The project objective is to improve clinical assessment and diagnosis of the voice disorder, vocal hyperfunction (VH). VH is a condition characterized by excessive laryngeal and paralaryngeal tension, and is assumed to be the underlying cause of the majority of voice disorders. Current clinical assessment of VH is subjective and demonstrates poor inter-rater reliability. Recent work indicates that a new acoustic measure, relative fundamental frequency (RFF) is sensitive to the maladaptive functional behaviors associated with VH and can potentially be used to objectively characterize VH. Here, we explored and enhanced the potential for RFF as a measure of VH in three ways. First, the current protocol for RFF estimation was optimized to simplify the recording procedure and reduce estimation time. Second, RFF was compared with the current state-of-the-art measures of VH – listener perception of vocal effort and the aerodynamic ratio of sound pressure level to subglottal pressure level. Third, an automated algorithm that utilized the optimized recording protocol was developed and validated against manual estimation methods and listener perception. This work enables large-scale studies on RFF to determine the specific physiological elements that contribute to the measure’s ability to capture VH and may potentially provide a non-invasive and readily implemented solution for this long-standing clinical issue.

No description available.

Relative fundamental frequency (RFF) is an acoustic measure that quantifies short-term changes in fundamental frequency during voicing transitions surrounding a voiceless consonant. RFF is hypothesized to be decreased by increased laryngeal tension during voice production and has been considered a potential objective measure of vocal hyperfunction. Previous studies have supported claims that decreased RFF values may indicate the severity of vocal hyperfunction and have attempted to improve the methods to obtain RFF. In order to make progress towards developing RFF into a clinical measure, this dissertation aimed to investigate further the validity and reliability of RFF. Specifically, we examined the underlying physiological mechanisms, the auditory-perceptual relationship with strained voice quality, and test-retest reliability. The first study evaluated one of the previously hypothesized physiological mechanisms for RFF, vocal fold abduction. Vocal fold kinematics and RFF were obtained from both younger and older typical speakers producing RFF stimuli with voiceless fricatives and stops during high-speed videoendoscopy. We did not find any statistical differences between younger and older speakers, but we found that vocal folds were less adducted and RFF was lower at voicing onset after the voiceless stop compared to the fricative. This finding is in accordance with the hypothesized positive association between vocal fold contact area during voicing transitions and RFF. The second study examined the relationship between RFF and strain, a major auditory-perceptual feature of vocal hyperfunction. RFF values were synthetically modified by exchanging the RFF contours between voice samples that were produced with a comfortable voice and with maximum vocal effort, while other acoustic features remained constant. We observed that comfortable voice samples with the RFF values of maximum vocal effort samples had increased strain ratings, whereas maximum vocal effort samples with the RFF values of comfortable voice samples had decreased strain ratings. These findings support the contribution of RFF to perceived strain. The third study compared the test-retest reliability of RFF with that of conventional voice measures. We recorded individuals with healthy voices during five consecutive days and obtained acoustic, aerodynamic, and auditory-perceptual measures from the recordings. RFF was comparably reliable as acoustic and aerodynamic measures and more reliable than auditory-perceptual measures. This dissertation supports the translational potential of RFF by providing empirical evidence of the physiological mechanisms of RFF, the relationship between RFF and perceived strain, and test-retest reliability of RFF. Clinical applications of RFF are expected to improve objective diagnosis and assessment of vocal hyperfunction, and thus to lead to better voice care for individuals with vocal hyperfunction. / 2021-09-25T00:00:00Z

The exploration of underlying pathophysiology of speech disorders is hampered by the limitations in quantitative assessment of speech production. Current assessments are driven by measures that couple underlying processes of speech production with mechanisms that compensate for speech deficits. We propose a multifactorial approach to decouple these effects and examine underlying processes of speech motor control. In study 1 we conducted a sensorimotor characterization of speech motor control via altered sensory feedback techniques. We applied these measures to investigate effects of dopaminergic medication on laryngeal and articulatory motor control mechanisms in persons with Parkinson’s disease (PwPD). The study outcomes provide preliminary indication that dopaminergic medication may have a differential effect on laryngeal sensorimotor function in PwPD, with a normalization (reduction of atypically large responses) of auditory reflexive responses and an exacerbation (further reduction of