Late-onset Tay-Sachs disease presenting with a neuromuscular phenotype-a case series.

BACKGROUND AND PURPOSE: Tay-Sachs disease is a rare and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in ß-hexosaminidase leads to accumulation of GM2 ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late-onset Tay-Sachs disease (LOTS) is extremely rare, especially in the non-Ashkenazi Jewish population, and is characterized by a more indolent presentation typically encompassing features of cerebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms. CASES: A case series of four unrelated patients of non-Ashkenazi Jewish origin with a predominantly, and in some cases pure, neuromuscular phenotype with evidence of a motor neuronopathy on electromyography is presented. Cerebellar atrophy, reported to be a ubiquitous feature in LOTS, was absent in all patients. CONCLUSION: This case series provides evidence to support a pure neuromuscular phenotype in LOTS, which should be considered in the differential diagnosis of anterior horn cell disorders.

Prosodic Similarity Effects in Short-Term Memory in Developmental Dyslexia.

Children with developmental dyslexia are characterized by phonological difficulties across languages. Classically, this 'phonological deficit' in dyslexia has been investigated with tasks using single-syllable words. Recently, however, several studies have demonstrated difficulties in prosodic awareness in dyslexia. Potential prosodic effects in short-term memory have not yet been investigated. Here we create a new instrument based on three-syllable words that vary in stress patterns, to investigate whether prosodic similarity (the same prosodic pattern of stressed and unstressed syllables) exerts systematic effects on short-term memory. We study participants with dyslexia and age-matched and younger reading-level-matched typically developing controls. We find that all participants, including dyslexic participants, show prosodic similarity effects in short-term memory. All participants exhibited better retention of words that differed in prosodic structure, although participants with dyslexia recalled fewer words accurately overall compared to age-matched controls. Individual differences in prosodic memory were predicted by earlier vocabulary abilities, by earlier sensitivity to syllable stress and by earlier phonological awareness. To our knowledge, this is the first demonstration of prosodic similarity effects in short-term memory. The implications of a prosodic similarity effect for theories of lexical representation and of dyslexia are discussed. © 2016 The Authors. Dyslexia published by John Wiley & Sons Ltd.

Neural encoding of the speech envelope by children with developmental dyslexia.

Developmental dyslexia is consistently associated with difficulties in processing phonology (linguistic sound structure) across languages. One view is that dyslexia is characterised by a cognitive impairment in the "phonological representation" of word forms, which arises long before the child presents with a reading problem. Here we investigate a possible neural basis for developmental phonological impairments. We assess the neural quality of speech encoding in children with dyslexia by measuring the accuracy of low-frequency speech envelope encoding using EEG. We tested children with dyslexia and chronological age-matched (CA) and reading-level matched (RL) younger children. Participants listened to semantically-unpredictable sentences in a word report task. The sentences were noise-vocoded to increase reliance on envelope cues. Envelope reconstruction for envelopes between 0 and 10Hz showed that the children with dyslexia had significantly poorer speech encoding in the 0-2Hz band compared to both CA and RL controls. These data suggest that impaired neural encoding of low frequency speech envelopes, related to speech prosody, may underpin the phonological deficit that causes dyslexia across languages.

Attentional Selection in a Cocktail Party Environment Can Be Decoded from Single-Trial EEG.

How humans solve the cocktail party problem remains unknown. However, progress has been made recently thanks to the realization that cortical activity tracks the amplitude envelope of speech. This has led to the development of regression methods for studying the neurophysiology of continuous speech. One such method, known as stimulus-reconstruction, has been successfully utilized with cortical surface recordings and magnetoencephalography (MEG). However, the former is invasive and gives a relatively restricted view of processing along the auditory hierarchy, whereas the latter is expensive and rare. Thus it would be extremely useful for research in many populations if stimulus-reconstruction was effective using electroencephalography (EEG), a widely available and inexpensive technology. Here we show that single-trial (≈60 s) unaveraged EEG data can be decoded to determine attentional selection in a naturalistic multispeaker environment. Furthermore, we show a significant correlation between our EEG-based measure of attention and performance on a high-level attention task. In addition, by attempting to decode attention at individual latencies, we identify neural processing at ∼200 ms as being critical for solving the cocktail party problem. These findings open up new avenues for studying the ongoing dynamics of cognition using EEG and for developing effective and natural brain-computer interfaces.

Endogenous auditory frequency-based attention modulates electroencephalogram-based measures of obligatory sensory activity in humans.

