Neural representation of phonological wordform in temporal cortex.

While the neural bases of the earliest stages of speech categorization have been widely explored using neural decoding methods, there is still a lack of consensus on questions as basic as how wordforms are represented and in what way this word-level representation influences downstream processing in the brain. Isolating and localizing the neural representations of wordform is challenging because spoken words activate a variety of representations (e.g., segmental, semantic, articulatory) in addition to form-based representations. We addressed these challenges through a novel integrated neural decoding and effective connectivity design using region of interest (ROI)-based, source-reconstructed magnetoencephalography/electroencephalography (MEG/EEG) data collected during a lexical decision task. To identify wordform representations, we trained classifiers on words and nonwords from different phonological neighborhoods and then tested the classifiers' ability to discriminate between untrained target words that overlapped phonologically with the trained items. Training with word neighbors supported significantly better decoding than training with nonword neighbors in the period immediately following target presentation. Decoding regions included mostly right hemisphere regions in the posterior temporal lobe implicated in phonetic and lexical representation. Additionally, neighbors that aligned with target word beginnings (critical for word recognition) supported decoding, but equivalent phonological overlap with word codas did not, suggesting lexical mediation. Effective connectivity analyses showed a rich pattern of interaction between ROIs that support decoding based on training with lexical neighbors, especially driven by right posterior middle temporal gyrus. Collectively, these results evidence functional representation of wordforms in temporal lobes isolated from phonemic or semantic representations.

Exploring Abstract Pattern Representation in The Brain and Non-symbolic Neural Networks.

Human cognitive and linguistic generativity depends on the ability to identify abstract relationships between perceptually dissimilar items. Marcus et al. (1999) found that human infants can rapidly discover and generalize patterns of syllable repetition (reduplication) that depend on the abstract property of identity, but simple recurrent neural networks (SRNs) could not. They interpreted these results as evidence that purely associative neural network models provide an inadequate framework for characterizing the fundamental generativity of human cognition. Here, we present a series of deep long short-term memory (LSTM) models that identify abstract syllable repetition patterns and words based on training with cochleagrams that represent auditory stimuli. We demonstrate that models trained to identify individual syllable trigram words and models trained to identify reduplication patterns discover representations that support classification of abstract repetition patterns. Simulations examined the effects of training categories (words vs. patterns) and pretraining to identify syllables, on the development of hidden node representations that support repetition pattern discrimination. Representational similarity analyses (RSA) comparing patterns of regional brain activity based on MRI-constrained MEG/EEG data to patterns of hidden node activation elicited by the same stimuli showed a significant correlation between brain activity localized in primarily posterior temporal regions and representations discovered by the models. These results suggest that associative mechanisms operating over discoverable representations that capture abstract stimulus properties account for a critical example of human cognitive generativity.

Neural representation of phonological wordform in bilateral posterior temporal cortex.

While the neural bases of the earliest stages of speech categorization have been widely explored using neural decoding methods, there is still a lack of consensus on questions as basic as how wordforms are represented and in what way this word-level representation influences downstream processing in the brain. Isolating and localizing the neural representations of wordform is challenging because spoken words evoke activation of a variety of representations (e.g., segmental, semantic, articulatory) in addition to form-based representations. We addressed these challenges through a novel integrated neural decoding and effective connectivity design using region of interest (ROI)-based, source reconstructed magnetoencephalography/electroencephalography (MEG/EEG) data collected during a lexical decision task. To localize wordform representations, we trained classifiers on words and nonwords from different phonological neighborhoods and then tested the classifiers' ability to discriminate between untrained target words that overlapped phonologically with the trained items. Training with either word or nonword neighbors supported decoding in many brain regions during an early analysis window (100-400 ms) reflecting primarily incremental phonological processing. Training with word neighbors, but not nonword neighbors, supported decoding in a bilateral set of temporal lobe ROIs, in a later time window (400-600 ms) reflecting activation related to word recognition. These ROIs included bilateral posterior temporal regions implicated in wordform representation. Effective connectivity analyses among regions within this subset indicated that word-evoked activity influenced the decoding accuracy more than nonword-evoked activity did. Taken together, these results evidence functional representation of wordforms in bilateral temporal lobes isolated from phonemic or semantic representations.

