties in handling non-Latin languages and depend heavily on extensive training data and computational resources to grasp the nuances of multiword expressions (MWEs). This article argues that tokenizers, more than mere technical tools, should drawing inspiration from the cognitive science about human language processing. This study then introduces the “Principle of Least Effort” from cognitive science, that humans naturally seek to reduce cognitive effort, and discusses the benefits of this principle for tokenizer development. Based on this principle, the paper proposes that the Less-is-Better (LiB) model could be a new approach for LLM tokenizer. The LiB model can autonomously learn an integrated vocabulary consisting of subwords, words, and MWEs, which effectively reduces both the numbers of tokens and types. Comparative evaluations show that the LiB tokenizer outperforms existing word and BPE tokenizers, presenting an innovative method for tokenizer development, and hinting at the possibility of future cognitive science-based tokenizers being more efficient.

Abstract

Early word learning involves mapping individual words to their meanings and building organized semantic representations among words. Previous corpus-based studies (e.g., using text from websites, newspapers, child-directed speech corpora) demonstrated that linguistic information such as word co-occurrence alone is sufficient to build semantically organized word knowledge. The present study explored two new research directions to advance understanding of how infants acquire semantically organized word knowledge. First, infants in the real world hear words surrounded by contextual information. Going beyond inferring semantic knowledge merely from language input, we examined the role of extra-linguistic contextual information in learning semantic knowledge. Second, previous research relies on large amounts of linguistic data to demonstrate in-principle learning, which is unrealistic compared with the input children receive. Here, we showed that incorporating extra-linguistic information provides an efficient mechanism through which semantic knowledge can be acquired with a small amount of data infants perceive in everyday learning contexts, such as toy play.

Abstract

There is substantial evidence that infants prefer infant-directed speech (IDS) to adult-directed speech (ADS). The strongest evidence for this claim has come from two large-scale investigations: i) a community-augmented meta-analysis of published behavioral studies and ii) a large-scale multi-lab replication study. In this paper, we aim to improve our understanding of the IDS preference and its boundary conditions by combining and comparing these two data sources across key population and design characteristics of the underlying studies. Our analyses reveal that both the meta-analysis and multi-lab replication show moderate effect sizes (d ≈ 0.35 for each estimate) and that both of these effects persist when relevant study-level moderators are added to the models (i.e., experimental methods, infant ages, and native languages). However, while the overall effect size estimates were similar, the two sources diverged in the effects of key moderators: both infant age and experimental method predicted IDS preference in the multi-lab replication study, but showed no effect in the meta-analysis. These results demonstrate that the IDS preference generalizes across a variety of experimental conditions and sampling characteristics, while simultaneously identifying key differences in the empirical picture offered by each source individually and pinpointing areas where substantial uncertainty remains about the influence of theoretically central moderators on IDS preference. Overall, our results show how meta-analyses and multi-lab replications can be used in tandem to understand the robustness and generalizability of developmental phenomena.

Abstract

This present study identified an optimal model representing the relationship between orthography and phonology in Chinese handwritten production using dynamic causal modeling, and further explored how this model was modulated by word frequency and syllable frequency. Each model contained five volumes of interest in the left hemisphere (angular gyrus [AG], inferior frontal gyrus [IFG], middle frontal gyrus [MFG], superior frontal gyrus [SFG], and supramarginal gyrus [SMG]), with the IFG as the driven input area. Results showed the superiority of a model in which both the MFG and the AG connected with the IFG, supporting the orthography autonomy hypothesis. Word frequency modulated the AG → SFG connection (information flow from the orthographic lexicon to the orthographic buffer), and syllable frequency affected the IFG → MFG connection (information transmission from the semantic system to the phonological lexicon). This study thus provides new insights into the connectivity architecture of neural substrates involved in writing.

Abstract

Electrophysiological brain activity has been shown to synchronize with the quasi-regular repetition of grammatical phrases in connected speech—so-called phrase-rate neural tracking. Current debate centers around whether this phenomenon is best explained in terms of the syntactic properties of phrases or in terms of syntax-external information, such as the sequential repetition of parts of speech. As these two factors were confounded in previous studies, much of the literature is compatible with both accounts. Here, we used electroencephalography (EEG) to determine if and when the brain is sensitive to both types of information. Twenty native speakers of Mandarin Chinese listened to isochronously presented streams of monosyllabic words, which contained either grammatical two-word phrases (e.g., catch fish, sell house) or non-grammatical word combinations (e.g., full lend, bread far). Within the grammatical conditions, we varied two structural factors: the position of the head of each phrase and the type of attachment. Within the non-grammatical conditions, we varied the consistency with which parts of speech were repeated. Tracking was quantified through evoked power and inter-trial phase coherence, both derived from the frequency-domain representation of EEG responses. As expected, neural tracking at the phrase rate was stronger in grammatical sequences than in non-grammatical sequences without syntactic structure. Moreover, it was modulated by both attachment type and head position, revealing the structure-sensitivity of phrase-rate tracking. We additionally found that the brain tracks the repetition of parts of speech in non-grammatical sequences. These data provide an integrative perspective on the current debate about neural tracking effects, revealing that the brain utilizes regularities computed over multiple levels of linguistic representation in guiding rhythmic computation.