atypically small responses) of auditory adaptive responses. The study outcomes also provide insight into the differential effects of dopaminergic medication on laryngeal and articulatory speech subsystems in PwPD. We hope the outcomes will eventually serve as a basis for designing better therapeutics focused on ameliorating voice and speech dysfunctions in PwPD. In study 2 we investigated laryngeal motor control in a population of individuals with and without hyperfunctional voice disorders (HVDs) using three different laryngeal kinematic measures extracted via high-speed video endoscopy techniques. We applied these measures to investigate differential effects of laryngeal tension, movement variability, and movement asymmetry present in individuals with HVDs. Results indicate that individuals with HVDs exhibit statistically significantly higher kinematic stiffness, spatiotemporal indices, and asymmetry indices across rate and effort conditions compared to controls, indicating higher laryngeal tension, production variability, and movement asymmetry. Laryngeal kinematics suggest differing underlying motor control strategies in individuals with HVD relative to controls, which may inform better understanding of the etiology of HVDs. The study outcomes also provide insight into the ability of laryngeal kinematics to differentiate underlying motor control strategies in individuals with various voice disorders with neurological and physiological pathophysiology that could provide crucial insight to guide future clinical intervention. In study 3, a novel neurocomputational model was developed, combining an established neurological framework of speech motor control, with a physics based vocal fold model. This numerical model decouples the neurological and physiological aspects of laryngeal motor control to provide important directions in expanding the understanding of the underlying pathophysiology of laryngeal motor control in PD and HVDs. The model has demonstrated capability to simulate different modes of laryngeal motor control, ranging from short-term (i.e., reflexive) and long-term (i.e., adaptive) auditory feedback paradigms, to generating prosodic contours in speech. LaDIVA can be used to expand the understanding of the physiology of human phonation to enable, for the first time, the investigation of causal effects of neural motor control in the fine structure of the vocal signal. / 2025-02-20T00:00:00Z

<p>We are study the spaces of convolutors and multipliers in the spaces of<br />tempered ultradistributions. There given theorems which gives us the characteri-zation of all the elements which belongs to spaces of convolutors and multipliers.<br />Structural theorem for ultradistribution semigroups and exponential ultradistri-bution semigroups is given. Fourier hyperfunction semigroups and hyperfunction<br />semigroups with non-densely dened generators are analyzed and also structural<br />theorems and spectral characterizations give necessary and sucient conditions<br />for the existence of such semigroups generated by a closed not necessarily densely<br />dened operator A. The abstract Cauchy problem is considered in the Banach<br />valued weighted Beurling ultradistribution setting and given some applications on<br />particular equations.</p> / <p>U disertaciji se proučavaju prostor konvolutora i multiplikatora na prostorima temperiranih ultradistribucija. Dokazane su&nbsp;teoreme koji karakteri&scaron;u elemente prostora konvolutora i multiplikatora. Date su strukturne teoreme za ultradistribucione &nbsp;polugrupe&nbsp;i eksponenecijalne polugrupe. Furijeve huperfunkciske polugrupe i&nbsp;hiperfunkciske polugrupe sa generatorima koji su negusto definisani&nbsp;<br />su analizirani, takođe su date strukturne teoreme i spektralne karakterizacije kao i dovoljni uslovi za postojenje na takvih polugrupa&nbsp;za operator A koji ne mora biti gust. Apstraktni Ko&scaron;ijev problem je&nbsp;proučavan za težinske Banahove prostore kao i za odgovarujuće prostora ultradistribucija. Takođe su date i primene za određene klase<br />jednačina.</p>

The purpose of the present study is to test the feasibility of implementing a video-game based intervention protocol as a means to improve therapy compliance in school age children with hyperfunctional voice disorders. Three levels of modification were made to an existing entertainment software program in order to implement the therapeutic protocol and test compatibility. The third level of modification included a two-phase quasi-experimental single subject design with a school age participant receiving the video game therapy protocol and traditional therapy for equal time. The independent variables for this study included the mode of voice therapy delivery (traditional vs. video game). The dependent variables included therapy compliance, perceptual evaluations and acoustic measures. This study found that a purely entertainment video game can be implemented as a therapeutic protocol for a school age child diagnosed with a vocal pathology. Results illustrated no change in compliance with non-traditional therapy versus traditional therapy. However, perceptual measures improved post treatment for breathiness, strain and overall severity, as well as significant differences for mean amplitude. Discussion will focus on implications of employing video game based therapy and design of future studies.