Abstract representations in temporal cortex support generative linguistic processing.

Generativity, the ability to create and evaluate novel constructions, is a fundamental property of human language and cognition. The productivity of generative processes is determined by the scope of the representations they engage. Here we examine the neural representation of reduplication, a productive phonological process that can create novel forms through patterned syllable copying (e.g. ba-mih → ba-ba-mih, ba-mih-mih, or ba-mih-ba). Using MRI-constrained source estimates of combined MEG/EEG data collected during an auditory artificial grammar task, we identified localized cortical activity associated with syllable reduplication pattern contrasts in novel trisyllabic nonwords. Neural decoding analyses identified a set of predominantly right hemisphere temporal lobe regions whose activity reliably discriminated reduplication patterns evoked by untrained, novel stimuli. Effective connectivity analyses suggested that sensitivity to abstracted reduplication patterns was propagated between these temporal regions. These results suggest that localized temporal lobe activity patterns function as abstract representations that support linguistic generativity.

A tale of two lexica: Investigating computational pressures on word representation with neural networks.

Introduction: The notion of a single localized store of word representations has become increasingly less plausible as evidence has accumulated for the widely distributed neural representation of wordform grounded in motor, perceptual, and conceptual processes. Here, we attempt to combine machine learning methods and neurobiological frameworks to propose a computational model of brain systems potentially responsible for wordform representation. We tested the hypothesis that the functional specialization of word representation in the brain is driven partly by computational optimization. This hypothesis directly addresses the unique problem of mapping sound and articulation vs. mapping sound and meaning. Results: We found that artificial neural networks trained on the mapping between sound and articulation performed poorly in recognizing the mapping between sound and meaning and vice versa. Moreover, a network trained on both tasks simultaneously could not discover the features required for efficient mapping between sound and higher-level cognitive states compared to the other two models. Furthermore, these networks developed internal representations reflecting specialized task-optimized functions without explicit training. Discussion: Together, these findings demonstrate that different task-directed representations lead to more focused responses and better performance of a machine or algorithm and, hypothetically, the brain. Thus, we imply that the functional specialization of word representation mirrors a computational optimization strategy given the nature of the tasks that the human brain faces.

Neural evidence suggests phonological acceptability judgments reflect similarity, not constraint evaluation.

Acceptability judgments are a primary source of evidence in formal linguistic research. Within the generative linguistic tradition, these judgments are attributed to evaluation of novel forms based on implicit knowledge of rules or constraints governing well-formedness. In the domain of phonological acceptability judgments, other factors including ease of articulation and similarity to known forms have been hypothesized to influence evaluation. We used data-driven neural techniques to identify the relative contributions of these factors. Granger causality analysis of magnetic resonance imaging (MRI)-constrained magnetoencephalography (MEG) and electroencephalography (EEG) data revealed patterns of interaction between brain regions that support explicit judgments of the phonological acceptability of spoken nonwords. Comparisons of data obtained with nonwords that varied in terms of onset consonant cluster attestation and acceptability revealed different cortical regions and effective connectivity patterns associated with phonological acceptability judgments. Attested forms produced stronger influences of brain regions implicated in lexical representation and sensorimotor simulation on acoustic-phonetic regions, whereas unattested forms produced stronger influence of phonological control mechanisms on acoustic-phonetic processing. Unacceptable forms produced widespread patterns of interaction consistent with attempted search or repair. Together, these results suggest that speakers' phonological acceptability judgments reflect lexical and sensorimotor factors.

Behavioral and Neurodynamic Effects of Word Learning on Phonotactic Repair.

