Publications

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 cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

Abstract

We carried out the first study on the relationship between individual language aptitude and structural connectivity of language pathways in the adult brain. We measured four components of language aptitude (vocabulary learning, VocL; sound recognition, SndRec; sound-symbol correspondence, SndSym; and grammatical inferencing, GrInf) using the LLAMA language aptitude test (Meara, 2005). Spatial working memory (SWM), verbal working memory (VWM) and IQ were also measured as control factors. Diffusion Tensor Imaging (DTI) was employed to investigate the structural connectivity of language pathways in the perisylvian language network. Principal Component Analysis (PCA) on behavioural measures suggests that a general ability might be important to the first stages of L2 acquisition. It also suggested that VocL, SndSy and SWM are more closely related to general IQ than SndRec and VocL, and distinguished the tasks specifically designed to tap into L2 acquisition (VocL, SndRec,SndSym and GrInf) from more generic measures (IQ, SWM and VWM). Regression analysis suggested significant correlations between most of these behavioural measures and the structural connectivity of certain language pathways, i.e., VocL and BA47-Parietal pathway, SndSym and inter-hemispheric BA45 pathway, GrInf and BA45-Temporal pathway and BA6-Temporal pathway, IQ and BA44-Parietal pathway, BA47-Parietal pathway, BA47-Temporal pathway and inter-hemispheric BA45 pathway, SWM and inter-hemispheric BA6 pathway and BA47-Parietal pathway, and VWM and BA47-Temporal pathway. These results are discussed in relation to relevant findings in the literature.

Abstract

Jedek is a previously unrecognized variety of the Northern Aslian subgroup of the Aslian branch of the Austroasiatic language family. It is spoken by c. 280 individuals in the resettlement area of Sungai Rual, near Jeli in Kelantan state, Peninsular Malaysia. The community originally consisted of several bands of foragers along the middle reaches of the Pergau river. Jedek’s distinct status first became known during a linguistic survey carried out in the DOBES project Tongues of the Semang (2005-2011). This paper describes the process leading up to its discovery and provides an overview of its typological characteristics.

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

Using the masked priming paradigm, we examined which phonological unit is used when naming Kanji compounds. Although the phonological unit in the Japanese language has been suggested to be the mora, Experiment 1 found no priming for mora-related Kanji prime-target pairs. In Experiment 2, significant priming was only found when Kanji pairs shared the whole sound of their initial Kanji characters. Nevertheless, when the same Kanji pairs used in Experiment 2 were transcribed into Kana, significant mora priming was observed in Experiment 3. In Experiment 4, matching the syllable structure and pitch-accent of the initial Kanji characters did not lead to mora priming, ruling out potential alternative explanations for the earlier absence of the effect. A significant mora priming effect was observed, however, when the shared initial mora constituted the whole sound of their initial Kanji characters in Experiments 5. Lastly, these results were replicated in Experiment 6. Overall, these results indicate that the phonological unit involved when naming Kanji compounds is not the mora but the whole sound of each Kanji character. We discuss how different phonological units may be involved when processing Kanji and Kana words as well as the implications for theories dealing with language production processes.

Abstract

Four experiments investigated the role of the syllable in Chinese spoken word production. Chen, Chen and Ferrand (2003) reported a syllable priming effect when primes and targets shared the first syllable using a masked priming paradigm in Chinese. Our Experiment 1 was a direct replication of Chen et al.'s (2003) Experiment 3 employing CV (e. g., /ba2.ying2/, strike camp) and CVG (e. g., /bai2.shou3/, white haired) syllable types. Experiment 2 tested the syllable priming effect using different syllable types: e. g., CV (/qi4.qiu2/, balloon) and CVN (/qing1.ting2/, dragonfly). Experiment 3 investigated this issue further using line drawings of common objects as targets that were preceded either by a CV (e. g., /qi3/, attempt), or a CVN (e. g., /qing2/, affection) prime. Experiment 4 further examined the priming effect by a comparison between CV or CVN priming and an unrelated priming condition using CV-NX (e. g., /mi2.ni3/, mini) and CVN-CX (e. g., /min2.ju1/, dwellings) as target words. These four experiments consistently found that CV targets were named faster when preceded by CV primes than when they were preceded by CVG, CVN or unrelated primes, whereas CVG or CVN targets showed the reverse pattern. These results indicate that the priming effect critically depends on the match between the structure of the prime and that of the first syllable of the target. The effect obtained in this study was consistent across different stimuli and different tasks (word and picture naming), and provides more conclusive and consistent data regarding the role of the syllable in Chinese speech production.