Auditory selective attention is the ability to enhance the processing of a single sound source, while simultaneously suppressing the processing of other competing sound sources. Recent research has addressed a long-running debate by showing that endogenous attention produces effects on obligatory sensory responses to continuous and competing auditory stimuli. However, until now, this result has only been shown under conditions where the competing stimuli differed in both their frequency characteristics and, importantly, their spatial location. Thus, it is unknown whether endogenous selective attention based only on nonspatial features modulates obligatory sensory processing. Here, we investigate this issue using a diotic paradigm, such that competing auditory stimuli differ in frequency, but had no separation in space. We find a significant effect of attention on electroencephalogram-based measures of obligatory sensory processing at several poststimulus latencies. We discuss these results in terms of previous research on feature-based attention and by comparing our findings with the previous work using stimuli that differed both in terms of spatial and frequency-based characteristics.

Neural entrainment to rhythmic speech in children with developmental dyslexia.

A rhythmic paradigm based on repetition of the syllable "ba" was used to study auditory, visual, and audio-visual oscillatory entrainment to speech in children with and without dyslexia using EEG. Children pressed a button whenever they identified a delay in the isochronous stimulus delivery (500 ms; 2 Hz delta band rate). Response power, strength of entrainment and preferred phase of entrainment in the delta and theta frequency bands were compared between groups. The quality of stimulus representation was also measured using cross-correlation of the stimulus envelope with the neural response. The data showed a significant group difference in the preferred phase of entrainment in the delta band in response to the auditory and audio-visual stimulus streams. A different preferred phase has significant implications for the quality of speech information that is encoded neurally, as it implies enhanced neuronal processing (phase alignment) at less informative temporal points in the incoming signal. Consistent with this possibility, the cross-correlogram analysis revealed superior stimulus representation by the control children, who showed a trend for larger peak r-values and significantly later lags in peak r-values compared to participants with dyslexia. Significant relationships between both peak r-values and peak lags were found with behavioral measures of reading. The data indicate that the auditory temporal reference frame for speech processing is atypical in developmental dyslexia, with low frequency (delta) oscillations entraining to a different phase of the rhythmic syllabic input. This would affect the quality of encoding of speech, and could underlie the cognitive impairments in phonological representation that are the behavioral hallmark of this developmental disorder across languages.

Erratum: Neural entrainment to rhythmically-presented auditory, visual and audio-visual speech in children.

[This corrects the article on p. 216 in vol. 3, PMID: 22833726.].

The effects of attention and visual input on the representation of natural speech in EEG.

Traditionally, the use of electroencephalography (EEG) to study the neural processing of natural stimuli in humans has been hampered by the need to repeatedly present discrete stimuli. Progress has been made recently by the realization that cortical population activity tracks the amplitude envelope of speech stimuli. This has led to studies using linear regression methods which allow the presentation of continuous speech. One such method, known as stimulus reconstruction, has so far only been utilized in multi-electrode cortical surface recordings and magnetoencephalography (MEG). Here, in two studies, we show that such an approach is also possible with EEG, despite the poorer signal-to-noise ratio of the data. In the first study, we show that it is possible to decode attention in a naturalistic cocktail party scenario on a single trial (≈60 s) basis. In the second, we show that the representation of the envelope of auditory speech in the cortex is more robust when accompanied by visual speech. The sensitivity of this inexpensive, widely-accessible technology for the online monitoring of natural stimuli has implications for the design of future studies of the cocktail party problem and for the implementation of EEG-based brain-computer interfaces.

Neural entrainment to rhythmically presented auditory, visual, and audio-visual speech in children.

Auditory cortical oscillations have been proposed to play an important role in speech perception. It is suggested that the brain may take temporal "samples" of information from the speech stream at different rates, phase resetting ongoing oscillations so that they are aligned with similar frequency bands in the input ("phase locking"). Information from these frequency bands is then bound together for speech perception. To date, there are no explorations of neural phase locking and entrainment to speech input in children. However, it is clear from studies of language acquisition that infants use both visual speech information and auditory speech information in learning. In order to study neural entrainment to speech in typically developing children, we use a rhythmic entrainment paradigm (underlying 2 Hz or delta rate) based on repetition of the syllable "ba," presented in either the auditory modality alone, the visual modality alone, or as auditory-visual speech (via a "talking head"). To ensure attention to the task, children aged 13 years were asked to press a button as fast as possible when the "ba" stimulus violated the rhythm for each stream type. Rhythmic violation depended on delaying the occurrence of a "ba" in the isochronous stream. Neural entrainment was demonstrated for all stream types, and individual differences in standardized measures of language processing were related to auditory entrainment at the theta rate. Further, there was significant modulation of the preferred phase of auditory entrainment in the theta band when visual speech cues were present, indicating cross-modal phase resetting. The rhythmic entrainment paradigm developed here offers a method for exploring individual differences in oscillatory phase locking during development. In particular, a method for assessing neural entrainment and cross-modal phase resetting would be useful for exploring developmental learning difficulties thought to involve temporal sampling, such as dyslexia.