PURPOSE: Vocal hyperfunction (VH) is considered a functional voice disorder, resulting in voice complaints of hoarseness and fatigue; however, recent work suggests that voice changes in VH may result from impairments in the neural control of voice (specifically, how voice perception is integrated into voice production). This study sought to clarify whether impaired auditory acuity of vocal pitch and the temporal production of voice, two known impairments in speakers with VH, were correlated. METHOD: The current study included 29 adults with VH. Vocal auditory perception was assessed via acuity to self-produced vocal pitch (quantified using an adaptive two-forced-choice paradigm). To investigate temporal acoustic measures of voice production, voice onset time (VOT) variability of voiced and voiceless stop consonants in a carrier phrase were separately assessed using a coefficient of variation (CoV). Two Pearson product-moment correlations were completed to assess the relationship between these measures of vocal perception and vocal production of either voiced or voiceless VOTs. RESULTS: No statistically significant correlations were observed between auditory acuity and CoV of VOT for neither voiced nor voiceless stop consonants. CONCLUSION: The current findings suggest that impairments in vocal pitch acuity and VOT production in VH are not governed by the same underlying mechanism. Further investigation is recommended to determine the etiology driving these vocal perception- and production-based impairments observed in prior work.

<p>Ova disertacija se bavi analizom slabo postavljenih apstraktnih Cauchyjevih problema. U prvoj glavi su proučavane konvolucione, ultradistribucione i hiper&shy; funkcione polugrupe, njihove medjusobne veze kao i veze sa lokalno integrisanim C-polugrupama.&nbsp; U drugoj glavi su date strukturne osobine C-distribucionih polugrupa, dok su u trećoj glavi dati rezultati vezani za klasu [r]-polugrupa i njihovih primena u teoriji funkcionalnih računa.<br />U sledećoj glavi je sistematski izložena teorija distribucionih kosinus funkcija, dok se peta glava bavi analizom analitičkih integrisanih polugrupa. &Scaron;esta glava je posvećena analizi konvolucionih C-polugrupa i konvolucionih C-kosinus funk&shy;cija, dok su u sedmoj glavi prezntovani rezultati vezani za analitičke konvolu&shy;cione polugrupe, konvolucione kosinus funkcije i njihove veze sa ultradistribucionim i hiperfunkcionim sinusima.</p>

Introdução: Os receptores do peptídeo insulinotrópico dependente de glicose (GIPR) e do hormônio luteinizante (LHCGR) são receptores acoplados à proteína G com amplo padrão de expressão tecidual. A expressão anômala destes receptores tem sido descrita em casos de hiperplasia adrenal macronodular independente de ACTH (AIMAH) e em alguns adenomas, resultando em aumento da secreção hormonal (cortisol, andrógenos e aldosterona) pelo cortex adrenal. O papel destes receptores em outras formas de hiperplasia, como a doença adrenocortical nodular pigmentosa primária (PPNAD), aumento da adrenal associado à neoplasia endócrina múltipla tipo 1 (MEN1), e em carcinoma do córtex adrenal tem sido pouco investigado; sendo assim, considera-se relevante estudar a expressão destes receptores nos pacientes com tumores adrenocorticais esporádicos, nos pacientes com AIMAH, PPNAD e aumento adrenal associado à MEN1. Objetivos: 1) Caracterização molecular dos casos de neoplasia endócrina múltipla tipo 1 e PPNAD: pesquisa de mutações dos genes MEN1 e PRKAR1A e análise da perda de heterozigose (LOH) destes genes no tecido adrenal destes pacientes. 