Adductor Laryngeal Dystonia Research Articles

Adductor Laryngeal Dystonia Versus Muscle Tension Dysphonia: Examining the Utility of Automated Acoustic Analysis to Detect Task Dependency as a Distinguishing Feature.

Differentiating adductor laryngeal dystonia (ADLD) and primary muscle tension dysphonia (pMTD) can be challenging. Unlike pMTD, ADLD is described as "task-dependent" with voiced phonemes purportedly provoking greater sign expression than voiceless phonemes. We evaluated the ability of two automated acoustic measures, the Cepstral Spectral Index of Dysphonia (CSID) and creak, to detect task dependency and to discriminate ADLD and pMTD. CSID, % creak, and listener ratings of dysphonia severity were obtained from audio recordings of patients with ADLD (n = 29) or pMTD (n = 33) reading two sentences loaded with either voiced or voiceless phonemes. Group × Sentence Type interaction effects confirmed that both "normalized" CSID and % creak detected task-dependent sign expression in ADLD (i.e., worse symptoms on the voiced- vs. voiceless-loaded sentence). However, a stepwise binary logistic regression analysis with group (ADLD vs. pMTD) as the dependent variable and % creak and normalized CSID variables (voiced, voiceless, and voiced vs. voiceless difference) as covariates revealed that the normalized CSID voiceless-laden sentence z score was the only significant predictor of group membership. Estimates of diagnostic precision from the normalized CSID voiceless sentence z scores were superior to % creak or listener ratings. Finally, the CSID possessed the strongest correlations with listener severity ratings regardless of group or sentence type. Although both normalized CSID and % creak detected task-dependent performance as a distinguishing feature of ADLD, a CSID profile wherein (a) the voiceless sentence z score was less severe than the voiced sentence and (b) the normalized voiceless sentence z score was within approximately 2 SDs (or less) of typical expectations provided the best estimates of diagnostic precision. Automated acoustic measures such as the CSID and creak provide useful information to objectively discriminate ADLD and pMTD.

Supraglottic Laryngeal Maneuvers in Adductor Laryngeal Dystonia During Connected Speech

ObjectiveAdductor laryngeal dystonia (AdLD) disrupts fine motor movements of vocal folds during speech, resulting in a strained, broken, and strangled voice. Laryngeal high-speed videoendoscopy (HSV) in connected speech enables the direct visualization of detailed laryngeal dynamics, hence, it can be effectively used to study AdLD. The current study utilizes HSV to investigate supraglottic laryngeal tissue maneuvers obstructing the view of the vocal folds, in AdLD and normophonic speakers during connected speech. Characterizing the laryngeal maneuvers in these groups can facilitate a deeper understanding of the normophonic voice physiology and AdLD voice pathophysiology. MethodsHSV data were obtained from six normophonic speakers and six patients with AdLD during production of connected speech. Three experienced raters visually analyzed the data to determine laryngeal tissues leading to obstructions of vocal folds in HSV images. The raters recorded the duration of each obstruction and indicated the specific tissue(s) leading to the obstruction After the completion of their individual visual analysis, the raters came to consensus about their observations and measurements. ResultsStatistical analysis indicated that AdLD patients exhibited higher occurrences of vocal fold obstructions and longer durations of obstructions compared to the normophonic group. Similar obstruction types were found in both groups, with the epiglottis being the primary site of obstruction for both. Participants with AdLD displayed significantly elevated occurrences of sphincteric compression resulting in vocal fold obstruction. ConclusionHSV can be used to study the movements of laryngeal tissues in detail during connected speech. The analysis of supraglottic laryngeal tissue dynamics in speech can help us characterize the AdLD pathophysiology. The study's findings regarding the tissues implicated in obstructions may potentially inform the development of patient-specific therapeutic strategies targeting individual control over specific laryngeal muscles during phonation and speech production.

"Lombard Effect" and Voice Changes in Adductor Laryngeal Dystonia: A Pilot Study.

