Primary Progressive Apraxia of Speech Caused by TDP-43: A Case Report.

Objectives: To introduce the first case in which primary progressive apraxia of speech (PPAOS) is associated with TAR DNA-binding protein 43 (TDP-43) instead of 4-repeat tau. Methods: This patient was identified through a postmortem autopsy. Following an initial diagnostic evaluation, he participated in 3 annual research visits during which speech, language, cognitive, and neurologic assessments were administered. Neuroimaging was also acquired. Results: Apraxia of speech was diagnosed at his initial visit with a comprehensive neurologic examination further revealing subtle motor findings in the right hand. At subsequent visits, agrammatic aphasia and motor symptoms consistent with corticobasal syndrome were evident. Cognition and behavior remained relatively intact until advanced stages. FDG-PET revealed hypometabolism in the right temporoparietal cortex and left premotor and motor cortices. There was also low-level signal in the right temporoparietal cortex on tau-PET. A sequence variation in the progranulin gene was identified (GRN c.1A>C, p.Met1). Pathologic diagnosis was TDP-43 Type A with an atypical distribution of inclusions in premotor and motor cortices. Discussion: This case report demonstrates that TDP-43 Type A inclusions in an atypical distribution can present clinically as PPAOS. The sequence variation in the progranulin gene and asymmetric temporoparietal cortex involvement were the strongest indications of the unusual neuropathophysiology prior to autopsy.

Combined assessment of progressive apraxia of speech brain microstructure by diffusion tensor imaging tractography and multishell neurite orientation dispersion and density imaging.

BACKGROUND: Progressive apraxia of speech (PAOS) is characterized by difficulties with motor speech programming and planning. PAOS targets gray matter (GM) and white matter (WM) microstructure that can be assessed using diffusion tensor imaging (DTI) and multishell applications, such as neurite orientation dispersion and density imaging (NODDI). In this study, we aimed to apply DTI and NODDI to add further insight into PAOS tissue microstructure. METHODS: Twenty-two PAOS patients and 26 age- and sex-matched controls, recruited by the Neurodegenerative Research Group (NRG) at Mayo Clinic, underwent diffusion MRI on 3T MRI. Brain maps of fractional anisotropy (FA) and mean diffusivity (MD) from DTI and intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) from NODDI were generated. Global WM and GM, and specific WM tracts were identified using tractography and lobar GM regions. RESULTS: Global WM differences between PAOS and controls were greatest for ICVF, and global GM differences were greatest for MD and IsoVF. Abnormalities in key WM tracts involved in PAOS, including the body of the corpus callosum and frontal aslant tract, were identified with FA, MD, and ICVF, with excellent differentiation of PAOS from controls (area under the receiver operating characteristic curves >.90). MD and ICVF identified abnormalities in arcuate fasciculus, thalamic radiations, and corticostriatal tracts. Significant correlations were identified between an index of articulatory errors and DTI and NODDI metrics from the arcuate fasciculus, frontal aslant tract, and inferior longitudinal fasciculus. CONCLUSIONS: DTI and NODDI represent different aspects of brain tissue microstructure, increasing the number of potential biomarkers for PAOS.

Longitudinal characterization of patients with progressive apraxia of speech without clearly predominant phonetic or prosodic speech features.

Most recent studies of progressive apraxia of speech (PAOS) have focused on patients with phonetic or prosodic predominant PAOS to understand the implications of the presenting clinical phenotype. Patients without a clearly predominating speech quality, or mixed AOS, have been excluded. Given the implications for disease progression, it is important to understand these patients early in the disease course to inform appropriate education and prognostication. The aim of this study was to describe a cohort of ten patients with initially mixed PAOS and how their clinical course evolves. Four patients were rated prosodic predominant later on (mild AOS at first visit); five were later designated phonetic (four with more than mild AOS at first visit); one was judged mixed at all visits. The study suggests patients without a clear predominance of speech featuresshould still be included in PAOS studies and thought of on the continuum of the disease spectrum.

Are form priming effects phonological or perceptual? Electrophysiological evidence from American Sign Language.