2) Quantificar a expressão do GIPR e do LHCGR em tecido adrenocortical normal, tumoral, hiperplásico e correlacionar a expressão destes com a classificação histológica dos tumores adrenocorticais. Pacientes: 55 pacientes (30 adultos) com tumores adrenocorticais (37 adenomas e 18 carcinomas); 7 pacientes com AIMAH, 4 com MEN1, 1 com PPNAD e tecidos controles (adrenal; testículo e pâncreas). Métodos: extração de DNA genômico, RNA e síntese de DNA complementar (cDNA); amplificação por PCR das regiões codificadoras dos genes MEN1 e PRKAR1A seguida por seqüenciamento automático. Pesquisa de LOH pela amplificação de microssatélites por PCR e análise pelo programa GeneScan. Quantificação da expressão do GIPR e do LHCGR por PCR em tempo real pelo método TaqMan e estudo de imunohistoquímica para GIPR nos tumores adrenocorticais. Resultados: identificação de 3 mutações (893+ 1G>A, W183X e A68fsX118) e dois polimorfirmos (S145S e D418D) no gene MEN1 e uma mutação (Y21X) no PRKAR1A. Ausência de LOH nos tecidos adrenais estudados. A expressão do GIPR e do LHCGR foi identificada em tecidos adrenais normais, tumorais e hiperplásicos. O nível de expressão do GIPR foi mais elevado nos tumores adrenocorticais malignos que nos benignos tanto no grupo pediátrico (mediana= 18,1 e 4,6, respectivamente; p <0,05), quanto no grupo adulto (mediana = 4,8 e 1,3 respectivamente; p <0,001). O nível de expressão do LHCGR, no grupo pediátrico, foi elevado tanto nos tumores benignos quanto nos malignos (mediana= 6,4 e 4,3, respectivamente). No grupo adulto os níveis de expressão deste receptor foram extremamente baixos nos tumores malignos em relação aos benignos (mediana= 0,06 e 2,3, respectivamente; p <0,001). A imunohistoquímica para o GIPR foi variável e não correlacionada à expressão do gene GIPR. Não houve diferença nos níveis de expressão do GIPR e do LHCGR nas hiperplasias do córtex adrenal. Conclusões: a presença de LOH e mutação em heterozigose composta do gene MEN1 e do PRKAR1A foram afastadas como mecanismos responsáveis pelo aumento adrenal tanto nos pacientes com MEN1 como no paciente com PPNAD. A hiperexpressão de GIPR está associada a malignidade nos tumores adrenocorticais nos grupos adulto e pediátrico e a baixa expressão de LHCGR está associada a malignidade nos tumores adrenocorticais somente no grupo adulto. / Introduction: The glucose- dependent insulinotropic peptide receptor (GIPR) and luteinizing hormone receptor (LHCGR) are G-protein coupled receptors with a wide tissue expression pattern. The aberrant expression of these receptors has been described in cases of ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in some adenomas, resulting in the increase of adrenal cortex hormonal secretion (cortisol, androgens and aldosterone). The role of these receptors in other forms of adrenocortical hyperplasia, such as primary pigmented nodular adrenocortical disease (PPNAD), adrenal enlargement associated with multiple endocrine neoplasia type 1 (MEN1), and adrenocortical carcinoma has been scarcely investigated. Thus, the study of the expression of these receptors in patients with sporadical adrenocortical tumors, AIMAH, PPNAD and adrenal enlargement associated to MEN1 was considered important. Objectives: 1) Molecular study in patients with multiple endocrine neoplasia type 1 and PPNAD: mutation screening of MEN1 and PRKAR1A genes and analysis of the loss of heterozygosis (LOH) of these genes in the adrenal lesions of these patients. 2) To quantify the GIPR and LHCGR expression, in normal, tumor and hyperplasic tissue and to correlate the expression of these receptors with the adrenocortical tumor histology. Patients: 55 patients (30 adults) with adrenocortical tumors (37 adenomas and 18 carcinomas); 7 patients with AIMAH, 4 with MEN1, 1 with PPNAD and control tissue (adrenal, testis and pancreas). Methods: Extraction of genomic DNA, RNA and synthesis of complementary DNA (cDNA); PCR-amplification of the coding regions of MEN1 and PRKAR1A, followed by direct sequencing. LOH study using polymorphic marker amplification by PCR and GeneScan software analysis. Quantification of GIPR and LHCGR expression using realtime PCR -TaqMan method and GIPR immunohistochemistry study in adrenocortical tumors. Results: Identification of 3 mutations (893+ 1G>A, W183X and A68fsX118) and two polymorphic alterations (S145S and D418D) in MEN1 and a mutation (Y21X) in the PRKAR1A gene; LOH was not identified in adrenal tissue. The GIPR and LHCGR