The aim was to describe the acoustic, auditory-perceptive, and subjective voice changes under the Lombard effect (LE) in adductor laryngeal dystonia (AdLD) patients. Subjective perception of vocal effort (OMNI Vocal Effort Scale OMNI-VES), Maximum Phonation Time (MPT), and the perceptual severity of dysphonia (GRBAS scale) were assessed in condition of stillness and under LE in 10 AdLD patients and in 10 patients with typical voice. Speakers were asked to produce the sustained vowel /a/ and to read a phonetically balanced text aloud. Using the PRAAT software, the following acoustic parameters were analyzed: Mean Pitch (Hz), Minimum and Maximum Intensity (dB), the Fraction of Locally Unvoiced Frames, the Number of Voice Breaks, the Degree of Voice Breaks (%), the Cepstral Peak Prominence-Smoothed (CPPS) (dB). Under LE, the AdLD group showed a decrease of both G and S parameters of GRBAS and subjective effort, mean MPT increased significantly; in the controls there were no significant changes. In both groups under LE, pitch and intensity of the sustained vowel /a/ significantly increased consistently with LE. In the AdLD group the mean gain of OMNI-VES score and the mean gain of each parameter of the speech analysis were significantly greater than the controls' ones. Auditory feedback deprivation obtained under LE improves subjective, perceptual-auditory, and acoustics parameters of AdLD patients. These findings encourage further research to provide new knowledge into the role of the auditory system in the pathogenesis of AdLD and to develop new therapeutic strategies. 4 Laryngoscope, 134:3754-3760, 2024.

The Effect of Rating Method on Reliability of Judgments of Strain Across Populations.

Variability in auditory-perceptual ratings of voice limits their utility, with the poorest reliability often noted for vocal strain. The purpose of this study was to determine whether an experimental method, called visual sort and rate (VSR), promoted stronger rater reliability than visual analog scale (VAS), for ratings of strain in two clinical populations: adductor laryngeal dystonia (ADLD) and vocal hyperfunction (VH). Connected speech samples from speakers with ADLD and VH as well as age- and sex-matched controls were selected from a database. Fifteen inexperienced listeners rated strain for two speaker sets (25 ADLD speakers and five controls; 25 VH speakers and five controls) across four rating blocks: VAS-ADLD, VSR-ADLD, VAS-VH, and VSR-VH. For the VAS task, listeners rated each speaker for strain using a vertically oriented 100-mm VAS. For the VSR task, stimuli were distributed into sets of samples with a range of severities in each set. Listeners sorted and ranked samples for strain within each set, and final ratings were captured on a vertically oriented 100-mm VAS. Intrarater reliability (Pearson's r) and interrater variability (mean of the squared differences between a listener's ratings and group mean ratings) were compared across rating methods and populations using two repeated-measures analyses of variance. Intrarater reliability of strain was significantly stronger when listeners used VSR compared to VAS; listeners also showed significantly better intrarater reliability in ADLD than VH. Listeners demonstrated significantly less interrater variability (better reliability) when using VSR compared to VAS. No significant effect of population or interactions was found between listeners for measures of interrater variability. VSR increases intrarater reliability for ratings of vocal strain in speakers with VH and ADLD. VSR decreases variability of auditory-perceptual judgments of strain between inexperienced listeners in these clinical populations. Future research should determine whether benefits of VSR extend to voice clinicians and/or clinical settings.

Deep Learning-Based Analysis of Glottal Attack and Offset Times in Adductor Laryngeal Dystonia.

Diagnosis of adductor laryngeal dystonia (AdLD) is challenging as it mimics voice features of other voice disorders. This could lead to misdiagnosis (or delayed diagnosis) and ineffective treatments of AdLD. This paper develops automated measurements of glottal attack time (GAT) and glottal offset time (GOT) from high-speed videoendoscopy (HSV) in connected speech as objective measures that can potentially facilitate the diagnosis of this disorder in the future. HSV data were recorded from vocally normal adults and patients with AdLD during the reading of the "Rainbow Passage" and six CAPE-V (Consensus Auditory-Perceptual Evaluation of Voice) sentences. A deep learning framework was designed and trained to segment the glottal area and detect the vocal fold edges in the HSV dataset. This automated framework allowed us to automatically measure and quantify the GATs and GOTs for the participants. Accordingly, a comparison was held between the obtained measurements among vocally normal speakers and those with AdLD. The automated framework was successfully developed and able to accurately segment the glottal area/edges. The precise automated measurements of GAT and GOT revealed minor, nonsignificant differences compared to the results of manual analysis-showing a strong correlation between the measures by the automated and manual methods. The results showed significant differences in the GAT values between the vocally normal subjects and AdLD patients, with larger variability in both the GAT and GOT measures in the AdLD group. The developed automated approach for GAT and GOT measurement can be valuable in clinical practice. These quantitative measurements can be used as meaningful biomarkers of the impaired vocal function in AdLD and help its differential diagnosis in the future.