Form priming has been used to identify and demarcate the processes that underlie word and sign recognition. The facilitation that results from the prime and target being related in form is typically interpreted in terms of pre-activation of linguistic representations, with little to no consideration for the potential contributions of increased perceptual overlap between related pairs. Indeed, isolating the contribution of perceptual similarity is impossible in spoken languages; there are no listeners who can perceive speech but have not acquired a sound-based phonological system. Here, we compared the electrophysiological indices of form priming effects in American Sign Language between hearing non-signers (i.e., who had no visual-manual phonological system) and deaf signers. We reasoned that similarities in priming effects between groups would most likely be perceptual in nature, whereas priming effects that are specific to the signer group would reflect pre-activation of phonological representations. Behavior in the go/no-go repetition detection task was remarkably similar between groups. Priming in a pre-N400 window was also largely similar across groups, consistent with an early effect of perceptual similarity. However, priming effects diverged between groups during the subsequent N400 and post-N400 windows. Signers had more typical form priming effects and were especially attuned to handshape overlap, whereas non-signers did not exhibit an N400 component and were more sensitive to location overlap. We attribute this pattern to an interplay between perceptual similarity and phonological knowledge. Perceptual similarity contributes to early phonological priming effects, while phonological knowledge tunes sensitivity to linguistically relevant dimensions of perceptual similarity.

Lexical selection in bimodal bilinguals: ERP evidence from picture-word interference.

The picture word interference (PWI) paradigm and ERPs were used to investigate whether lexical selection in deaf and hearing ASL-English bilinguals occurs via lexical competition or whether the response exclusion hypothesis (REH) for PWI effects is supported. The REH predicts that semantic interference should not occur for bimodal bilinguals because sign and word responses do not compete within an output buffer. Bimodal bilinguals named pictures in ASL, preceded by either a translation equivalent, semantically-related, or unrelated English written word. In both the translation and semantically-related conditions bimodal bilinguals showed facilitation effects: reduced RTs and N400 amplitudes for related compared to unrelated prime conditions. We also observed an unexpected focal left anterior positivity that was stronger in the translation condition, which we speculate may be due to articulatory priming. Overall, the results support the REH and models of bilingual language production that assume lexical selection occurs without competition between languages.

Language control in bimodal bilinguals: Evidence from ERPs.

It is currently unclear to what degree language control, which minimizes non-target language interference and increases the probability of selecting target-language words, is similar for sign-speech (bimodal) bilinguals and spoken language (unimodal) bilinguals. To further investigate the nature of language control processes in bimodal bilinguals, we conducted the first event-related potential (ERP) language switching study with hearing American Sign Language (ASL)-English bilinguals. The results showed a pattern that has not been observed in any unimodal language switching study: a switch-related positivity over anterior sites and a switch-related negativity over posterior sites during ASL production in both early and late time windows. No such pattern was found during English production. We interpret these results as evidence that bimodal bilinguals uniquely engage language control at the level of output modalities.

Orthographic neighborhood density modulates the size of transposed-letter priming effects.

We used transposed-letter (TL) priming to test the lexical tuning hypothesis, which states that words from high-density orthographic neighborhoods have more precise orthographic codes than words from low-density neighborhoods. Replicating standard TL priming effects, target words elicited faster lexical decision responses and smaller amplitude N250s and N400s when preceded by TL primes (e.g., leomn-LEMON) compared with substitution primes (e.g., leuzn-LEMON) overall. We expected that if high-density words have more precise orthographic representations (i.e., with each letter assigned to a specific position), then they should be relatively less activated by TL primes and should give rise to smaller TL priming effects. In line with our prediction, N250 (but not N400 or behavioral) TL priming was significantly smaller for high-density words compared with low-density words over posterior sites. Such an interaction was not observed for pseudoword targets. Consistent with the lexical tuning hypothesis then, this pattern suggests that the nature of the orthographic code used to access lexical representations differs depending on the number of neighboring words in the lexicon. We conclude by discussing how lexical tuning could be implemented in current models of orthographic processing.

Parallel semantic processing in the flankers task: Evidence from the N400.

The extent to which higher-order representations can be extracted from more than one word in parallel remains an unresolved issue with theoretical import. Here, we used ERPs to investigate the timing with which semantic information is extracted from parafoveal words. Participants saw animal and non-animal targets paired with response congruent or incongruent flankers in a semantic categorization task. Animal targets elicited smaller amplitude negativities when they were paired with semantically related and response congruent animal flankers (e.g., wolf coyote wolf) compared to unrelated and response incongruent flankers (e.g., sock coyote sock) in the N400 window and a post-N400 window. We interpret the N400 effect in terms of facilitated processing from the joint activation of shared semantic features (e.g., animal, furry) across target and flanker words and the later effect in terms of post-lexical decision-making. Thus, semantic information can be extracted from flankers in parallel and impacts various stages of processing.