At what time is the cocktail party? A late locus of selective attention to natural speech.

Distinguishing between speakers and focusing attention on one speaker in multi-speaker environments is extremely important in everyday life. Exactly how the brain accomplishes this feat and, in particular, the precise temporal dynamics of this attentional deployment are as yet unknown. A long history of behavioral research using dichotic listening paradigms has debated whether selective attention to speech operates at an early stage of processing based on the physical characteristics of the stimulus or at a later stage during semantic processing. With its poor temporal resolution fMRI has contributed little to the debate, while EEG-ERP paradigms have been hampered by the need to average the EEG in response to discrete stimuli which are superimposed onto ongoing speech. This presents a number of problems, foremost among which is that early attention effects in the form of endogenously generated potentials can be so temporally broad as to mask later attention effects based on the higher level processing of the speech stream. Here we overcome this issue by utilizing the AESPA (auditory evoked spread spectrum analysis) method which allows us to extract temporally detailed responses to two concurrently presented speech streams in natural cocktail-party-like attentional conditions without the need for superimposed probes. We show attentional effects on exogenous stimulus processing in the 200-220 ms range in the left hemisphere. We discuss these effects within the context of research on auditory scene analysis and in terms of a flexible locus of attention that can be deployed at a particular processing stage depending on the task.

Endogenous auditory spatial attention modulates obligatory sensory activity in auditory cortex.

Endogenous attention is the self-directed focus of attention to a region or feature of the environment. In this study, we assess the effects of endogenous attention on temporally detailed responses to continuous and competing auditory stimuli obtained using the novel auditory evoked spread spectrum analysis (AESPA) method. There is some debate as to whether an enhancement of sensory processing is involved in endogenous attention. It has been suggested that attentional effects are not due to increased sensory activity but are due to engagement of separate temporally overlapping nonsensory attention-related activity. There are also issues with the fact that the influence of exogenous attention grabbing mechanisms may hamper studies of endogenous attention. Due to the nature of the AESPA method, the obtained responses represent activity directly related to the stimulus envelope and thus predominantly correspond to obligatory sensory processing. In addition, the continuous nature of the stimuli minimizes exogenous attentional influence. We found attentional modulations at ~136 ms (during the Nc component of the AESPA response) and localized this to auditory cortex. Although the involvement of separate nonsensory attentional centers cannot be ruled out, these findings clearly demonstrate that endogenous attention does modulate obligatory sensory activity in auditory cortex.

Comparing linear and quadratic models of the human auditory system using EEG.

Recent studies have highlighted the importance of system identification as an approach for assessing sensory processing in humans using electroencephalography (EEG). These studies typically use linear impulse response estimates of visual and, more recently, auditory function. These methods, which are known as the VESPA and AESPA (Visual/Auditory Evoked Spread Spectrum Analysis) respectively, have been found to be useful for studying sensory processing in both healthy populations and clinical groups and for studying the effects of cognition on sensory processing. While a nonlinear extension of the VESPA has been previously described, no such extension has yet been examined for the AESPA. This paper investigates such an extension and quantifies the relative contribution of linear and quadratic processes to the EEG in response to novel auditory stimuli. While the ability to accurately predict novel EEG is poor, it is highly significant, with a slightly, but again significantly, greater ability to predict using a quadratic model (r=0.0418) over a linear model (r=0.0361).

Resolving precise temporal processing properties of the auditory system using continuous stimuli.

