The rise and fall of fasciculations in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a median survival of 3 years from symptom onset. Accessible and reliable biomarkers of motor neuron decline are urgently needed to quicken the pace of drug discovery. Fasciculations represent an early pathophysiological hallmark of amyotrophic lateral sclerosis and can be reliably detected by high-density surface electromyography. We set out to quantify fasciculation potentials prospectively over 14 months, seeking comparisons with established markers of disease progression. Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome underwent up to seven assessments each. At each assessment, we performed the amyotrophic lateral sclerosis-functional rating scale, sum power score, slow vital capacity, 30-min high-density surface electromyography recordings from biceps and gastrocnemius and the motor unit number index. We employed the Surface Potential Quantification Engine, which is an automated analytical tool to detect and characterize fasciculations. Linear mixed-effect models were employed to account for the pseudoreplication of serial measurements. The amyotrophic lateral sclerosis-functional rating scale declined by 0.65 points per month (P < 0.0001), 35% slower than average. A total of 526 recordings were analysed. Compared with benign fasciculation syndrome, biceps fasciculation frequency in amyotrophic lateral sclerosis was 10 times greater in strong muscles and 40 times greater in weak muscles. This was coupled with a decline in fasciculation frequency among weak muscles of -7.6/min per month (P = 0.003), demonstrating the rise and fall of fasciculation frequency in biceps muscles. Gastrocnemius behaved differently, whereby strong muscles in amyotrophic lateral sclerosis had fasciculation frequencies five times greater than patients with benign fasciculation syndrome while weak muscles were increased by only 1.5 times. Gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles (2.4/min per month, P < 0.0001), which levelled off in weak muscles. Fasciculation amplitude, an easily quantifiable surrogate of the reinnervation process, was highest in the biceps muscles that transitioned from strong to weak during the study. Pooled analysis of >900 000 fasciculations revealed inter-fasciculation intervals <100 ms in the biceps of patients with amyotrophic lateral sclerosis, particularly in strong muscles, consistent with the occurrence of doublets. We hereby present the most comprehensive longitudinal quantification of fasciculation parameters in amyotrophic lateral sclerosis, proposing a unifying model of the interactions between motor unit loss, muscle power and fasciculation frequency. The latter showed promise as a disease biomarker with linear rates of decline in strong gastrocnemius and weak biceps muscles, reflecting the motor unit loss that drives clinical progression.

Arrays of rectangular subcritical speech bands: Intelligibility improved by noise-vocoding and expanding to critical bandwidths.

A previous study [Warren, Bashford, and Lenz (2017). J. Acoust. Soc. Am. 141, EL222-EL227] reported that arrays of subcritical width rectangular speech bands can produce near ceiling sentence intelligibility. The present study used noise-vocoded subcritical band speech arrays with analysis bandwidths of 4%, 2%, 1%, or 0.5% of center frequency. Intelligibility decreased when analysis and noise carrier bandwidths were matched. However, expanding carrier noise bandwidths to a critical bandwidth of 1/3-octave (26%) produced array intelligibilities either equaling or substantially exceeding that of the original speech band arrays. Implications concerning bandwidth requirements of envelope processing and the redundancy of envelope cues are discussed.

Maintaining intelligibility at high intensities with arrays of subcritical width speech bands and interpolated noise.

Speech intelligibility normally declines at high intensities, but this "rollover" effect decreases when steep filtering reduces sentences to an array of rectangular subcritical bands. The present study found that interpolating low intensity noise between the speech bands further decreases rollover, supporting the hypothesis that rollover is normally reduced by lateral inhibition of input from rate-saturated auditory nerve fibers. With noise also present within the speech (a 15 dB signal-to-noise ratio) an array of 6%-wide speech bands with interpolated noise was found to be 9% more intelligible at 100 dB than a spectrally continuous band of speech covering the same frequency range.

Critical bandwidth speech: Arrays of subcritical band speech maintain near-ceiling intelligibility at high amplitudes.

Removal of transition bands from narrow speech passbands through very steep filtering has made it possible to isolate and determine (for the first time) intelligibility of critical bandwidth as well as subcritical bandwidth speech. These rectangular bands have unique intelligibilities when heard singly, paired, or in various multiband arrays spanning the speech spectrum. Thus, a particular sparse spectral array of unfamiliar everyday sentences in this study has demonstrated 98% intelligibility up to 100 dB. Some theoretical and practical applications are suggested.

Remarkable motor recovery after riboflavin therapy in adult-onset Brown-Vialetto-Van Laere syndrome.

