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    Topic review

    Vocal Deficits in Parkinson’s Disease

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    Submitted by: Michelle R. Ciucci

    Definition

    This reviews vocalization deficits in models of Parkinson disease.

    1. Introduction

    Parkinson’s disease (PD) is a progressive, degenerative disorder that affects 10 million people worldwide [1][2]. While the disease is known for hallmark motor signs including a resting tremor, bradykinesia, and rigidity that arise as a result of nigrostriatal dopamine depletion, other signs of disease appear years prior to diagnosis, including changes to voice [3][4][5][6]. More than 90% of individuals with PD develop hypokinetic dysarthria, a motor speech disorder that greatly impairs vocal communication [7][8]. Vocal deficits include decreased loudness, monotone pitch, imprecise articulation, and overall decreased intelligibility [9][10][11][12]. This negatively impacts vocal quality and overall quality of life [12]. Pharmacological treatments for PD typically target dopamine pathways by increasing neurotransmitter levels or as dopamine receptor agonists [13][14]. These treatments, however, are not effective in alleviating voice dysfunction, suggesting pathology for voice differs in important ways from classical limb motor alterations [13][14]. Similarly, surgical treatments, like deep brain stimulation, improve limb motor signs, yet do not improve vocal communication and may in fact worsen deficits [15][16][17][18][19][20][21]. Despite the prevalence of hypokinetic dysarthria in PD, pharmacological and surgical treatment options remain limited. Behavioral therapies continue to be the gold standard in treating voice disorders in this population [22]. While research investigating the efficacy of speech-language interventions for PD-related voice dysfunction has grown, a robust understanding of the underlying biological mechanisms responsible for the onset, progression, and treatment-related improvement in vocal dysfunction is limited. Furthermore, while about 10% of PD cases are familial in nature, a vast majority are deemed idiopathic [23]. There are differences among patients with regard to phenotypic expression of PD, including but not limited to akinetic (freezing), tremor-predominant, young onset, etc. Variability is also noted regarding the presence and severity of signs and symptoms, age of onset, and rate of progression of the disease [24]. This extends to vocal deficits, which often present variably. As such, optimizing treatment remains a universal challenge.
    The study of ultrasonic vocalizations (USVs) in rat models of PD has increased understanding of vocal communication changes that occur with PD. Similar to humans, rats are highly social animals, generate sound within the larynx, and produce vocalizations that are semiotic in nature [25][26][27][28][29]. USVs are typically categorized by two call types—22-kilohertz (kHz) alarm calls and 50-kHz calls [30][31][32][33][34][35]. 22-kHz calls occur in response to aversive conditions or in negative affective states and are initiated via activation of the ascending cholinergic system [30][34][36][37][38]. 50-kHz calls occur in response to activity in the mesolimbic dopaminergic system originating in the ventral tegmental area, and are produced in social, nonaggressive, positive affective states [30][31][32][33][34][35]. They represent purposeful affiliative vocalizations, are highly relevant to human communication, and as such, are commonly studied and will be the focus of this review. 50-kHz calls are also more complex, varying by acoustic parameters, such as duration (ms), intensity (dB), bandwidth (Hz), and peak frequency (Hz), as well as non-acoustic parameters, such as complexity (%), call rate (calls/s), latency to call (s), and call type (categorical). There are many different approaches to categorizing call type and categories should correspond to the research question [39][40][41][42][43]. Generally, 50-kHz calls are defined as simple or complex and, depending on the research group, can have sub-categories. Simple calls have constant, non-modulating frequency, and complex calls contain two or more directional changes in frequency of at least 3 kHz each [39][40]. Commonly described complex calls include frequency modulated (FM) calls (frequency changes within a call) and harmonic calls (calls with a fundamental frequency near 30 kHz with a visible harmonic one octave above) [40]. In contrast to human voice, 50-kHz USV production does not involve the vibration of vocal folds [44][45]. USV production shares characteristics with human vocalization including the generation of airflow via buildup of lung pressure, the activation of intrinsic laryngeal muscles, and the modulation of the vocal tract during egressive airflow [28][29]. As such, USVs are used to study vocal sensorimotor control in models of PD.