The organization of the American Sign Language lexicon: Comparing one- and two-parameter ERP phonological priming effects across tasks.

We used phonological priming and ERPs to investigate the organization of the lexicon in American Sign Language. Across go/no-go repetition detection and semantic categorization tasks, targets in related pairs that shared handshape and location elicited smaller N400s than targets in unrelated pairs, indicative of facilitated processing. Handshape-related targets also elicited smaller N400s than unrelated targets, but only in the repetition task. The location priming effect reversed direction across tasks, with slightlylargeramplitude N400s for targets in related versus unrelated pairs in the semantic task, indicative of interference. These patterns imply that handshape and location play different roles during sign recognition and that there is a hierarchical organization for the sign lexicon. Similar to interactive-activation models of word recognition, we argue for differentiation between sublexical facilitation and lexical competition. Lexical competition is primarily driven by the location parameter and is more engaged when identification of single lexico-semantic entries is required.

Language Dominance Modulates Transposed-Letter N400 Priming Effects in Bilinguals.

Models of visual word recognition differ as to how print exposure modulates orthographic precision. In some models, precision is the optimal end state of a lexical representation; the associations between letters and positions are initially approximate and become more precise as readers gain exposure to the word. In others, flexible orthographic coding that allows for rapid access to semantics (i.e., 'good enough' orthographic processing) is the optimal end state. To adjudicate between these trajectories, we compared the size of transposed-letter ERP priming effects on two ERP components thought to reflect orthographic and lexico-semantic processing across languages in late English-Spanish bilinguals. Words that are represented precisely should be less susceptible to activation by transposed-letter primes (e.g., shpae-SHAPE) than words that are not, and should therefore yield smaller priming effects. Overall, targets elicited smaller N250s and N400s and faster responses when preceded by transposed-letter primes compared to substitution primes (e.g., shgue-SHAPE). The only effect that significantly differed between languages was N400 priming, which was larger in English, the dominant language. We suggest that these results favor models of learning to read according to which 'good enough' orthographic processing increases with print exposure.

On the Connection Between Language Control and Executive Control-An ERP Study.

Models vary in the extent to which language control processes are domain general. Those that posit that language control is at least partially domain general insist on an overlap between language control and executive control at the goal level. To further probe whether or not language control is domain general, we conducted the first event-related potential (ERP) study that directly compares language-switch costs, as an index of language control, and task-switch costs, as an index of executive control. The language switching and task switching methodologies were identical, except that the former required switching between languages (English or Spanish) whereas the latter required switching between tasks (color naming or category naming). This design allowed us to directly compare control processes at the goal level (cue-locked ERPs) and at the task performance level (picture-locked ERPs). We found no significant differences in the switch-related cue-locked and picture-locked ERP patterns across the language and task switching paradigms. These results support models of domain-general language control.

An ERP investigation of orthographic precision in deaf and hearing readers.

Phonology is often assumed to play a role in the tuning of orthographic representations, but it is unknown whether deaf readers' reduced access to spoken phonology reduces orthographic precision. To index how precisely deaf and hearing readers encode orthographic information, we used a masked transposed-letter (TL) priming paradigm. Word targets were preceded by TL primes formed by reversing two letters in the word and substitution primes in which the same two letters were replaced. The two letters that were manipulated were either in adjacent or non-adjacent positions, yielding four prime conditions: adjacent TL (e.g., chikcen-CHICKEN), adjacent substitution (e.g., chidven- CHICKEN), non-adjacent TL (e.g., ckichen-CHICKEN), and non-adjacent substitution (e.g., cticfen-CHICKEN). Replicating the standard TL priming effects, targets preceded by TL primes elicited smaller amplitude negativities and faster responses than those preceded by substitution primes overall. This indicates some degree of flexibility in the associations between letters and their positions within words. More flexible (i.e., less precise) representations are thought to be more susceptible to activation by TL primes, resulting in larger TL priming effects. However, the size of the TL priming effects was virtually identical between groups. Moreover, the ERP effects were shifted in time such that the adjacent TL priming effect arose earlier than the non-adjacent TL priming effect in both groups. These results suggest that phonological tuning is not required to represent orthographic information in a precise manner.

The role of phonology during visual word learning in adults: An integrative review.