Reliability of Phonemically Loaded Sentences in Spanish for Identifying Laryngeal Dystonia by Non-Spanish Speaking Speech-Language Pathologists

Laryngeal dystonia (LD) is a focal dystonia affecting the intrinsic laryngeal muscles. Clinical diagnosis requires subjective evaluation by experienced clinicians and is primarily based on auditory-perceptual assessment. Several speech tasks are widely accepted to elicit diagnosis specific auditory-perceptual symptoms of glottal stops in adductor LD or breathy breaks in abductor LD in spoken English. With the growing Spanish speaking population in the US and lack of Spanish speech tasks to assist in identifying LD in Spanish speaking subjects, assessing the reliability of phonemically loaded sentences in Spanish for use by non-Spanish speaking providers is critical. The first aim of this study was to develop and assess the reliability of a set of Spanish language phonemically loaded sentences designed to elicit signs and symptoms of LD. The second aim was to determine the effectiveness of non-Spanish speaking speech-language pathologists (SLPs) in identifying LD in Spanish speaking subjects using these stimuli. Phonemically loaded sentences were developed for this study following current guidelines for assessment of LD. Voice samples were obtained from native Spanish speaking individuals. Participant-speakers included 20 people with LD and 20 people without LD who served as controls. All participant-speakers were assessed by a Spanish-speaking laryngologist. Audio samples were presented to non-Spanish speaking SLPs with expertise in working with people with LD who served as raters and classified the samples as either presence or absence of LD. Kappa and the intra-class correlation coefficient were calculated and mixed effects logistic regression was used for prediction. The inter and intra-rater reliability indicated statistically significant agreement. Sensitivity, specificity, and predictive values for the diagnosis of LD by the raters were overall strong. Findings demonstrate that non-Spanish speaking SLPs with expertise in the assessment and treatment of LD can reliably identify the presence of LD using Spanish language stimuli in Spanish-speaking individuals. This study supports the use of newly developed Spanish language phonemically loaded voiced and voiceless sentences by English speaking clinicians as an effective tool for identifying LD in Spanish speakers, perhaps mitigating diagnostic delays experienced by patients with LD.

Vocal Vibration Opening Onset Position Abnormality in Patients With Adductor Spasmodic Dystonia by Using High-Speed Endoscopy

To analyze vocal fold vibration onset in patients with adductor laryngeal dystonia (ADLD) by analyzing vocal vibration opening onset position (VVOOP). Case-control study SETTING: A voice center. Eleven patients with ADLD diagnosed in our voice center were enrolled in the ADLD group. Eleven healthy subjects matched by exact age and gender to the ADLD patients were selected as the control group. All subjects underwent laryngeal high-speed video endoscopy. VVOOP and its change were assessed by two otolaryngologists. The multiline video kymography was used to analyze the openquotient (OQ) and standard deviation of OQ. VVOOP had more than one position in 54.6% (6/11) of the patients with ADLD, which was higher than the control group (P<0.05). VVOOP appeared in the front of the vocal fold in 54.6% (6/11) of patients with ADLD and in the back of the vocal fold in 81.8% (9/11) of patients with ADLD. VVOOP can be abnormal in 90.9% (10/11) of patients with ADLD, and the rate of VVOOP abnormality was higher than that of the control group (P<0.05). Of 11, 6 (54.6%) patients with ADLD had a variable VVOOP; thevariability rate of VVOOP was higher than that in the control group(P<0.05). OQ and OQ standard deviation in the ADLD group were significantly greater than in the control group (P<0.05). In patients with ADLD, vocal fold vibration was irregular, and VVOOP was abnormal and had a variable position and could reflect variability of the vocal vibration. Level 4.