The clinical diagnosis of Brown-Vialetto-Van Laere syndrome in this woman with rapidly progressive pontobulbar palsy led to empirical high-dose oral riboflavin (1200 mg/day) therapy. This resulted in a dramatic improvement in her motor function from being anarthric, dysphagic, tetraparetic and in ventilatory failure to living independently with mild dysarthria and distal limb weakness. DNA sequencing of the SLC52A3 gene found compound heterozygous C-terminus mutations, V413A1/D461Y, consistent with recent reports of mutations within the riboflavin transporter genes (SLC52A2 and SLC52A3) in this condition. Early diagnosis and empirical riboflavin therapy can lead to major motor recovery in this condition, that can be sustained with long-term maintenance therapy.

How broadband speech may avoid neural firing rate saturation at high intensities and maintain intelligibility.

Three experiments examined the intelligibility enhancement produced when noise bands flank high intensity rectangular band speech. When white noise flankers were added to the speech individually at a low spectrum level (-30 dB relative to the speech) only the higher frequency flanker produced a significant intelligibility increase (i.e., recovery from intelligibility rollover). However, the lower-frequency flanking noise did produce an equivalent intelligibility increase when its spectrum level was increased by 10 dB. This asymmetrical intensity requirement, and other results, support previous suggestions that intelligibility loss at high intensities is reduced by lateral inhibition in the cochlear nuclei.

When intelligibilities of paired speech bands do not behave the way they are supposed to.

Two rectangular 1/3-octave passbands were derived from different spectral regions of everyday sentences, with the intelligibility of one band approximately twice the others. Both passbands were then filtered to produce a series of narrower rectangular passbands. Each of the original 1/3-octave passbands in turn served as the fixed bandwidth "pedestal" and was paired with each of the series of narrower passbands of the other band. Remarkably, dual band intelligibilities were the same, regardless of which band served as pedestal, so the summed bandwidths determined intelligibility: The summed intelligibilities were irrelevant. Implications of this paradoxical "summed bandwidth rule" are discussed.

Maintaining intelligibility at high speech intensities: evidence of lateral inhibition in the lower auditory pathway.

Three experiments examined the intelligibility enhancement produced when noise bands flank high intensity narrowband speech. Enhancement was unaffected by noise gating (experiment 1), ruling out peripheral adaptation as a source, and was also unaffected by interaural decorrelation of noise bands flanking diotic speech (experiment 2), indicating that enhancement occurs prior to binaural processing. These results support previous suggestions that intelligibility loss at high intensities is reduced by lateral inhibition in the cochlear nuclei. Results from a final experiment suggest that this effect is only ipsilateral, implicating a specific population of inhibitory neurons.

An alternative to the computational Speech Intelligibility Index estimates: direct measurement of rectangular passband intelligibilities.

The need for determining the relative intelligibility of passbands spanning the speech spectrum has been addressed by publications of the American National Standards Institute (ANSI). When the Articulation Index (AI) standard (ANSI, S3.5, 1969, R1986) was developed, available filters confounded passband and slope contributions. The AI procedure and its updated successor, the Speech Intelligibility Index (SII) standard (ANSI, S3.5, 1997, R2007), cancel slope contributions by using intelligibility scores for partially masked highpass and lowpass speech to calculate passband importance values; these values can be converted to passband intelligibility predictions using transfer functions. However, by using very high-order digital filtering, it is now possible to eliminate contributions from filter skirts and produce rectangular passbands. Employing the same commercial recording and the same one-octave passbands published in the SII standard (Table B.3), the present study compares Rectangular Passband Intelligibility (RPI) with SII estimates of intelligibility. The directly measured RPI differs from the computational SII predictions. Advantages resulting from direct measurement are discussed.

Enhancing the intelligibility of high intensity speech: Evidence of inhibition in the lower auditory pathway.

Intelligibility of narrowband speech declines considerably at high intensities, but substantial recovery from this "rollover" occurs when flanking noise bands are added. The present study employed two types of added noise: narrowband noise matching the spectral limits of the rectangular speech band (producing within band masking) versus broadband noise (producing within band masking plus simultaneous enhancement by out of band noise components). When noise added to diotic speech in experiment 1 was interaurally uncorrelated rather than diotic, intelligibility increased 5%, regardless of noise bandwidth. Interestingly, regardless of interaural correlation, intelligibility was 13% higher with broadband rather than narrowband noise, indicating that noise induced recovery from rollover precedes binaural processing. In experiment 2, diotic noise was presented either continuously or gated on and off with individual sentences. Intelligibility was 5% higher with continuous noise, showing adaptation of masking, which occurred regardless of noise bandwidth. Moreover, intelligibility was about 11% higher with broadband rather than narrowband noise, regardless of gating, ruling out peripheral adaptation as a source of recovery from rollover. These and other findings discussed are consistent with previous suggestions that intelligibility at high intensities is preserved by inhibition of rate-saturated auditory nerve input to secondary neurons of the cochlear nucleus.