Throughout their lifetime, adults learn new words in their native lannguage, and potentially also in a second language. However, they do so with variable levels of success. In the auditory word learning literature, some of this variability has been attributed to phonological skills, including decoding and phonological short-term memory. Here I examine how the relationship between phonological skills and word learning applies to the visual modality. I define the availability of phonology in terms of (1) the extent to which it is biased by the learning environment, (2) the characteristics of the words to be learned, and (3) individual differences in phonological skills. Across these three areas of research, visual word learning improves when phonology is made more available to adult learners, suggesting that phonology can facilitate learning across modalities. However, the facilitation is largely specific to alphabetic languages, which have predictable sublexical correspondences between orthography and phonology. Therefore, I propose that phonology bootstraps visual word learning by providing a secondary code that constrains and refines developing orthographic representations.

Unified syntax in the bilingual mind.

Are syntactic representations shared across languages, and how might that inform the nature of syntactic computations? To investigate these issues, we presented French-English bilinguals with mixed-language word sequences for 200 ms and asked them to report the identity of one word at a post-cued location. The words either formed an interpretable grammatical sequence via shared syntax (e.g., ses feet sont big - where the French words ses and sont translate into his and are, respectively) or an ungrammatical sequence with the same words (e.g., sont feet ses big). Word identification was significantly greater in the grammatical sequences - a bilingual sentence superiority effect. These results not only provide support for shared syntax, but also reveal a fascinating ability of bilinguals to simultaneously connect words from their two languages through these shared syntactic representations.

ERP effects of masked orthographic neighbour priming in deaf readers.

In masked priming studies with hearing readers, neighbouring words (e.g., wine, vine) compete through lateral inhibition. Here, we asked whether lateral inhibition also characterizes visual word recognition in deaf readers and whether the neural signature of this competition is the same as for hearing readers. Only real words have lexical representations that engage in lateral inhibition. Therefore, we compared processing of target words following neighbouring prime words (e.g., wine-VINE) and pseudowords (e.g., bine-VINE). Targets following words elicited larger amplitude N400s and slower lexical decision responses than those following pseudowords, indicating more effortful processing due to lateral inhibition. Although these effects went in the same direction for hearing and deaf readers, the distribution of the N400 effect differed. We associate the more anterior effect in hearing readers with stronger co-activation of, and competition among, phonological representations. Thus, deaf readers use lexical competition to recognize visual words, but it is primarily restricted to orthographic representations.

ERP Evidence for Co-Activation of English Words during Recognition of American Sign Language Signs.

Event-related potentials (ERPs) were used to investigate co-activation of English words during recognition of American Sign Language (ASL) signs. Deaf and hearing signers viewed pairs of ASL signs and judged their semantic relatedness. Half of the semantically unrelated signs had English translations that shared an orthographic and phonological rime (e.g., BAR-STAR) and half did not (e.g., NURSE-STAR). Classic N400 and behavioral semantic priming effects were observed in both groups. For hearing signers, targets in sign pairs with English rime translations elicited a smaller N400 compared to targets in pairs with unrelated English translations. In contrast, a reversed N400 effect was observed for deaf signers: target signs in English rime translation pairs elicited a larger N400 compared to targets in pairs with unrelated English translations. This reversed effect was overtaken by a later, more typical ERP priming effect for deaf signers who were aware of the manipulation. These findings provide evidence that implicit language co-activation in bimodal bilinguals is bidirectional. However, the distinct pattern of effects in deaf and hearing signers suggests that it may be modulated by differences in language proficiency and dominance as well as by asymmetric reliance on orthographic versus phonological representations.

An electrophysiological investigation of orthographic spatial integration in reading.

During reading, word recognition speed is influenced by the amount of orthographic overlap with surrounding words. The nature of this phenomenon is not understood: some theories attribute it to low-level visual operations (i.e., parafoveal feature detectors influencing foveal letter detectors), whereas other theories assume that orthographic processing (i.e., letter position coding and word activation) occurs across multiple words in parallel. To arbitrate between these theories, we used electroencephalography to reveal the time course of orthographic spatial integration in a lexical decision task. Foveal target words were flanked on each side by parafoveal words, manipulated across three conditions: repetition flankers (e.g. rock rock rock), unrelated flankers (step rock step) and a no-flanker condition. Linear mixed-effect models were constructed to analyze EEG data on a trial-by-trial basis. Word recognition was worse in the unrelated flanker condition than in the repetition and no-flanker conditions. This behavioral pattern was accompanied by increased negativity in the N250 and N400 windows, associated with the activation of sub-lexical and lexico-semantic representations, respectively. Crucially, the absence of effects prior to 200 ms post-stimulus onset provides evidence against the involvement of low-level visual processes. We conclude that orthographic spatial integration is driven by parallel processing of multiple words, which leads to the activation of a larger set of sub-lexical nodes and more difficult processing at the lexical level when those words are orthographically unrelated.