Probing the inhibitory motor circuits in adductor laryngeal dystonia during a dystonia-unrelated task

BackgroundThe pathophysiology of adductor laryngeal dystonia (AdLD) remains unknown; however, there is growing evidence that dystonia is associated with disruptions in the inhibitory regulation of sensorimotor cortical areas. Using functional MRI (fMRI) and transcranial magnetic stimulation (TMS) complementarily, we previously demonstrated an overly activated laryngeal motor cortex and revealed correlations between blood-oxygen-level dependent (BOLD) activation and intracortical inhibition in a phonation (dystonia-related) task in adductor laryngeal dystonia (AdLD). ObjectiveHere, we aimed to characterize the brain-based findings in the primary motor cortex (M1) during a dystonia-unrelated (finger tapping) task in AdLD and controls (CTL). MethodsWe examined the between-group differences in task-dependent BOLD activation and intracortical inhibition, measured by the TMS-evoked cortical silent period (cSP), in the M1. The correlations between fMRI and TMS responses were assessed. ResultsThere is more broadly dispersed BOLD activation, not confined to the hand motor cortex, and reduced intracortical inhibition in AdLD compared to CTL. Further, there are more positive correlations between cSP and BOLD activation in a task unrelated to dystonic symptoms in AdLD compared with CTL. This is in contrast to our previous work that demonstrated fewer positive correlations in AdLD during a dystonic phonation task. ConclusionsIn unaffected musculature activation, there is dispersed BOLD activation that is correlated with intracortical inhibition suggesting a possible compensatory strategy in the non-dystonic muscles.

Improved vocal quality and decreased vocal effort after botulinum toxin treatment for laryngeal dystonia

Objectives: Laryngeal dystonia (LD) is characterized by irregular and involuntary task-specific spasms of the intrinsic laryngeal muscles. There is no curative treatment for it, however, laryngeal botulinum neurotoxin injections (BoNT-I) are considered the standard of care therapy. This study aims to characterize the population of LD patients and to assess the results of laryngeal BoNT-I.Methods: A Retrospective cohort study was conducted. Medical records were reviewed for all the patients with LD diagnosis seen in the Voice Unit of the Red de Salud UCChristus between January 2013 and October 2021. Biodemographic, clinical and treatment data were collected. Additionally, a telephonic survey was completed by the patients that underwent laryngeal BoNT-I, including self-reported voice outcomes and Voice Handicap Index 10 (VHI-10).Results: Of the 34 patients with LD included in the study, 23 received a total of 93 laryngeal BoNT-I and 19 completed the telephone survey. The majority (97%) of the injections corresponded to patients with adductor LD and 3% to abductor LD. Patients received a median of 3 (1–17) injections, with a more frequent cricothyroid approach (94.4%), while the thyrohyoid approach accounted for 5.6% of cases. Most injections were bilateral (96.8%). A significant improvement in the vocal quality and effort was noted after the last injection and the overall BoNT-I treatment (P < 0.001). Similarly, the VHI-10 score improved from a median of 31 (7–40) to 2 (0–19) (P < 0.001) after the last injection. A post-treatment breathy voice was reported in 95% of patients, and dysphagia to liquids and solids in 68% and 21%, respectively.Conclusions: Laryngeal BoNT-I is an effective treatment for LD, achieving an improvement in self-reported vocal quality and VHI-10 scores, and a reduction of the self-reported vocal effort. Adverse effects are mild in the majority of cases, constituting a safe and effective therapy for these patients.

Assessment of Patients Receiving Short-Interval Botulinum Toxin Chemodenervation Treatment for Laryngeal Dystonia and Essential Tremor of the Vocal Tract