    2. Vocal Deficits in Parkinson’s Disease

    2.1Neurotoxin Models

    Oxidopamine, or 6-hydroxydopamine (6-OHDA), is a catecholaminergic neurotoxin classically used to model PD by inducing significant neurodegeneration of the nigrostriatal dopamine system by unilateral or bilateral infusion to the medical forebrain bundle or the striatum [46][47][48][49][50][51][52][53]. The well-established 6-OHDA rat model has been used to study behavioral changes, mechanisms of cell death, and therapies that could potentially improve PD signs [48][54][55][56][57][58]. Deficits in this model are widespread. In addition to affecting limb movements [59][60][61][62][63], unilateral lesions to the medial forebrain bundle or the striatum have been shown to reduce tongue force, lick force, and lick frequency [64][65][66], as well as chewing behaviors [67], suggesting that nigrostriatal dopaminergic systems may contribute, at least in part, to oral sensorimotor dysfunction.
    Nigrostriatal dopamine depletion via unilateral 6-OHDA infusion into the medial forebrain bundle leads to significant changes in USV production. Rat 50-kHz USVs show decreased call intensity, amplitude, and bandwidth [25][68][69]. Additionally, call complexity degrades as a result of the unilateral 6-OHDA lesion. Of all call types (simple, FM, and harmonic), harmonic calls were produced the least frequently; however, this was observed regardless of dopamine depletion [68]. Subsequent work has largely supported these findings, and further showed decreases in call rate, call duration, and bandwidth when tested in a novel cage environment, suggesting that environment can have a significant impact on behavioral outcomes [69]. Observed decreases in complexity and intensity of calls are analogous to hypophonia noted in individuals with PD, thereby demonstrating utility of USVs in assessing phonatory deficits [70]. The effect of time post-lesion on USV production was also studied at acute (72 h) and chronic (4 weeks) timepoints. Results show that after 72 h, call complexity, bandwidth, and intensity of FM calls correlate with striatal dopamine loss. After 4 weeks, bandwidth, intensity of simple calls, and duration of FM calls were correlated with measures of dopamine depletion. Call complexity was less affected at 4 weeks and was only significantly correlated with percent of tyrosine hydroxylase loss [71]. The 6-OHDA model itself does not fully embody the progressive nature of PD. While dopamine loss may play a role in vocal dysfunction, particularly around the time of diagnosis when dopamine has significantly depleted in the substantia nigra pars compacta (SNpc), other systems may be implicated earlier in disease progression that cannot be fully captured with a 6-OHDA model.
    The control of vocalization is complex, involving multiple sensorimotor, cognitive, and limbic brain regions [72][73]. The basal ganglia are certainly implicated in the initiation and modulation of vocalizations. Disrupting nigrostriatal pathways disrupts the quality of vocalization because of altered input to the striatum and consequently the complex circuitry of the basal ganglia and related brain areas. The 6-OHDA lesion to nigrostriatal pathways models one aspect of this complex disease.

    2.2. Alpha-Synuclein Overexpression Models

    Overexpressing alpha-synuclein using viral vectors models nigrostriatal pathology by injecting within or near the SNpc. In contrast to transgenic models, overexpression via viral vector allows for induction at different timepoints, allows for the targeting of a defined region of the brain, and results in rapid degeneration of nigrostriatal neurons [74]. Furthermore, viral-vector mediated models also show the presence of limb motor deficits [75][76][77][78]. Until recently, vocal deficits were not studied in alpha-synuclein overexpressing models. This is still a largely understudied area, with only two articles discussing vocal deficits in viral-vector-mediated rat models.