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

Statistical learning (SL) is postulated to play an important role in the process of language acquisition as well as in other cognitive functions. It was found to enable learning of various types of statistical patterns across different sensory modalities. However, few studies have distinguished distributional SL (DSL) from sequential and spatial SL, or examined DSL across modalities using comparable tasks. Considering the relevance of such findings to the nature of SL, the current study investigated the modality- and stimulus-specificity of DSL. Using a within-subject design we compared DSL performance in auditory and visual modalities. For each sensory modality, two stimulus types were used: linguistic versus non-linguistic auditory stimuli and temporal versus spatial visual stimuli. In each condition, participants were exposed to stimuli that varied in their length as they were drawn from two categories (short versus long). DSL was assessed using a categorization task and a production task. Results showed that learners’ performance was only correlated for tasks in the same sensory modality. Moreover, participants were better at categorizing the temporal signals in the auditory conditions than in the visual condition, where in turn an advantage of the spatial condition was observed. In the production task participants exaggerated signal length more for linguistic signals than non-linguistic signals. Together, these findings suggest that DSL is modality- and stimulus-sensitive.

Abstract

Prosodic prominence can enhance memory for the prominent words. This mnemonic benefit has been linked to listeners’ allocation of attention and deeper processing, which leads to more robust semantic representations. We investigated whether, in addition to the well-established effect at the semantic level, there was a memory benefit for prominent words at the phonological level. To do so, participants (48 native speakers of Dutch), first performed an accent judgement task, where they had to discriminate accented from unaccented words, and accented from unaccented pseudowords. All stimuli were presented in lists. They then performed an old/new recognition task for the stimuli. Accuracy in the accent judgement task was equally high for words and pseudowords. In the recognition task, performance was, as expected, better for words than pseudowords. More importantly, there was an interaction of accent with word type, with a significant advantage for accented compared to unaccented words, but not for pseudowords. The results confirm the memory benefit for accented compared to unaccented words seen in earlier studies, and they are consistent with the view that prominence primarily affects the semantic encoding of words. There was no evidence for an additional memory benefit arising at the phonological level.

Abstract

Research into the role of brain oscillations in basic perceptual and cognitive functions has suggested that the alpha rhythm reflects functional inhibition while the beta rhythm reflects neural ensemble (re)activation. However, little is known regarding the generalization of these proposed fundamental operations to linguistic processes, such as speech comprehension and production. Here, we recorded magnetoencephalography in participants performing a novel rule-switching paradigm. Specifically, Dutch native speakers had to produce an alternative exemplar from the same category or a feature of a given target word embedded in spoken sentences (e.g., for the word “tuna”, an exemplar from the same category—“seafood”—would be “shrimp”, and a feature would be “pink”). A cue indicated the task rule—exemplar or feature—either before (pre-cue) or after (retro-cue) listening to the sentence. Alpha power during the working memory delay was lower for retro-cue compared with that for pre-cue in the left hemispheric language-related regions. Critically, alpha power negatively correlated with reaction times, suggestive of alpha facilitating task performance by regulating inhibition in regions linked to lexical retrieval. Furthermore, we observed a different spatiotemporal pattern of beta activity for exemplars versus features in the right temporoparietal regions, in line with the proposed role of beta in recruiting neural networks for the encoding of distinct categories. Overall, our study provides evidence for the generalizability of the role of alpha and beta oscillations from perceptual to more “complex, linguistic processes” and offers a novel task to investigate links between rule-switching, working memory, and word production.

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

In Swedish, words are associated with either of two pitch contours known as Accent 1 and Accent 2. Using a psychometric test, we investigated how listeners judge pitch accent violations while interpreting discourse. Forty native speakers of Central Swedish were presented with auditory dialogues, where test words were appropriately or inappropriately accented in a given context, and asked to judge the correctness of sentences containing the test words. Data indicated a statistically significant effect of wrong accent pattern on the correctness judgment. Both Accent 1 and Accent 2 violations interfered with the coherent interpretation of discourse and were judged as incorrect by the listeners. Moreover, there was a statistically significant difference in the perceived correctness between the accent patterns. Accent 2 violations led to a lower correctness score compared to Accent 1 violations, indicating that the listeners were more sensitive to pitch accent violations in Accent 2 words than in Accent 1 words. This result is in line with the notion that Accent 2 is marked and lexically represented in Central Swedish. Taken together, these findings indicate that listeners use both Accent 1 and Accent 2 to arrive at the correct interpretation of the linguistic input, while assigning varying degrees of relevance to them depending on their markedness.