The gold-standard treatment for laryngeal dystonia (LD) and essential tremor of the vocal tract (ETVT) is botulinum toxin (BoNT) chemodenervation. Although safe and effective, it is not curative, and periodic injections are required. Some medical insurance companies only cover injections at a 3-month interval, though some patients benefit from injections more frequently. To determine the proportion and characteristics of patients who receive BoNT chemodenervation treatment in intervals shorter than 90 days. This retrospective cohort study across 3 quaternary care neurolaryngology specialty practices in Washington and California recruited patients who underwent at least 4 consecutive laryngeal BoNT injections for LD and/or ETVT in the past 5 years. Data were collected from March through June 2022 and analyzed from June through December 2022. Laryngeal BoNT treatment. Biodemographic and clinical variables, injection characteristics, evolution during the 3 interinjection intervals, and lifetime laryngeal BoNT treatment data were collected from patient medical records. Logistic regression was used to assess association to the short-interval outcome, defined as an average injection interval shorter than 90 days. Of 255 patients included from the 3 institutions, 189 (74.1%) were female, and the mean (SD) age was 62.7 (14.3) years. The predominant diagnosis was adductor LD (n = 199 [78.0%]), followed by adductor dystonic voice tremor (n = 26 [10.2%]) and ETVT (n = 13 [5.1%]). Seventy patients (27.5%) received short-interval injections (<90 days). The short-interval group was younger than the long-interval group (≥90 days), with a mean (SD) age of 58.6 (15.5) years and 64.2 (13.5) years, respectively, and a mean difference of -5.7 years (95% CI, -9.6 to -1.8 years). There were no patient-related differences between the short- and long-interval groups in terms of sex, employment status, or diagnosis. This cohort study demonstrated that while insurance companies often mandate a 3-month or greater interval for BoNT chemodenervation financial coverage, there is a considerable subset of patients with LD and ETVT who receive short-interval treatment to optimize their vocal function. Short-interval chemodenervation injections demonstrate a similar adverse effect profile and do not appear to predispose to resistance through antibody formation.

Comparison of Outcome Measures (Subjective, Objective, and Patient-Based) in Laryngeal Dystonia Treatment With Botulinum Toxin A Injection

Outcome assessment in laryngeal dystonia is hindered by lack of consensus on a core set of outcome measures to quantify treatment effect and disease severity on quality of life. Potential outcome measure domains include objective voice, clinician reported, and patient reported outcome measures (PROMs) for determining treatment success and longitudinal disease tracking. We aim to determine correlations between a selections of outcome measure tools following Botulinum toxin injection. A selection of instruments were administered to assess adductor laryngeal dystonia patient outcomes before and after Botulinum toxin injection. Voice samples recorded using a cellular telephone application were used for objective acoustic measures (CPPS, acoustic voice quality index) and speech language pathologist perceptual analysis (CAPE-V). Additionally, patients completed a PROMs battery consisting of the Voice Handicap Index-10, Communicative Participation Item Bank-10, OMNI-Vocal Effort Scale, 3 visual analog scale (VAS) questions. Changes in these outcome measures pre-post treatment were compared between each other and with a global rating of change questionnaire (GRCQ) using Spearman's rank correlation coefficients. Twenty six patients (20 female, mean age 57.7 years) participated. Using an anchor based GRCQ, patients reported Botox efficacy was the only outcome measure found to have significant correlation (r=0.54, P=0.022); all other outcome measures did not meet statistically significant correlation. Amongst the selected outcome tools, several moderate-strong correlations were identified, largely for outcome measures within the same domain. Most notable were correlations between the patient reported OMNI-VES and VAS questions (r > 0.68, P < 0.05), clinician CAPE-V strain and overall severity (r=0.900, P < 0.001), and acoustic voice quality index with sustained vowel CPPs (r=-0.797, P=0.002). Correlation between outcome measures instruments used for patients with adductor laryngeal dystonia requires further attention. Weak correlations with an anchor based GRCQ were found for this study's selected outcome instruments. A select number of correlations were found between outcome instruments within each of the individual outcome measure domains (patient perception, clinical perception, objective acoustics), but there was largely a lack of correlation found for instruments between these three separate domains.

Automated Creak Differentiates Adductor Laryngeal Dystonia and Muscle Tension Dysphonia.

The purpose of this study was to determine whether automated estimates of vocal creak would differentiate speakers with adductor laryngeal dystonia (AdLD) from speakers with muscle tension dysphonia (MTD) and speakers without voice disorders. Sixteen speakers with AdLD, sixteen speakers with MTD, and sixteen speakers without voice disorders were recorded in a quiet environment reading aloud a standard paragraph. An open-source creak detector was used to calculate the percentage of creak (% creak) in each of the speaker's six recorded sentences. A Kruskal-Wallis one-way analysis of variance revealed a statistically significant effect of group on the % creak with a large effect size. Pairwise Wilcoxon tests revealed a statistically significant difference in % creak between speakers with AdLD and controls as well as between speakers with AdLD and MTD. Receiver operating characteristic curve analyses indicated that % creak differentiated AdLD from both controls and speakers with MTD with high sensitivity and specificity (area under the curve statistics of 0.94 and 0.86, respectively). Percentage of creak as calculated by an automated creak detector may be useful as a quantitative indicator of AdLD, demonstrating the potential for use as a screening tool or to aid in a differential diagnosis. 3 Laryngoscope, 2023.