expression was identified in normal, tumor and hyperplasic adrenal tissues; the GIPR expression level was more elevated in malignant tumors compared to benign tumors in pediatric (median = 18.1 and 4.6, respectively; p <0.05) and adult patients (median = 4.8 and 1.3 respectively; p <0.001). The LHCGR expression in pediatric patients was elevated in benign as well as in malignant tumors (median = 6.4 and 4.3, respectively). In the adult group, the expression level of these receptors was extremely low in malignant tumors in relation to benign ones (median = 0.06 and 2.3, respectively; p <0.001). The GIPR immunohistochemistry was variable and did not correlate with GIPR gene expression. No difference between GIPR and LHCGR expression levels was observed in the different forms of hyperplasia. Conclusions: The presence of LOH and mutations in compound heterozygosis of MEN1 and PRKAR1A genes were ruled out as the mechanisms responsible for the adrenal enlargement in patients with multiple endocrine neoplasia type 1. GIPR overexpression is associated with malignant adrenocortical tumors in the adult and pediatric patients and low LHCGR expression is associated with malignant adrenocortical tumors only in the adult patients.

Introdução: Os receptores do peptídeo insulinotrópico dependente de glicose (GIPR) e do hormônio luteinizante (LHCGR) são receptores acoplados à proteína G com amplo padrão de expressão tecidual. A expressão anômala destes receptores tem sido descrita em casos de hiperplasia adrenal macronodular independente de ACTH (AIMAH) e em alguns adenomas, resultando em aumento da secreção hormonal (cortisol, andrógenos e aldosterona) pelo cortex adrenal. O papel destes receptores em outras formas de hiperplasia, como a doença adrenocortical nodular pigmentosa primária (PPNAD), aumento da adrenal associado à neoplasia endócrina múltipla tipo 1 (MEN1), e em carcinoma do córtex adrenal tem sido pouco investigado; sendo assim, considera-se relevante estudar a expressão destes receptores nos pacientes com tumores adrenocorticais esporádicos, nos pacientes com AIMAH, PPNAD e aumento adrenal associado à MEN1. Objetivos: 1) Caracterização molecular dos casos de neoplasia endócrina múltipla tipo 1 e PPNAD: pesquisa de mutações dos genes MEN1 e PRKAR1A e análise da perda de heterozigose (LOH) destes genes no tecido adrenal destes pacientes. 2) Quantificar a expressão do GIPR e do LHCGR em tecido adrenocortical normal, tumoral, hiperplásico e correlacionar a expressão destes com a classificação histológica dos tumores adrenocorticais. Pacientes: 55 pacientes (30 adultos) com tumores adrenocorticais (37 adenomas e 18 carcinomas); 7 pacientes com AIMAH, 4 com MEN1, 1 com PPNAD e tecidos controles (adrenal; testículo e pâncreas). Métodos: extração de DNA genômico, RNA e síntese de DNA complementar (cDNA); amplificação por PCR das regiões codificadoras dos genes MEN1 e PRKAR1A seguida por seqüenciamento automático. Pesquisa de LOH pela amplificação de microssatélites por PCR e análise pelo programa GeneScan. Quantificação da expressão do GIPR e do LHCGR por PCR em tempo real pelo método TaqMan e estudo de imunohistoquímica para GIPR nos tumores adrenocorticais. Resultados: identificação de 3 mutações (893+ 1G>A, W183X e A68fsX118) e dois polimorfirmos (S145S e D418D) no gene MEN1 e uma mutação (Y21X) no PRKAR1A. Ausência de LOH nos tecidos adrenais estudados. A expressão do GIPR e do LHCGR foi identificada em tecidos adrenais normais, tumorais e hiperplásicos. O nível de expressão do GIPR foi mais elevado nos tumores adrenocorticais malignos que nos benignos tanto no grupo pediátrico (mediana= 18,1 e 4,6, respectivamente; p <0,05), quanto no grupo adulto (mediana = 4,8 e 1,3 respectivamente; p <0,001). O nível de expressão do LHCGR, no grupo pediátrico, foi elevado tanto nos tumores benignos quanto nos malignos (mediana= 6,4 e 4,3, respectivamente). No grupo adulto os níveis de expressão deste receptor foram extremamente baixos nos tumores malignos em relação aos benignos (mediana= 0,06 e 