Abstract

In face-to-face communication, multimodal cues such as prosody, gestures, and mouth movements can play a crucial role in language processing. While several studies have addressed how these cues contribute to native (L1) language processing, their impact on non-native (L2) comprehension is largely unknown. Comprehension of naturalistic language by L2 comprehenders may be supported by the presence of (at least some) multimodal cues, as these provide correlated and convergent information that may aid linguistic processing. However, it is also the case that multimodal cues may be less used by L2 comprehenders because linguistic processing is more demanding than for L1 comprehenders, leaving more limited resources for the processing of multimodal cues. In this study, we investigated how L2 comprehenders use multimodal cues in naturalistic stimuli (while participants watched videos of a speaker), as measured by electrophysiological responses (N400) to words, and whether there are differences between L1 and L2 comprehenders. We found that prosody, gestures, and informative mouth movements each reduced the N400 in L2, indexing easier comprehension. Nevertheless, L2 participants showed weaker effects for each cue compared to L1 comprehenders, with the exception of meaningful gestures and informative mouth movements. These results show that L2 comprehenders focus on specific multimodal cues – meaningful gestures that support meaningful interpretation and mouth movements that enhance the acoustic signal – while using multimodal cues to a lesser extent than L1 comprehenders overall.

Abstract

Background: Developmental language disorder (DLD) is a condition that significantly affects children's achievement but has been understudied. We aim to estimate the prevalence of DLD in Shanghai, compare the co-occurrence of difficulties between children with DLD and those with typical development (TD), and investigate the early risk factors for DLD.

Methods: We estimated DLD prevalence using data from a population-based survey with a cluster random sampling design in Shanghai, China. A subsample of children (aged 5-6 years) received an onsite evaluation, and each child was categorized as TD or DLD. The proportions of children with socio-emotional behavior (SEB) difficulties, low non-verbal IQ (NVIQ), and poor school readiness were calculated among children with TD and DLD. We used multiple imputation to address the missing values of risk factors. Univariate and multivariate regression models adjusted with sampling weights were used to estimate the correlation of each risk factor with DLD.

Findings: Of 1082 children who were approached for the onsite evaluation, 974 (90.0%) completed the language ability assessments, of whom 74 met the criteria for DLD, resulting in a prevalence of 8.5% (95% CI 6.3-11.5) when adjusted with sampling weights. Compared with TD children, children with DLD had higher rates of concurrent difficulties, including SEB (total difficulties score at-risk: 156 [17.3%] of 900 TD vs. 28 [37.8%] of 74 DLD, p < 0.0001), low NVIQ (3 [0.3%] of 900 TD vs. 8 [10.8%] of 74 DLD, p < 0.0001), and poor school readiness (71 [7.9%] of 900 TD vs. 13 [17.6%] of 74 DLD, p = 0.0040). After accounting for all other risk factors, a higher risk of DLD was associated with a lack of parent-child interaction diversity (adjusted odds ratio [aOR] = 3.08, 95% CI = 1.29-7.37; p = 0.012) and lower kindergarten levels (compared to demonstration and first level: third level (aOR = 6.15, 95% CI = 1.92-19.63; p = 0.0020)).

Interpretation: The prevalence of DLD and its co-occurrence with other difficulties suggest the need for further attention. Family and kindergarten factors were found to contribute to DLD, suggesting that multi-sector coordinated efforts are needed to better identify and serve DLD populations at home, in schools, and in clinical settings.