Symptom Expression Across Voiced Speech Sounds in Adductor Laryngeal Dystonia

Differential diagnosis for adductor laryngeal dystonia (AdLD) is often carried out by comparing symptom expression during sentences with either all voiced or voiced and voiceless consonants. However, empirical research examining the effects of phonetic context on symptoms is sparse. The purpose of this study was to examine whether symptom probabilities varied across voiced speech segments in an all-voiced sentence, and whether this variability was systematic with respect to phonetic features. Eighteen speakers with AdLD read aloud a sentence comprised entirely of voiced speech sounds. Speech segment boundaries and AdLD symptoms (phonatory breaks, frequency shifts, and creak) were labeled separately, and speech segments were coded as symptomatic or asymptomatic based on their temporal overlap. Generalized linear mixed effects models with a binomial outcome variable were used to compare the probability of symptom expression across: 1) all speech segments in the sentence, and 2) four speech sound classes (vowels, approximants, nasals, and obstruents). Significant symptom variability was found across voiced speech segments in the sentence. Furthermore, the estimated probability of a symptom occurring on vowels and approximants was significantly greater than that of nasals and obstruents. These results indicate that AdLD symptoms are not uniformly distributed across voiced speech segments with systematic variation across speech sound classes.To explain these findings, future work should investigate how the complex interactions between the vocal tract articulators and glottal configurations may influence symptom expression in this population.

Abnormal Laryngopharyngeal Sensation in Adductor Laryngeal Dystonia Compared to Healthy Controls.

Laryngeal sensory abnormality has been implicated as a component of adductor laryngeal dystonia (AdLD). The study objective was to assess laryngopharyngeal sensation in AdLD utilizing a calibrated, tactile aesthesiometer to deliver differential stimuli to lateral pyriform sinus (LPS), aryepiglottic fold (AEF), and false vocal fold (FVF). Patients with known Botox-responsive AdLD underwent sensory testing using a previously-validated methodology involving calibrated tactile stimuli (6-0, 5-0, 4.5-0, 4-0 nylon monofilaments). Laryngeal adductor reflex (LAR) and participant-rated perceptual strength of stimulI were evaluated. Responses were compared to normative controls (n=33). Two-samples, Mann-Whitney and Fisher exact tests compared mean strength ratings and LAR between AdLD and control groups. Mixed-effects logistic regression and linear models assessed association of filament size, stimulus site, age, sex, and LD status on LAR and perceptual strength rating respectively. Thirteen AdLD patients (nine women, mean age 60+/-15 years) completed testing. Average LAR response rates were higher amongst all filament sizes in AdLD versus controls at LPS (56.3% vs. 35.7%) and AEF (96.1% vs. 70.2%) with comparable rates at FVF (90.2% vs. 91.7%). AdLD had 3.3 times the odds of observed LAR compared to controls (p=0.005), but differences in subjective detection of stimuli, perceptual strength ratings, and cough/gag rates were insignificant on multivariate modeling (p > 0.05). This is the first study to objectively assess laryngopharyngeal sensation in AdLD. Findings demonstrated increased laryngopharyngeal sensation in AdLD compared to controls. The identification of increased laryngeal hypersensitivity in these patients may improve understanding of AdLD pathophysiology and identify future targets for intervention. 2 Laryngoscope, 133:2271-2278, 2023.

Spectral Aggregate of the High-Passed Fundamental Frequency and Its Relationship to the Primary Acoustic Features of Adductor Laryngeal Dystonia.

