Publications

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

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

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

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

This study investigates the influence of both phonotactic and acoustic cues on the segmentation of spoken English. Listeners detected embedded English words in nonsense sequences (word spotting). Words aligned with phonotactic boundaries were easier to detect than words without such alignment. Acoustic cues to boundaries could also have signaled word boundaries, especially when word onsets lacked phonotactic alignment. However, only one of several durational boundary cues showed a marginally significant correlation with response times (RTs). The results suggest that word segmentation in English is influenced primarily by phonotactic constraints and only secondarily by acoustic aspects of the speech signal.

Abstract

Previous research has shown that listeners make use of their knowledge of phonotactic constraints to segment speech into individual words. The present study investigates the influence of phonotactics when segmenting a non-native language. German and English listeners detected embedded English words in nonsense sequences. German listeners also had knowledge of English, but English listeners had no knowledge of German. Word onsets were either aligned with a syllable boundary or not, according to the phonotactics of the two languages. Words aligned with either German or English phonotactic boundaries were easier for German listeners to detect than words without such alignment. Responses of English listeners were influenced primarily by English phonotactic alignment. The results suggest that both native and non-native phonotactic constraints influence lexical segmentation of a non-native, but familiar, language.

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

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

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

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

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

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.