2,3, respectivamente; p <0,001). A imunohistoquímica para o GIPR foi variável e não correlacionada à expressão do gene GIPR. Não houve diferença nos níveis de expressão do GIPR e do LHCGR nas hiperplasias do córtex adrenal. Conclusões: a presença de LOH e mutação em heterozigose composta do gene MEN1 e do PRKAR1A foram afastadas como mecanismos responsáveis pelo aumento adrenal tanto nos pacientes com MEN1 como no paciente com PPNAD. A hiperexpressão de GIPR está associada a malignidade nos tumores adrenocorticais nos grupos adulto e pediátrico e a baixa expressão de LHCGR está associada a malignidade nos tumores adrenocorticais somente no grupo adulto. / Introduction: The glucose- dependent insulinotropic peptide receptor (GIPR) and luteinizing hormone receptor (LHCGR) are G-protein coupled receptors with a wide tissue expression pattern. The aberrant expression of these receptors has been described in cases of ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in some adenomas, resulting in the increase of adrenal cortex hormonal secretion (cortisol, androgens and aldosterone). The role of these receptors in other forms of adrenocortical hyperplasia, such as primary pigmented nodular adrenocortical disease (PPNAD), adrenal enlargement associated with multiple endocrine neoplasia type 1 (MEN1), and adrenocortical carcinoma has been scarcely investigated. Thus, the study of the expression of these receptors in patients with sporadical adrenocortical tumors, AIMAH, PPNAD and adrenal enlargement associated to MEN1 was considered important. Objectives: 1) Molecular study in patients with multiple endocrine neoplasia type 1 and PPNAD: mutation screening of MEN1 and PRKAR1A genes and analysis of the loss of heterozygosis (LOH) of these genes in the adrenal lesions of these patients. 2) To quantify the GIPR and LHCGR expression, in normal, tumor and hyperplasic tissue and to correlate the expression of these receptors with the adrenocortical tumor histology. Patients: 55 patients (30 adults) with adrenocortical tumors (37 adenomas and 18 carcinomas); 7 patients with AIMAH, 4 with MEN1, 1 with PPNAD and control tissue (adrenal, testis and pancreas). Methods: Extraction of genomic DNA, RNA and synthesis of complementary DNA (cDNA); PCR-amplification of the coding regions of MEN1 and PRKAR1A, followed by direct sequencing. LOH study using polymorphic marker amplification by PCR and GeneScan software analysis. Quantification of GIPR and LHCGR expression using realtime PCR -TaqMan method and GIPR immunohistochemistry study in adrenocortical tumors. Results: Identification of 3 mutations (893+ 1G>A, W183X and A68fsX118) and two polymorphic alterations (S145S and D418D) in MEN1 and a mutation (Y21X) in the PRKAR1A gene; LOH was not identified in adrenal tissue. The GIPR and LHCGR expression was identified in normal, tumor and hyperplasic adrenal tissues; the GIPR expression level was more elevated in malignant tumors compared to benign tumors in pediatric (median = 18.1 and 4.6, respectively; p <0.05) and adult patients (median = 4.8 and 1.3 respectively; p <0.001). The LHCGR expression in pediatric patients was elevated in benign as well as in malignant tumors (median = 6.4 and 4.3, respectively). In the adult group, the expression level of these receptors was extremely low in malignant tumors in relation to benign ones (median = 0.06 and 2.3, respectively; p <0.001). The GIPR immunohistochemistry was variable and did not correlate with GIPR gene expression. No difference between GIPR and LHCGR expression levels was observed in the different forms of hyperplasia. Conclusions: The presence of LOH and mutations in compound heterozygosis of MEN1 and PRKAR1A genes were ruled out as the mechanisms responsible for the adrenal enlargement in patients with multiple endocrine neoplasia type 1. GIPR overexpression is associated with malignant adrenocortical tumors in the adult and pediatric patients and low LHCGR expression is associated with malignant adrenocortical tumors only in the adult patients.