    Mouse models overexpressing alpha-synuclein [79] have also shown relationships between nigrostriatal alpha-synuclein overexpression and early and progressive decline in behavior. Although not widely studied in the context of vocalization, one additional study characterized vocal deficits in mice overexpressing human wild-type alpha-synuclein under a broad neuronal promoter (Thy1-aSyn) [80]. Grant (2014) found call profile of Thy1-aSyn mice to be significantly different compared to wildtype (WT; healthy) controls. The percent of two-cycle calls and jump down calls was significantly reduced in the Thy1-aSyn model at 2–3 months and 6–7 months, respectively. Furthermore, at 2–3 months, the average duration of calls was significantly decreased (for harmonic, jump down, half cycle, and cycle calls) and at 6–7 months, intensity was significantly reduced in the Thy1-aSyn group. Immunohistochemical findings also revealed alpha-synuclein aggregates in the periaqueductal gray at 5 months in the Thy1-aSyn mice [80]. These deficits coincided with previously reported early sensorimotor deficits, deficits in olfaction, circadian rhythm, and gastrointestinal functioning, and high extracellular striatal dopamine levels [80][81]. Similar to alpha-synuclein overexpressing rat models, mice show early and progressive vocal deficits compared to WTs, suggesting similar underlying mechanisms between both species. Results from these studies indicate that vocal deficits can be induced by alpha-synuclein overexpression, in the absence of dopamine depletion.

    2.3. Genetic Models

    The DJ1 knockout (DJ1-/-) model demonstrates early onset and progressive limb motor, oromotor, and cranial sensorimotor deficits, including decreased limb, tongue/chewing, and vocalization functions. Yang and colleagues (2018) assessed vocalization abilities in the DJ1-/- rat model in prodromal to early timepoints of disease (2–8 months of age) and correlated findings to noradrenergic cell loss within the locus coeruleus. Compared to WT controls, DJ1-/- rats were found to develop early and progressive ultrasonic vocalization deficits. Specifically, DJ1-/- rats produced longer average and maximum calls, and a greater overall percentage of complex calls. At 8 months of age, DJ1-/- rats showed a lower average intensity of calls, a deficit analogous to the decreased vocal loudness (i.e., hypophonia) PD patients typically experience. Findings also revealed that at 8 months of age, DJ1-/- rats demonstrated loss of tyrosine hydroxylase-immunoprotective cells in the locus coeruleus, a brainstem region responsible for the synthesis and regulation of noradrenaline. With widespread connections to the central nervous system, including projections into the prefrontal cortex, striatum, hippocampus, and thalamus, the locus coeruleus has a large impact on PD pathology. Disruptions in the central noradrenergic system are associated with motor and non-motor signs of PD, including vocalization [82]. Tyrosine hydroxylase-positive cells in the locus coeruleus were also found to be negatively correlated with tongue force, suggesting that the greater the loss of neurons within the locus coeruleus, the greater the disruption to oromotor functioning [83]. Whether the loss of these neurons is progressive, however, is still unknown. Overall, noradrenaline has been shown to have widespread implications for PD pathology, including vocalization deficits. 

    3. Conclusions

    While hallmark motor deficits are relatively well-understood, certain signs of PD, including vocal deficits, remain poorly understood due to their prodromal onset and complex pathology. As such, multiple complementary models are necessary to provide insights into the progression and pathophysiological underpinnings of communication deficits.
    Each of the different models of PD have unique advantages and limitations. Neurotoxin models such as 6-OHDA are useful for the study of mid- to late-stage PD associated with nigrostriatal dopamine depletion, and demonstrate widespread deficits; however, this model shows minimal alpha-synuclein aggregation and does not account for the progressive nature of the disease. In contrast, genetic models like DJ1-/- and Pink1-/- allow for the study of disease progression, as well as the study of intervention at early, prodromal, and later timepoints. However, genetic mutations make up only a small subset of PD cases and may not capture the subtle differences associated with the pathogenesis of other forms of PD. 

    The entry is from 10.3390/brainsci11070925

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