Tongue and laryngeal exercises improve tongue strength and vocal function outcomes in a Pink1-/- rat model of early Parkinson disease.

Parkinson disease (PD) causes voice and swallow dysfunction even in early stages of the disease. Treatment of this dysfunction is limited, and the neuropathology underlying this dysfunction is poorly defined. Targeted exercise provides the greatest benefit for offsetting voice and swallow dysfunction, and previous data suggest the hypoglossal nucleus and noradrenergic-locus coeruleus (LC) may be involved in its early pathology. To investigate relationships between targeted exercise and neuropathology of voice and swallow dysfunction, we implemented a combined exercise paradigm that included tongue force and vocalization exercises early in the Pink1-/- rat model. We tested the hypotheses that (1) tongue and vocal exercise improves tongue force and timing behaviors and vocalization outcomes, and (2) exercise increases optical density of serotonin (5-HT) in the hypoglossal nucleus, and tyrosine hydroxylase immunoreactive (Th-ir) cell counts in the LC. At two months of age Pink1-/- rats were randomized to exercise or non-exercise treatment. Age-matched wildtype (WT) control rats were assigned to non-exercise treatment. Tongue force and timing behaviors and ultrasonic vocalizations were measured at baseline (two months) and final (four months) timepoints. Optical density of 5-HT in the hypoglossal nucleus and TH-ir cell counts in the LC were obtained. Pink1-/- rats produced greater tongue forces, faster tongue contraction, and higher-intensity vocalization following exercise. There were no differences in LC TH-ir. The non-exercised Pink1-/- group had reduced density of 5-HT in the hypoglossal nucleus compared to the WT control group. The changes to tongue function and vocalization after targeted exercise suggests exercise intervention may be beneficial in early PD.

Stress Effects on Pharyngeal Air Pressure and Upper Esophageal Sphincter Pressure During Phonation: The Influence of Vocal Tract Semi-Occlusion.

OBJECTIVES/HYPOTHESIS: The objective of this study was to determine whether vocal tract semi-occlusion (SOVT) influenced stress effects on pharyngeal air pressure and upper esophageal sphincter (UES) pressure during phonation. Relationships between dysphonia and stress are well recognized but poorly understood. Stress effects act globally on the body, and may be observed beyond intrinsic laryngeal muscles to include pharyngeal muscles and the UES, which contribute to voice modulation. Phonation with SOVT may provide resistance to stress effects on the vocal tract. We hypothesized that stress effects on pharyngeal air pressure and UES pressure would be measurable with a high-resolution, 360° pressure catheter, and that stress effects would be impacted differently by occlusal and non-occlusal phonatory tasks. METHODS: Ten healthy adults performed sustained vowel tasks (comfortable /a/, and loud /a/), and SOVT tasks (bilabial fricative and straw phonation). Each task was performed during a baseline condition, and during stress induced through a cold pressor task. Pharyngeal air pressure and UES pressure were measured via high-resolution manometry. Changes in pressure between baseline and stress were compared among phonatory tasks. RESULTS: Stress-induced changes to UES pressure differed by phonatory task (P < 0.01). Stress increased UES pressures during vowels, but had no effect during bilabial fricative, and decreased UES pressures during straw phonation. Change in UES pressure with stress was greater for comfortable /a/ and loud /a/ than straw phonation (P = 0.048 and P = 0.019, respectively), and was not significantly different between comfortable /a/ or loud /a/ and bilabial fricative. Stress-induced changes in pharyngeal air pressure were not significantly different among tasks. CONCLUSIONS: These findings help identify possible mechanisms underlying the relationship between stress and voice, and point to the utility of SOVT tasks for training vocal tract resistance to stress. This methodology provides a foundation for measuring changes to extra-laryngeal components of the vocal tract during phonation.

Manipulation of vocal communication and anxiety through pharmacologic modulation of norepinephrine in the Pink1-/- rat model of Parkinson disease.

Vocal deficits and anxiety are common, co-occurring, and interacting signs of Parkinson Disease (PD) that have a devastating impact on quality of life. Both manifest early in the disease process. Unlike hallmark motor signs of PD, neither respond adequately to dopamine replacement therapies, suggesting that their disease-specific mechanisms are at least partially extra-dopaminergic. Because noradrenergic dysfunction is also a defining feature of PD, especially early in the disease progression, drug therapies targeting norepinephrine are being trialed for treatment of motor and non-motor impairments in PD. Research assessing the effects of noradrenergic manipulation on anxiety and vocal impairment in PD, however, is sparse. In this pre-clinical study, we quantified the influence of pharmacologic manipulation of norepinephrine on vocal impairment and anxiety in Pink1-/- rats, a translational model of PD that demonstrates both vocal deficits and anxiety. Ultrasonic vocalization acoustics, anxiety behavior, and limb motor activity were tested twice for each rat: after injection of saline and after one of three drugs. We hypothesized that norepinephrine reuptake inhibitors (atomoxetine and reboxetine) and a ß receptor antagonist (propranolol) would decrease vocal impairment and anxiety compared to saline, without affecting spontaneous motor activity. Our results demonstrated that atomoxetine and reboxetine decreased anxiety behavior. Atomoxetine also modulated ultrasonic vocalization acoustics, including an increase in vocal intensity, which is almost always reduced in animal models and patients with PD. Propranolol did not affect anxiety or vocalization. Drug condition did not influence spontaneous motor activity. These studies demonstrate relationships among vocal impairment, anxiety, and noradrenergic systems in the Pink1-/- rat model of PD.