Task modulates ERP effects of orthographic neighborhood for pseudowords but not words.

Words and pseudowords from high-density orthographic neighborhoods elicit larger amplitude N400s than similar items from low-density orthographic neighborhoods in the lexical decision task. This pattern could be interpreted as an increase in the amount of lexico-semantic information to be processed or as an increase in difficulty identifying a word (or rejecting a pseudoword) amongst many co-activated alternatives. In order to dissociate between these mechanisms, we compared neighborhood effects between a lexical decision task (LDT) and a letter search task (LST). Behaviorally, we found the standard neighborhood and lexicality effects in the LDT, but no significant effects in the LST. Thus, behavioral responses were sensitive to the decisions required by the respective tasks. Electrophysiologically, we found similar N400 neighborhood effects between tasks for words, but the N400 neighborhood effect for pseudowords was only present in the LDT. Moreover, the effect of neighborhood in the LDT occurred earlier for words than for pseudowords. These nuanced differences in the time course and automaticity of word and pseudoword neighborhood effects lend insight into the processes that underlie N400 effects of orthographic neighborhood and how they unfold over time. We propose that the early neighborhood effects for words across tasks were driven by highly automatized word identification processes that were sensitive to the lateral inhibition generated by orthographic neighbors. In contrast, the later neighborhood effects for pseudowords in the LDT could have been driven by task-specific processes tied to how global lexical activity is used to make a lexical decision.

An ERP Investigation of L2-L1 Translation Priming in Adult Learners.

A longstanding debate centers around how beginning adult bilinguals process words in their second language (L2). Do they access the meaning of the L2 words directly or do they first activate the native language (L1) translation equivalents in order to access meaning? To address this question, we used ERPs to investigate how newly learned L2 words influence processing of their L1 translation equivalents. We taught participants the meanings of 80 novel L2 (pseudo)words by presenting them with pictures of familiar objects. After 3 days of learning, participants were tested in a backward translation priming paradigm with a short (140 ms) stimulus onset asynchrony. L1 targets preceded by their L2 translations elicited faster responses and smaller amplitude negativities than the same L1 targets preceded by unrelated L2 words. The bulk of the ERP translation priming effect occurred within the N400 window (350-550 ms), suggesting that the new L2 words were automatically activating their semantic representations. A weaker priming effect in the preceding window (200-350 ms) was found at anterior sites, providing some evidence that the forms of the L1 translation equivalents had also been activated. These results have implications for models of L2 processing at the earliest stages of learning.

From sublexical facilitation to lexical competition: ERP effects of masked neighbor priming.

Interactive-activation models posit that visual word recognition involves co-activation of orthographic neighbors (e.g., note, node) and competition among them via lateral inhibitory connections. Behavioral evidence of this lexical competition comes from masked priming paradigms, in which target words elicit slower responses when preceded by a neighbor (e.g., note-NODE) than when preceded by an unrelated word (e.g., kiss-NODE). In the present study, we used ERPs to investigate how masked high frequency word primes influence processing of low frequency word and pseudoword targets. Word targets preceded by a neighbor prime elicited larger negativities within the N400 window than those preceded by an unrelated prime across bilateral anterior sites, which we call a reversed N400 priming effect. Consistent with the behavioral literature, the size of the reversed N400 priming effect was larger for targets from high-density orthographic neighborhoods and for participants who scored higher on a behavioral measure of spelling recognition. Indeed, the opposite effect (i.e., smaller negativities within the N400 window for word targets preceded by a neighbor) was observed for words from low-density orthographic neighborhoods and for less-skilled spellers. Traditional priming was also observed within the N250 window for word targets and within both the N250 or N400 windows for pseudoword targets. The specificity of the reversed N400 priming effect to situations in which both words have precise lexical representations suggests that it, like the behavioral interference effect, indexes lexical competition during visual word recognition.