Funding: The study was supported by Shanghai Municipal Education Commission (No. 2022you1-2, D1502), the Innovative Research Team of High-level Local Universities in Shanghai (No. SHSMU-ZDCX20211900), Shanghai Municipal Health Commission (No.GWV-10.1-XK07), and the National Key Research and Development Program of China (No. 2022YFC2705201).

Abstract

Scene-selective regions (SSRs), including the parahippocampal place area (PPA), retrosplenial cortex (RSC), and transverse occipital sulcus (TOS), are among the most widely characterized functional regions in the human brain. However, previous studies have mostly focused on the commonality within each SSR, providing little information on different aspects of their variability. In a large group of healthy adults (N = 202), we used functional magnetic resonance imaging to investigate different aspects of topographical and functional variability within SSRs, including interindividual, interhemispheric, and sex differences. First, the PPA, RSC, and TOS were delineated manually for each individual. We then demonstrated that SSRs showed substantial interindividual variability in both spatial topography and functional selectivity. We further identified consistent interhemispheric differences in the spatial topography of all three SSRs, but distinct interhemispheric differences in scene selectivity. Moreover, we found that all three SSRs showed stronger scene selectivity in men than in women. In summary, our work thoroughly characterized the interindividual, interhemispheric, and sex variability of the SSRs and invites future work on the origin and functional significance of these variabilities. Additionally, we constructed the first probabilistic atlases for the SSRs, which provide the detailed anatomical reference for further investigations of the scene 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

Semantic unification, the process by which small blocks of semantic information are combined into a coherent utterance, has been studied with various types of tasks. However, whether the brain activations reported in these studies are attributed to semantic unification per se or to other task-induced concomitant processes still remains unclear. The neural basis for semantic unification in sentence comprehension was examined using event-related potentials (ERP) and functional Magnetic Resonance Imaging (fMRI). The semantic unification load was manipulated by varying the goodness of fit between a critical word and its preceding context (in high cloze, low cloze and violation sentences). The sentences were presented in a serial visual presentation mode. The participants were asked to perform one of three tasks: semantic congruency judgment (SEM), silent reading for comprehension (READ), or font size judgment (FONT), in separate sessions. The ERP results showed a similar N400 amplitude modulation by the semantic unification load across all of the three tasks. The brain activations associated with the semantic unification load were found in the anterior left inferior frontal gyrus (aLIFG) in the FONT task and in a widespread set of regions in the other two tasks. These results suggest that the aLIFG activation reflects a semantic unification, which is different from other brain activations that may reflect task-specific strategic processing.

Abstract

Brain oscillations are prevalent in all species and are involved in numerous perceptual operations. α oscillations are thought to facilitate processing through the inhibition of task-irrelevant networks, while β oscillations are linked to the putative reactivation of content representations. Can the proposed functional role of α and β oscillations be generalized from low-level operations to higher-level cognitive processes? Here we address this question focusing on naturalistic spoken language comprehension. Twenty-two (18 female) Dutch native speakers listened to stories in Dutch and French while MEG was recorded. We used dependency parsing to identify three dependency states at each word: the number of (1) newly opened dependencies, (2) dependencies that remained open, and (3) resolved dependencies. We then constructed forward models to predict α and β power from the dependency features. Results showed that dependency features predict α and β power in language-related regions beyond low-level linguistic features. Left temporal, fundamental language regions are involved in language comprehension in α, while frontal and parietal, higher-order language regions, and motor regions are involved in β. Critically, α- and β-band dynamics seem to subserve language comprehension tapping into syntactic structure building and semantic composition by providing low-level mechanistic operations for inhibition and reactivation processes. Because of the temporal similarity of the α-β responses, their potential functional dissociation remains to be elucidated. Overall, this study sheds light on the role of α and β oscillations during naturalistic spoken language comprehension, providing evidence for the generalizability of these dynamics from perceptual to complex linguistic processes.