Processes governing the creation, perception and production of spoken words are sensitive to the patterns of speech sounds in the language user's lexicon. Generative linguistic theory suggests that listeners infer constraints on possible sound patterning from the lexicon and apply these constraints to all aspects of word use. In contrast, emergentist accounts suggest that these phonotactic constraints are a product of interactive associative mapping with items in the lexicon. To determine the degree to which phonotactic constraints are lexically mediated, we observed the effects of learning new words that violate English phonotactic constraints (e.g., srigin) on phonotactic perceptual repair processes in nonword consonant-consonant-vowel (CCV) stimuli (e.g., /sre/). Subjects who learned such words were less likely to "repair" illegal onset clusters (/sr/) and report them as legal ones (/∫r/). Effective connectivity analyses of MRI-constrained reconstructions of simultaneously collected magnetoencephalography (MEG) and EEG data showed that these behavioral shifts were accompanied by changes in the strength of influences of lexical areas on acoustic-phonetic areas. These results strengthen the interpretation of previous results suggesting that phonotactic constraints on perception are produced by top-down lexical influences on speech processing.

Tracking reorganization of large-scale effective connectivity in aphasia following right hemisphere stroke.

In this paper we demonstrate the application of new effective connectivity analyses to characterize changing patterns of task-related directed interaction in large (25-55 node) cortical networks following the onset of aphasia. The subject was a left-handed woman who became aphasic following a right-hemisphere stroke. She was tested on an auditory word-picture verification task administered one and seven months after the onset of aphasia. MEG/EEG and anatomical MRI data were used to create high spatiotemporal resolution estimates of task-related cortical activity. Effective connectivity analyses of those data showed a reduction of bilateral network influences on preserved right-hemisphere structures, and an increase in intra-hemispheric left-hemisphere influences. She developed a connectivity pattern that was more left lateralized than that of right-handed control subjects. Her emergent left hemisphere network showed a combination of increased functional subdivision of perisylvian language areas and recruitment of medial structures.

Sentential influences on acoustic-phonetic processing: A Granger causality analysis of multimodal imaging data.

Sentential context influences the way that listeners identify phonetically ambiguous or perceptual degraded speech sounds. Unfortunately, inherent inferential limitations on the interpretation of behavioral or BOLD imaging results make it unclear whether context influences perceptual processing directly, or acts at a post-perceptual decision stage. In this paper, we use Kalman-filter enabled Granger causation analysis of MR-constrained MEG/EEG data to distinguish between these possibilities. Using a retrospective probe verification task, we found that sentential context strongly affected the interpretation of words with ambiguous initial voicing (e.g. DUSK-TUSK). This behavioral context effect coincided with increased influence by brain regions associated with lexical representation on regions associated with acoustic-phonetic processing. These results support an interactive view of sentence context effects on speech perception.

A novel DNMT1 mutation associated with early onset hereditary sensory and autonomic neuropathy, cataplexy, cerebellar atrophy, scleroderma, endocrinopathy, and common variable immune deficiency.

DNA methyltransferase 1 (DNMT1) is an enzyme which has a role in methylation of DNA, gene regulation, and chromatin stability. Missense mutations in the DNMT1 gene have been previously associated with two neurological syndromes: hereditary sensory and autonomic neuropathy type 1 with dementia and deafness (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). We report a case showing overlap of both of these syndromes plus associated clinical features of common variable immune deficiency, scleroderma, and endocrinopathy that could also be mutation associated. Our patient was found to be heterozygous for a previously unreported frameshift mutation, c.1635_1637delCAA p.(Asn545del) in the DNMT1 gene exon 20. This case displays both the first frameshift mutation described in the literature which is associated with a phenotype with a high degree of overlap between HSAN1E and ADCA-DN and early age of onset (c. 8 years). Our case is also of interest as the patient displays a number of new non-neurological features, which could also be DNMT1 mutation related.

The Missing-Phoneme Effect in Aural Prose Comprehension.

When participants search for a target letter while reading for comprehension, they miss more instances if the target letter is embedded in frequent function words than in less frequent content words. This phenomenon, called the missing-letter effect, has been considered a window on the cognitive mechanisms involved in the visual processing of written language. In the present study, one group of participants read two texts for comprehension while searching for a target letter, and another group listened to a narration of the same two texts while listening for the target letter's corresponding phoneme. The ubiquitous missing-letter effect was replicated and extended to a missing-phoneme effect Item-based correlations between the reading and listening tasks were high, which led us to conclude that both tasks involve cognitive processes that reading and listening have in common and that both processes are rooted in psycholinguistically driven allocation of attention.