When noise vocoding can improve the intelligibility of sub-critical band speech.

This study examined the redundancy of spectral and temporal information in everyday sentences, which were reduced to 16 rectangular spectral bands having center frequencies ranging from 250 to 8000 Hz, spaced at 1/3 octave intervals. High-order filtering eliminated contributions from transition bands, and the widths of the resulting effectively rectangular speech bands were varied from 4% down to 0.5%. Intelligibility of these sub-critical bandwidth stimuli ranged from nearly perfect in the 4% bandwidth conditions, down to nearly zero in the 0.5% bandwidth conditions. However, a large intelligibility increase was obtained under the narrower filtering conditions when the speech bands were used to vocode broader noise bands that approximated critical bandwidths (ERBn) at the 16 center frequencies. For example, the 0.5%-and 1%-bandwidth speech stimuli were only about 1% and 20% intelligible, respectively, whereas scores of about 26% and 60%, respectively, were obtained for the ERBn-wide noise bands modulated by the speech bands. These large intelligibility increases occurred despite elimination of spectral fine structure and the addition of stochastic fluctuations to the speech-envelope cues. Results from additional experiments indicate that optimal temporal processing requires that envelope cues stimulate a majority of the fibers comprising an ERBn.

Is intelligibility of adjacent passbands hypoadditive or hyperadditive?

Based on their own findings and reports from other laboratories, H. Müsch and S. Buus [H. Müsch and S. Buus, J. Acoust. Soc. Am. 109, 2896-2909 (2001)] suggested that when heard together, the intelligibilities of adjacent passbands were hypoadditive, and those of disjoint passbands were hyperadditive. A subsequent study employed extremely high order Finite Impulse Response (FIR) filtering that had been shown to effectively eliminate contributions from transition band slopes [R. M. Warren, J. A. Bashford, Jr., and P. W. Lenz, J. Acoust. Soc. Am. 118, 3261-3266 (2005)]. That study measured the intelligibility for each of the 15 possible pairings of six one-octave effectively rectangular passbands (3 dB/Hz filter skirts) that spanned the speech spectrum with center frequencies ranging from 0.25 to 8 kHz. Each pairing, whether contiguous or disjoint, exhibited hyperadditivity. The present study determined whether decreasing the filter skirts to 0.5 dB/Hz (considered quite steep by conventional standards) would produce the hypoadditivity reported in literature for adjacent bands. Results obtained support the hypothesis that redundancy introduced by overlapping transition band slopes could be responsible for the redundancy correction factor employed by some models for estimating intelligibility of paired adjacent passbands. [Work supported by NIH.].

The spread and density of the phonological neighborhood can strongly influence the verbal transformation illusion.

When a recorded verbal stimulus repeats over and over, adaptation occurs and listeners hear competing forms. Reports of these "verbal transformations" (VTs) were obtained for 36 consonant-vowel (CV) syllables that varied both in frequency-weighted neighborhood density (ranging from 12.73 to 90.42) and in neighborhood spread [i.e., for 18 CVs, changes at either phoneme position could yield real words (spread = 2) while for the remaining 18 CVs, changes at only one position could yield words (spread = 1)]. The strength of the VT illusion, measured by the amount of time the stimuli were heard nonveridically during the 300-s repetition period, decreased substantially with both increasing neighborhood density [r=-0.74, F(1,34)=42.6, p<0.0001] and increasing spread [r=-0.75, F(1,34) = 44.1, p<0.0001]. Stepwise regression revealed that density and spread collectively accounted for approximately 70% of the variance in illusion strength [F(1,33)>=10.0, p<0.003 or better]. These effects are larger than, but generally consistent with, neighborhood effects obtained with other psycholinguistic tasks, and they suggest that VTs can provide a highly sensitive measure of lexical competition. [Work supported by NIH.].

Evoking biphone neighborhoods with verbal transformations: illusory changes demonstrate both lexical competition and inhibition.

When a recorded verbal stimulus repeats over and over, perceptual changes occur and listeners hear competing forms. These verbal transformations (VTs) were obtained for a phonemically related set of 24 consonant-vowel syllables that varied widely in frequency-weighted neighborhood density (FWND). Listener's initial transformations involving substitution of consonants versus vowels were strongly correlated with the lexical substitution neighborhood [r=+0.82, p<0.0001]. Interestingly, as stimulus FWND increased, average time spent hearing illusory forms substantially decreased [r=-0.75, p<0.0001]. These results suggest that VTs not only reveal underlying competitors, but also provide a highly sensitive measure of lexical inhibition.