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

Research into the neural foundation of perception asserts a model where top-down predictions modulate the bottom-up processing of sensory input. Despite becoming increasingly influential in cognitive neuroscience, the precise account of this predictive coding framework remains debated. In this study, we aim to contribute to this debate by investigating how predictions about prosody facilitate speech perception, and to shed light especially on lexical access influenced by simultaneous predictions in different domains, inter alia, prosodic and semantic. Using a passive auditory oddball paradigm, we examined neural responses to prosodic changes, leading to a semantic change as in Dutch nouns canon [ˈkaːnɔn] ‘cannon’ vs kanon [kaːˈnɔn] ‘canon’, and used acoustically identical pseudowords as controls. Results from twenty-eight native speakers of Dutch (age range 18–32 years) indicated an enhanced P50/N100 complex to prosodic change in pseudowords as well as an MMN response to both words and pseudowords. The enhanced P50/N100 response to pseudowords is claimed to indicate that all relevant auditory information is still processed by the brain, whereas the reduced response to words might reflect the suppression of information that has already been encoded. The MMN response to pseudowords and words, on the other hand, is best justified by the unification of previously established prosodic representations with sensory and semantic input respectively. This pattern of results is in line with the predictive coding framework acting on multiple levels and is of crucial importance to indicate that predictions about linguistic prosodic information are utilized by the brain as early as 50 ms.

Abstract

Language is used in communicative contexts to identify and successfully transmit new information that should be later remembered. In three studies, we used question–answer pairs, a naturalistic device for focusing information, to examine how properties of conversations inform later item memory. In Experiment 1, participants viewed three pictures while listening to a recorded question–answer exchange between two people about the locations of two of the displayed pictures. In a memory recognition test conducted online a day later, participants recognized the names of pictures that served as answers more accurately than the names of pictures that appeared as questions. This suggests that this type of focus indeed boosts memory. In Experiment 2, participants listened to the same items embedded in declarative sentences. There was a reduced memory benefit for the second item, confirming the role of linguistic focus on later memory beyond a simple serial-position effect. In Experiment 3, two participants asked and answered the same questions about objects in a dialogue. Here, answers continued to receive a memory benefit, and this focus effect was accentuated by language production such that information-seekers remembered the answers to their questions better than information-givers remembered the questions they had been asked. Combined, these studies show how people’s memory for conversation is modulated by the referential status of the items mentioned and by the speaker’s roles of the conversation participants.

Abstract

How does language comprehension interact with motor activity? We investigated the conditions under which comprehending an action sentence affects people's balance. We performed two experiments to assess whether sentences describing forward or backward movement modulate the lateral movements made by subjects who made sensibility judgments about the sentences. In one experiment subjects were standing on a balance board and in the other they were seated on a balance board that was mounted on a chair. This allowed us to investigate whether the action compatibility effect (ACE) is robust and persists in the face of salient incompatibilities between sentence content and subject movement. Growth-curve analysis of the movement trajectories produced by the subjects in response to the sentences suggests that the ACE is indeed robust. Sentence content influenced movement trajectory despite salient inconsistencies between implied and actual movement. These results are interpreted in the context of the current discussion of embodied, or grounded, language comprehension and meaning representation.

Abstract

This paper explores the expression of multiple entities in Turkish Sign Language (Türk İşaret Dili; TİD), a less well-studied sign language. It aims to provide a comprehensive description of the ways and frequencies in which entity plurality in this language is expressed, both within and outside the noun phrase. We used a corpus that includes both elicited and spontaneous data from native signers. The results reveal that most of the expressions of multiple entities in TİD are iconic, spatial strategies (i.e. localization and spatial plural predicate inflection) none of which, we argue, should be considered as genuine plural marking devices with the main aim of expressing plurality. Instead, the observed devices for localization and predicate inflection allow for a plural interpretation when multiple locations in space are used. Our data do not provide evidence that TİD employs (productive) morphological plural marking (i.e. reduplication) on nouns, in contrast to some other sign languages and many spoken languages. We relate our findings to expression of multiple entities in other signed languages and in spoken languages and discuss these findings in terms of modality effects on expression of multiple entities in human language.