In natural environments complex and continuous auditory stimulation is virtually ubiquitous. The human auditory system has evolved to efficiently process an infinity of everyday sounds, which range from short, simple bursts of noise to signals with a much higher order of information such as speech. Investigation of temporal processing in this system using the event-related potential (ERP) technique has led to great advances in our knowledge. However, this method is restricted by the need to present simple, discrete, repeated stimuli to obtain a useful response. Alternatively the continuous auditory steady-state response is used, although this method reduces the evoked response to its fundamental frequency component at the expense of useful information on the timing of response transmission through the auditory system. In this report, we describe a method for eliciting a novel ERP, which circumvents these limitations, known as the AESPA (auditory-evoked spread spectrum analysis). This method uses rapid amplitude modulation of audio carrier signals to estimate the impulse response of the auditory system. We show AESPA responses with high signal-to-noise ratios obtained using two types of carrier wave: a 1-kHz tone and broadband noise. To characterize these responses, they are compared with auditory-evoked potentials elicited using standard techniques. A number of similarities and differences between the responses are noted and these are discussed in light of the differing stimulation and analysis methods used. Data are presented that demonstrate the generalizability of the AESPA method and a number of applications are proposed.

Eliciting audio evoked potentials using continuous stimuli.

Noise input signals are commonly used in both linear and non-linear system identification of physiological systems. This method can be applied to electrophysiological analysis of the human auditory system by controlling the modulation of the amplitude of a sound stimulus using a precomputed noise signal. In this study we describe how one can obtain an estimate of the linear response of the auditory system using noise signals and we compare it to a standard auditory evoked potential (AEP). Two different noise modulated sounds are tested, broadband noise (BBN) and a 2kHz tone. Results show that the BBN is better at eliciting notable responses. Results also show that although the SNR of the proposed response to the modulated BBN is generally lower than the standard AEP the two responses do correlate well suggesting that the spread spectrum stimulus is a valid method for elicitation of an AEP.

Can visual evoked potentials be used in biometric identification?

Due to known differences in the anatomical structure of the visual pathways and generators in different individuals, the use of visual evoked potentials offers the possibility of an alternative to existing biometrics methods. A study based on visual evoked potentials from 13 individuals was carried out to assess the best combination of temporal, spectral and AR modeling features to realize a robust biometric. From the results it can be concluded that visual evoked potentials show considerable biometric qualities, with classification accuracies reaching a high of 86.54% and that a specific temporal and spectral combination was found to be optimal. Based on these results the visual evoked potential may be a useful tool in biometric identification when used in conjunction with more established biometric methods.

Psychosocial factors and the response to influenza vaccination in older adults.

OBJECTIVE: We examined the influence of psychological state (depression, negative affect, perceived stress) and social support on pre- and post-vaccination response to influenza vaccine. METHODS: Venous blood was drawn from 37 nursing home residents before and following injection of the trivalent influenza vaccine (comprised of the New Caledonia (NC), Hong Kong (HK), and Panama (Pan) strains of flu). The Geriatric Depression Scale, Perceived Stress Scale, Positive and Negative Affect Schedule, and Multidimensional Scale of Perceived Social Support were completed following the initial blood draw. RESULTS: Social support and perceived stress were correlated with pre-vaccine antibody responses to two of the three vaccine components (HK and NC). Social support was negatively correlated with both pre- and post-vaccine titers to Pan. Depression, positive affect, and negative affect were not related to vaccine response. CONCLUSIONS: Perceived stress and social support influence the rate of decline of antibody titers to previous exposures to some strains of influenza occurring either naturally or via deliberate vaccination.

Genetic sex determination, gender identification and pseudohermaphroditism in the knobbed whelk, Busycon carica (Mollusca: Melongenidae).

We report perhaps the first genic-level molecular documentation of a mammalian-like 'X-linked' mode of sex determination in molluscs. From family inheritance data and observed associations between sex-phenotyped adults and genotypes in Busycon carica, we deduce that a polymorphic microsatellite locus (bc2.2) is diploid and usually heterozygous in females, hemizygous in males, and that its alleles are transmitted from mothers to sons and daughters but from fathers to daughters only. We also employ bc2.2 to estimate near-conception sex ratio in whelk embryos, where gender is indeterminable by visual inspection. Statistical corrections are suggested at both family and population levels to accommodate the presence of homozygous bc2.2 females that could otherwise be genetically mistaken for hemizygous males. Knobbed whelks were thought to be sequential hermaphrodites, but our evidence for genetic dioecy supports an earlier hypothesis that whelks are pseudohermaphroditic (falsely appear to switch functional sex when environmental conditions induce changes in sexual phenotype). These findings highlight the distinction between gender in a genetic versus phenotypic sense.