Lexical mediation of phonotactic frequency effects on spoken word recognition: A Granger causality analysis of MRI-constrained MEG/EEG data.

Phonotactic frequency effects play a crucial role in a number of debates over language processing and representation. It is unclear however, whether these effects reflect prelexical sensitivity to phonotactic frequency, or lexical "gang effects" in speech perception. In this paper, we use Granger causality analysis of MR-constrained MEG/EEG data to understand how phonotactic frequency influences neural processing dynamics during auditory lexical decision. Effective connectivity analysis showed weaker feedforward influence from brain regions involved in acoustic-phonetic processing (superior temporal gyrus) to lexical areas (supramarginal gyrus) for high phonotactic frequency words, but stronger top-down lexical influence for the same items. Low entropy nonwords (nonwords judged to closely resemble real words) showed a similar pattern of interactions between brain regions involved in lexical and acoustic-phonetic processing. These results contradict the predictions of a feedforward model of phonotactic frequency facilitation, but support the predictions of a lexically mediated account.

Gerstmann-Straüssler-Scheinker disease: novel PRNP mutation and VGKC-complex antibodies.

OBJECTIVE: To describe a unique case of Gerstmann-Straüssler-Scheinker (GSS) disease caused by a novel prion protein (PRNP) gene mutation and associated with strongly positive voltage-gated potassium channel (VGKC)-complex antibodies (Abs). METHODS: Clinical data were gathered from retrospective review of the case notes. Postmortem neuropathologic examination was performed, and DNA was extracted from frozen brain tissue for full sequence analysis of the PRNP gene. RESULTS: The patient was diagnosed in life with VGKC-complex Ab-associated encephalitis based on strongly positive VGKC-complex Ab titers but no detectable LGI1 or CASPR2 Abs. He died despite 1 year of aggressive immunosuppressive treatment. The neuropathologic diagnosis was GSS disease, and a novel mutation, P84S, in the PRNP gene was found. CONCLUSION: VGKC-complex Abs are described in an increasingly broad range of clinical syndromes, including progressive encephalopathies, and may be amenable to treatment with immunosuppression. However, the failure to respond to aggressive immunotherapy warns against VGKC-complex Abs being pathogenic, and their presence does not preclude the possibility of prion disease.

Rules from words: a dynamic neural basis for a lawful linguistic process.

Listeners show a reliable bias towards interpreting speech sounds in a way that conforms to linguistic restrictions (phonotactic constraints) on the permissible patterning of speech sounds in a language. This perceptual bias may enforce and strengthen the systematicity that is the hallmark of phonological representation. Using Granger causality analysis of magnetic resonance imaging (MRI)-constrained magnetoencephalography (MEG) and electroencephalography (EEG) data, we tested the differential predictions of rule-based, frequency-based, and top-down lexical influence-driven explanations of processes that produce phonotactic biases in phoneme categorization. Consistent with the top-down lexical influence account, brain regions associated with the representation of words had a stronger influence on acoustic-phonetic regions in trials that led to the identification of phonotactically legal (versus illegal) word-initial consonant clusters. Regions associated with the application of linguistic rules had no such effect. Similarly, high frequency phoneme clusters failed to produce stronger feedforward influences by acoustic-phonetic regions on areas associated with higher linguistic representation. These results suggest that top-down lexical influences contribute to the systematicity of phonological representation.

Investigating the bundle compliance of IVIG delivery in the Greater Manchester Neuroscience centre.

Salford Royal Hospital is one of the largest users of IVIG for chronic neurological illnesses within the UK. The majority of patients are being treated for chronic inflammatory polyneuropathy and multifocal motor neuropathy. We hypothesised that the components of care being delivered to these patients differed to our stated standard of care (IVIG care bundle). We performed a service review exercise to identify shortcomings and improve quality of patient care. The aim was to measure overall bundle compliance being delivered to 75 patients with a view to improving the overall quality of care being delivered in the future. A retrospective case note study was carried out to measure compliance with the 17 areas of care, which constituted the IVIG bundle. Nine areas of care were being delivered to all 75 patients. This meant that all patients were receiving three monthly bloods, a documented cannula pathway, a filed prescription, a medical assessment, and the correct follow-up. Not all patients had a filed consent form, ECG or HAT assessment and an even smaller number of patients had a documented calculation for the amount of IVIG that needed to be given and few had a serum save. No patient in the group was receiving the intended complete bundle of care. The results led to the development of an electronic treatment dashboard for the delivery of chronic IVIG therapy to this group. A re-audit has shown that rates of individual areas of care being delivered has increased markedly but overall compliance has only increased a slightly due to a lack of serum saves for patients.