Quantification of brainstem norepinephrine relative to vocal impairment and anxiety in the Pink1-/- rat model of Parkinson disease.

Vocal communication impairment and anxiety are co-occurring and interacting signs of Parkinson Disease (PD) that are common, poorly understood, and under-treated. Both vocal communication and anxiety are influenced by the noradrenergic system. In light of this shared neural substrate and considering that noradrenergic dysfunction is a defining characteristic of PD, tandem investigation of vocal impairment and anxiety in PD relative to noradrenergic mechanisms is likely to yield insights into the underlying disease-specific causes of these impairments. In order to address this gap in knowledge, we assessed vocal impairment and anxiety behavior relative to brainstem noradrenergic markers in a genetic rat model of early-onset PD (Pink1-/-) and wild type controls (WT). We hypothesized that 1) brainstem noradrenergic markers would be disrupted in Pink1-/-, and 2) brainstem noradrenergic markers would be associated with vocal acoustic changes and anxiety level. Rats underwent testing of ultrasonic vocalization and anxiety (elevated plus maze) at 4, 8, and 12 months of age. At 12 months, brainstem norepinephrine markers were quantified with immunohistochemistry. Results demonstrated that vocal impairment and anxiety were increased in Pink1-/- rats, and increased anxiety was associated with greater vocal deficit in this model of PD. Further, brainstem noradrenergic markers including TH and α1 adrenoreceptor immunoreactivity in the locus coeruleus, and ß1 adrenoreceptor immunoreactivity in vagal nuclei differed by genotype, and were associated with vocalization and anxiety behavior. These findings demonstrate statistically significant relationships among vocal impairment, anxiety, and brainstem norepinephrine in the Pink1-/- rat model of PD.

Rat Models of Vocal Deficits in Parkinson's Disease.

Parkinson's disease (PD) is a progressive, degenerative disorder that affects 10 million people worldwide. More than 90% of individuals with PD develop hypokinetic dysarthria, a motor speech disorder that impairs vocal communication and quality of life. Despite the prevalence of vocal deficits in this population, very little is known about the pathological mechanisms underlying this aspect of disease. As such, effective treatment options are limited. Rat models have provided unique insights into the disease-specific mechanisms of vocal deficits in PD. This review summarizes recent studies investigating vocal deficits in 6-hydroxydopamine (6-OHDA), alpha-synuclein overexpression, DJ1-/-, and Pink1-/- rat models of PD. Model-specific changes to rat ultrasonic vocalization (USV), and the effects of exercise and pharmacologic interventions on USV production in these models are discussed.

Measurement of Pharyngeal Air Pressure During Phonation Using High-Resolution Manometry.

Purpose The study of air pressure in the vocal tract is essential to understanding vocal function. Changes in vocal tract shape during different phonatory gestures are hypothesized to produce nonuniform air pressure across lower vocal tract locations. Current methods of air pressure measurement, however, are limited to a single location in the anterior oral cavity. The purposes of this study were (a) to assess the feasibility of a novel method of simultaneously measuring phonatory air pressure at multiple locations across the lower vocal tract using high-resolution pharyngeal manometry (HRM) and (b) to compare pressure across locations and among phonatory tasks. Method Two subjects underwent HRM while performing phonatory tasks. A catheter was passed transnasally and air pressure was measured simultaneously at five locations between the velopharyngeal port and the upper esophageal sphincter. Descriptive statistics were calculated for each location by task, and for each task averaged across locations. Results HRM was well tolerated, and air pressures from multiple locations in the lower vocal tract were able to be obtained simultaneously. During vocal tract semi-occlusion tasks, air pressures differed by location. Pressures averaged across locations demonstrated a pattern of increasing pressure with increasing semi-occlusion. Conclusions HRM is feasible for measuring air pressure simultaneously at multiple locations in the lower vocal tract during phonation with high spatial and temporal resolution, providing rich data to augment understanding of vocal function. The high spatial and temporal resolution yielded by this new method, paired with preliminary evidence that pressures change by location as a function of phonatory task, may be useful in future assays exploring differences in lower vocal tract air pressures between normal and disordered populations.