Currently, no clinically feasible objective measures exist that are specific to the signs of adductor laryngeal dystonia (LD), deterring effective diagnosis and treatment. This project sought to establish concurrent validity of a new automated acoustic outcome measure, designed to be specific to adductor laryngeal dystonia (AdLD): the spectral aggregate of the high-passed fundamental frequency contour (SAHf o). Twenty speakers with AdLD read voiced phoneme-loaded (more symptomatic) and voiceless phoneme-loaded (less symptomatic) sentences. LD discontinuities (defined as phonatory breaks, frequency shifts, and creak), the acoustic ramifications of laryngeal spasms, were manually identified. The frequency content of the f o contour was examined as a function of time, and content above 1000 Hz was summed to automatically calculate SAHf o. Multiple linear regression analysis was applied to SAHf o based on LD discontinuities and sentence type (voiced or voiceless phoneme-loaded). The regression model accounted for 41.1% of the variance in SAHf o. Both the LD discontinuities and sentence type were statistically related to SAHf o. Results of this study provide evidence of concurrent validity. SAHf o is an automatic outcome measure specific to acoustic signs of AdLD that may be useful to track treatment progress.

A novel phenotype in an Italian family with a rare progranulin mutation

IntroductionProgranulin (PGRN) is a secreted glycoprotein encoded in humans by the GRN gene, located on chromosome 17q21. Several nonsense and missense pathogenetic GRN mutations have been described.ObjectiveWe herein describe two sisters carrying a rare GRN mutation with extremely different clinical features and family history of dementia and behavioral disorders, with a novel presentation with stridor and dysphonia.MethodsPatients underwent a multidimensional assessment including neurological and neuropsychological evaluation, structural and functional imaging, and genetic screening.ResultsThe younger sister presented at the age of 64 with inspiratory stridor, dysphonia and exercise-induced dyspnea. Transnasal fiberoptic laryngoscopy showed bilateral adduction of the vocal cords at rest and paradoxical further adduction of the vocal cords during forced inspiration, suggesting the hypothesis of an adductor laryngeal dystonia. The older sister presented at the age of 63 with a rapidly progressive corticobasal syndrome. The only clinical feature common to both sisters was a dysexecutive syndrome. The c.893G > A mutation in exon 9 of GRN was found in heterozygosis in both sisters, causing a missense Arginine to Histidine substitution in position 298 of the protein (p.R298H).ConclusionsOur report supports the pathogenicity of the GRN p.R298H mutation, which is first detected in two members from the same family, showing an extremely different phenotypes. Moreover, we report the first case of an FTD-associated mutation presenting with inspiratory stridor and dysphonia linked to adductor laryngeal dystonia, thus expanding the clinical spectrum of GRN-related disorders.

The Patho-Neurophysiological Basis and Treatment of Focal Laryngeal Dystonia: A Narrative Review and Two Case Reports Applying TMS over the Laryngeal Motor Cortex.

Focal laryngeal dystonia (LD) is a rare, idiopathic disease affecting the laryngeal musculature with an unknown cause and clinically presented as adductor LD or rarely as abductor LD. The most effective treatment options include the injection of botulinum toxin (BoNT) into the affected laryngeal muscle. The aim of this narrative review is to summarize the patho-neuro-physiological and genetic background of LD, as well as the standard recommended therapy (BoNT) and pharmacological treatment options, and to discuss possible treatment perspectives using neuro-modulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and vibrotactile stimulation. The review will present two LD cases, patients with adductor and abductor LD, standard diagnostic procedure, treatments and achievement, and the results of cortical excitability mapping the primary motor cortex for the representation of the laryngeal muscles in the assessment of corticospinal and corticobulbar excitability.

Temporal specificity of abnormal neural oscillations during phonatory events in laryngeal dystonia.