Polling the effective neighborhoods of spoken words with the verbal transformation effect.

Studies of the effects of lexical neighbors upon the recognition of spoken words have generally assumed that the most salient competitors differ by a single phoneme. The present study employs a procedure that induces the listeners to perceive and call out the salient competitors. By presenting a recording of a monosyllable repeated over and over, perceptual adaptation is produced, and perception of the stimulus is replaced by perception of a competitor. Reports from groups of subjects were obtained for monosyllables that vary in their frequency-weighted neighborhood density. The findings are compared with predictions based upon the neighborhood activation model.

Intelligibilities of 1-octave rectangular bands spanning the speech spectrum when heard separately and paired.

There is a need, both for speech theory and for many practical applications, to know the intelligibilities of individual passbands that span the speech spectrum when they are heard singly and in combination. While indirect procedures have been employed for estimating passband intelligibilities (e.g., the Speech Intelligibility Index), direct measurements have been blocked by the confounding contributions from transition band slopes that accompany filtering. A recent study has reported that slopes of several thousand dBA/octave produced by high-order finite impulse response filtering were required to produce the effectively rectangular bands necessary to eliminate appreciable contributions from transition bands [Warren et al., J. Acoust. Soc. Am. 115, 1292-1295 (2004)]. Using such essentially vertical slopes, the present study employed sentences, and reports the intelligibilities of their six 1-octave contiguous passbands having center frequencies from 0.25 to 8 kHz when heard alone, and for each of their 15 possible pairings.

Enhancing intelligibility of narrowband speech with out-of-band noise: evidence for lateral suppression at high-normal intensity.

Previous studies have shown that the intelligibility of filtered speech can be enhanced by filling stopbands with noise. The present study found that this enhancement occurred only when speech intensity was sufficiently high to degrade performance. Intelligibility decreased by about 15% when narrowband speech was increased from 45 to 65 dBA (corresponding to broadband speech levels of about 60 and 80 dBA), and decreased by 20% at a level of 75 dBA. However, when flanking bands of low-pass and high-pass filtered white noise were added at spectrum levels of -40 to -20 dB relative to the speech, intelligibility of the 75-dBA speech band increased by about 13%. Additional findings confirm that this enhancement of intelligibility depends upon out-of-band stimulation, in agreement with theories proposing that lateral suppressive interactions extend the dynamic range of intensity coding by counteracting effects of auditory-nerve firing-rate saturation at high signal levels.

Intelligibility of bandpass filtered speech: steepness of slopes required to eliminate transition band contributions.

Despite the recognition that the steepness of filter slopes can play an important role in the intelligibility of bandpass speech, there has been no systematic examination of its importance. The present study used high orders of finite impulse response (FIR) filtering to produce slopes ranging from 150 to 10,000 dB/octave. The slopes flanked 1/3-octave passbands of everyday sentences having a center frequency of 1500 Hz (the region of highest intelligibility for the male speaker's voice). Presentation levels were approximately 75 and 45 dB. No significant differences were found for the two presentation levels. Average intelligibility scores ranged from 77% at 150 dB/octave down to the asymptotic intelligibility score of 12% at 4800 dB/octave. These results indicate that slopes of several thousand dB/octave may be required for accurate and unambiguous specification of the range of frequencies contributing to intelligibility of filtered speech. In addition, the extremely steep slopes are needed to ensure that none of the spectral components contributing to intelligibility has its relative importance diminished by spectral tilt.

Relative contributions of passband and filter skirts to the intelligibility of bandpass speech: Some effects of context and amplitude.

Warren et al. (1995) reported over 90% intelligibility for everyday sentences reduced to a 1/3-octave band (center frequency 1,500 Hz, slopes 100 dB/octave, slow-rms peak levels 75 dB). To investigate the basis of this high intelligibility, Warren and Bashford (1999) partitioned the sentences. Surprisingly, the rectangular 1/3-octave passband had only 24% intelligibility, whereas the filter skirts separated by a 1/3-octave notch had an intelligibility of 83%, despite their severe spectral tilts. Experiment 1 of the present study substituted monosyllabic words for sentences. Wholeband intelligibility was 26%, the passband 4%, and the filter skirts 16%. Experiment 2 measured intelligibility for 1/3-octave sentences having peak levels ranging from 85 down to 35 dB. Whole band intelligibility ranged from 90% to 68%, and the filter skirt pairs had from two to four times the passband's intelligibility (which did not vary significantly with level). Hence, steep (100 dB/octave) filter skirts make the dominant contribution to intelligibility of nominally 1/3-octave speech across a wide range of presentation levels.