The cortical organization of lexical knowledge: a dual lexicon model of spoken language processing.

Current accounts of spoken language assume the existence of a lexicon where wordforms are stored and interact during spoken language perception, understanding and production. Despite the theoretical importance of the wordform lexicon, the exact localization and function of the lexicon in the broader context of language use is not well understood. This review draws on evidence from aphasia, functional imaging, neuroanatomy, laboratory phonology and behavioral results to argue for the existence of parallel lexica that facilitate different processes in the dorsal and ventral speech pathways. The dorsal lexicon, localized in the inferior parietal region including the supramarginal gyrus, serves as an interface between phonetic and articulatory representations. The ventral lexicon, localized in the posterior superior temporal sulcus and middle temporal gyrus, serves as an interface between phonetic and semantic representations. In addition to their interface roles, the two lexica contribute to the robustness of speech processing.

Effects of tasks on BOLD signal responses to sentence contrasts: Review and commentary.

Functional neuroimaging studies of syntactic processing have been interpreted as identifying the neural locations of parsing and interpretive operations. However, current behavioral studies of sentence processing indicate that many operations occur simultaneously with parsing and interpretation. In this review, we point to issues that arise in discriminating the effects of these concurrent processes from those of the parser/interpreter in neural measures and to approaches that may help resolve them.

New levels of language processing complexity and organization revealed by granger causation.

Granger causation analysis of high spatiotemporal resolution reconstructions of brain activation offers a new window on the dynamic interactions between brain areas that support language processing. Premised on the observation that causes both precede and uniquely predict their effects, this approach provides an intuitive, model-free means of identifying directed causal interactions in the brain. It requires the analysis of all non-redundant potentially interacting signals, and has shown that even "early" processes such as speech perception involve interactions of many areas in a strikingly large network that extends well beyond traditional left hemisphere perisylvian cortex that play out over hundreds of milliseconds. In this paper we describe this technique and review several general findings that reframe the way we think about language processing and brain function in general. These include the extent and complexity of language processing networks, the central role of interactive processing dynamics, the role of processing hubs where the input from many distinct brain regions are integrated, and the degree to which task requirements and stimulus properties influence processing dynamics and inform our understanding of "language-specific" localized processes.

Itraconazole associated quadriparesis and edema: a case report.

INTRODUCTION: Itraconazole is an anti-fungal agent widely used to treat various forms of mycosis. It is particularly useful in allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization. Side effects are uncommon and usually mild. Mild neuropathy is noted to occur very rarely. We present an unusual and, to the best of our knowledge, as yet unreported case of severe neuropathy and peripheral edema due to itraconazole in the absence of a concomitant risk factor. CASE PRESENTATION: A 72-year-old Caucasian man was started on itraconazole following diagnosis of severe asthma with fungal sensitization. One month later he presented with severe bilateral ankle edema with an elevated serum itraconazole level. The itraconazole dose was reduced but his ankle edema persisted and he developed weakness of all four limbs. Itraconazole was completely stopped leading to improvement in his leg edema but he became bed bound due to weakness. He gradually improved with supportive care and neurorehabilitation. On review at six months, our patient was able to mobilize with the aid of two elbow crutches and power had returned to 5/5 in distal extremities and 4+/5 in proximal extremities. The diagnosis was established based on the classical presentation of drug-induced neuropathy and negative investigatory findings for any alternative diagnoses. CONCLUSION: We report the case of a patient presenting with an unusual complication of severe neuropathy and peripheral edema due to itraconazole. Clinicians should be alert to this association when encountered with neuropathy and/or edema in an itraconazole therapy recipient.