Phenotype‐ and genotype‐specific structural alterations in spasmodic dysphonia

Abstract

Background Spasmodic dysphonia is a focal dystonia characterized by involuntary spasms in the laryngeal muscles that occur selectively during speaking. Although hereditary trends have been reported in up to 16% of patients, the causative etiology of spasmodic dysphonia is unclear, and the influences of various phenotypes and genotypes on disorder pathophysiology are poorly understood. In this study, we examined structural alterations in cortical gray matter and white matter integrity in relationship to different phenotypes and putative genotypes of spasmodic dysphonia to elucidate the structural component of its complex pathophysiology. Methods Eighty-nine patients with spasmodic dysphonia underwent high-resolution magnetic resonance imaging and diffusion-weighted imaging to examine cortical thickness and white matter fractional anisotropy in adductor versus abductor forms (distinct phenotypes) and in sporadic versus familial cases (distinct genotypes). Results Phenotype-specific abnormalities were localized in the left sensorimotor cortex and angular gyrus and the white matter bundle of the right superior corona radiata. Genotype-specific alterations were found in the left superior temporal gyrus, supplementary motor area, and the arcuate portion of the left superior longitudinal fasciculus. Conclusions Our findings suggest that phenotypic differences in spasmodic dysphonia arise at the level of the primary and associative areas of motor control, whereas genotype-related pathophysiological mechanisms may be associated with dysfunction of regions regulating phonological and sensory processing. Identification of structural alterations specific to disorder phenotype and putative genotype provides an important step toward future delineation of imaging markers and potential targets for novel therapeutic interventions for spasmodic dysphonia.

Functional and structural neural bases of task specificity in isolated focal dystonia

“…These structures are known to contribute to the important aspects of speech comprehension, motor planning and coordination, articulatory modulations, and pitch and tone control during singing . Functional and structural alterations in the inferior frontal gyrus and anterior insula are in line with previous neuroimaging studies in SD, which identified abnormal relationships between inferior frontal volume and activity during symptomatic task production as well as between insular volume and the disorder severity . Furthermore, a spatial disorganization of anterior insular structural connectivity with the inferior frontal gyrus was recently demonstrated in SD patients compared to healthy individuals .…”

“…12,[34][35][36][37][38][39][40][41] Functional and structural alterations in the inferior frontal gyrus and anterior insula are in line with previous neuroimaging studies in SD, which identified abnormal relationships between inferior frontal volume and activity during symptomatic task production as well as between insular volume and the disorder severity. 42,43 Furthermore, a spatial disorganization of anterior insular structural connectivity with the inferior frontal gyrus was recently demonstrated in SD patients compared to healthy individuals. 40 Given that the neural circuits responsible for the control of speaking and singing potentially overlap, 36 our findings suggest that these regional alterations, too, reflect a commonly affected voice-specialized modality across different forms of laryngeal dystonia.…”

Neuroimaging Applications in Dystonia

“…Among these, primary sensorimotor changes tended to localize to dystonia-affected body regions within the sensorimotor homunculus. For example, gray matter volumetric increases in patients with focal hand dystonia were observed in the hand area of sensori-motor cortex (Delmaire et al, 2005; Egger et al, 2007; Garraux et al, 2004), whereas in patients with laryngeal dystonia these were found within the larynx representation (Bianchi et al, 2017; Kostic et al, 2016; Simonyan & Ludlow, 2012), further showing relevance of cortical aberrations to the pathophysiology of distinct forms of dystonia.…”

“…As gene discovery for isolated focal dystonias remains stagnant and extremely challenging due, in part, to rare availability of large families, low penetrance, and variable expressivity, the design of neuroimaging studies has also been limited by somewhat arbitrary assignments of experimental cohorts based on a confirmed family history of dystonia only. Based on such approach, one recent study in patients with sporadic and familial forms of laryngeal dystonia identified phenotype-specific gray matter abnormalities in primary and associative areas of motor control that were distinct from genotype-specific changes within the cortical regions controlling sensory processing (Bianchi et al, 2017) (Fig. 2C).…”

“…doi:10.1016/j.neuro-image.2009.03.057. Panel (C): Adapted from Bianchi, S., Battistella, G., Huddlestone, H., Scharf, R., Fleysher, L., Rumbach, A. F., et al (2017). Phenotype- and genotype-specific structural alterations in spasmodic dysphonia .…”