Laryngeal dystonia is a debilitating disorder of voicing in which the laryngeal muscles are intermittently in spasm resulting in involuntary interruptions during speech. The central pathophysiology of laryngeal dystonia, underlying computational impairments in vocal motor control, remains poorly understood. Although prior imaging studies have found aberrant activity in the CNS during phonation in patients with laryngeal dystonia, it is not known at what timepoints during phonation these abnormalities emerge and what function may be impaired. To investigate this question, we recruited 22 adductor laryngeal dystonia patients (15 female, age range = 28.83–72.46 years) and 18 controls (eight female, age range = 27.40–71.34 years). We leveraged the fine temporal resolution of magnetoencephalography to monitor neural activity around glottal movement onset, subsequent voice onset and after the onset of pitch feedback perturbations. We examined event-related beta-band (12–30 Hz) and high-gamma-band (65–150 Hz) neural oscillations. Prior to glottal movement onset, we observed abnormal frontoparietal motor preparatory activity. After glottal movement onset, we observed abnormal activity in the somatosensory cortex persisting through voice onset. Prior to voice onset and continuing after, we also observed abnormal activity in the auditory cortex and the cerebellum. After pitch feedback perturbation onset, we observed no differences between controls and patients in their behavioural responses to the perturbation. But in patients, we did find abnormal activity in brain regions thought to be involved in the auditory feedback control of vocal pitch (premotor, motor, somatosensory and auditory cortices). Our study results confirm the abnormal processing of somatosensory feedback that has been seen in other studies. However, there were several remarkable findings in our study. First, patients have impaired vocal motor activity even before glottal movement onset, suggesting abnormal movement preparation. These results are significant because (i) they occur before movement onset, abnormalities in patients cannot be ascribed to deficits in vocal performance and (ii) they show that neural abnormalities in laryngeal dystonia are more than just abnormal responses to sensory feedback during phonation as has been hypothesized in some previous studies. Second, abnormal auditory cortical activity in patients begins even before voice onset, suggesting abnormalities in setting up auditory predictions before the arrival of auditory feedback at voice onset. Generally, activation abnormalities identified in key brain regions within the speech motor network around various phonation events not only provide temporal specificity to neuroimaging phenotypes in laryngeal dystonia but also may serve as potential therapeutic targets for neuromodulation.

Effects of low-frequency repetitive transcranial magnetic stimulation in adductor laryngeal dystonia: a safety, feasibility, and pilot study

PurposeThe effects of neuromodulation are virtually unexplored in adductor laryngeal dystonia (AdLD), a disorder characterized by involuntary contraction of intrinsic laryngeal muscles. Recent findings indicated that intracortical inhibition is reduced in people with AdLD. Low-frequency repetitive transcranial magnetic stimulation (rTMS) induces prolonged intracortical inhibition, but the effects in AdLD are unexplored. This pilot and feasibility study aimed to examine the safety, feasibility, and effects of a single session 1 Hz rTMS over the laryngeal motor cortex (LMC) in people with AdLD and healthy individuals.MethodsThe stimulation location was individualized and determined through TMS-evoked responses in the thyroarytenoid muscles using fine-wire electrodes. 1200 pulses of 1 Hz rTMS were delivered to the left LMC in two groups: Control (n = 6) and AdLD (n = 7). Tolerance, adverse effects, intracortical inhibition, and voice recordings were collected immediately before and after rTMS. Voice quality was assessed with acoustic-based and auditory-perceptual measures.ResultsAll participants tolerated the procedures, with no unexpected adverse events or worsening of symptoms. No significant effects on intracortical inhibition were observed. In the AdLD group, there was a large-effect size after rTMS in vocal perturbation measures and a small-effect size in decreased phonatory breaks.ConclusionsOne rTMS session over the LMC is safe and feasible, and demonstrated trends of beneficial effects on voice quality and phonatory function in AdLD. These preliminary findings support further investigation to assess clinical benefits in a future randomized sham-controlled trial.ClinicalTrials.govNCT02957942, registered on November 8, 2016.

Comparison of clinical characteristics of patients with adductor laryngeal dystonia in the focal and segmental types

AbstractDystonia is a central motor processing neurological disorder characterized by abnormal, often action-induced, involuntary movements or uncontrolled spasms. AimTo compare patients with the diagnoses of focal and segmental adductor laryngeal dystonia at the Neurolarynx Outpatient Clinic of the Federal University of São Paulo. Materials and methodsA clinical retrospective study of data collected from patient registries from 2003 to 2009. ResultsOf 34 patients, 25 presented focal dystonia and 9 presented segmental dystonia. There were 30 females (88.2%) and 4 males (11.8%). A relation with a traumatic event was reported in 11 cases (32.4%). Vocal tremor was observed in 21 patients (61.8%). The mean age at onset, the age at diagnosis, and time between the onset and the diagnosis were respectively 55, 61.3 and 6.3 years. There was no statistical difference between patients with focal laryngeal adductor dystonia and segmental dystonia in the study data. ConclusionThere were no statistical differences among patients with focal adductor laryngeal dystonia and segmental dystonia relating to age of onset, age of diagnosis, gender, time between onset and diagnosis, presence of associated tremor, and relation to trauma.