Neural processing of speech production has been traditionally attributed to the left hemisphere. However, it remains unclear if there are structural bases for speech functional lateralization and if these may be partially explained by sexual dimorphism of cortical morphology. We used a combination of high-resolution MRI and speech-production functional MRI to examine cortical thickness of brain regions involved in speech control in healthy males and females. We identified greater cortical thickness of the left Heschl’s gyrus in females compared to males. Additionally, rightward asymmetry of the supramarginal gyrus and leftward asymmetry of the precentral gyrus were found within both male and female groups. Sexual dimorphism of the Heschl’s gyrus may underlie known differences in auditory processing for speech production between males and females, whereas findings of asymmetries within cortical areas involved in speech motor execution and planning may contribute to the hemispheric localization of functional activity and connectivity of these regions within the speech production network. Our findings highlight the importance of consideration of sex as a biological variable in studies on neural correlates of speech control.

OBJECTIVES: To determine the directionality of regional interactions and influences of one region on another within the functionally abnormal sensorimotor network in isolated focal dystonia. METHODS: A total of 40 patients with spasmodic dysphonia with and without dystonic tremor of voice and 35 healthy controls participated in the study. Independent component analysis (ICA) of resting-state fMRI was used to identify 4 abnormally coupled brain regions within the functional sensorimotor network in all patients compared to controls. Follow-up spectral dynamic causal modeling (DCM) estimated regional effective connectivity between patients and controls and between patients with spasmodic dysphonia with and without dystonic tremor of voice to expand the understanding of symptomatologic variability associated with this disorder. RESULTS: ICA found abnormally reduced functional connectivity of the left inferior parietal cortex, putamen, and bilateral premotor cortex in all patients compared to controls, pointing to a largely overlapping pathophysiology of focal dystonia and dystonic tremor. DCM determined that the disruption of the sensorimotor network was both top-down, involving hyperexcitable parieto-putaminal influence, and interhemispheric, involving right-to-left hyperexcitable premotor coupling in all patients compared to controls. These regional alterations were associated with their abnormal self-inhibitory function when comparing patients with spasmodic dysphonia patients with and without dystonic tremor of voice. CONCLUSIONS: Abnormal hyperexcitability of premotor-parietal-putaminal circuitry may be explained by altered information transfer between these regions due to underlying deficient connectivity. Identification of brain regions involved in processing of sensorimotor information in preparation for movement execution suggests that complex network disruption is staged well before the dystonic behavior is produced by the primary motor cortex.

INTRODUCTION: Spasmodic dysphonia (SD) is an isolated focal dystonia characterized by laryngeal spasms during voluntary voice production. Environmental factors have been assumed to play a role in SD pathophysiology; however, the exact extrinsic risk factors and their association with neural alterations remain unknown. METHODS: A total of 186 SD patients and 85 healthy controls completed a structured 177-question survey, consisting of questions on general biographical information, medical history, symptomatology of dystonia. Data were imputed in a stepwise regression model to identify extrinsic risk factors for SD. In addition, functional MRI data from a subset of this cohort were analyzed to determine brain activation abnormalities associated with the SD extrinsic risk. RESULTS: We found that (1) recurrent upper respiratory infections, gastroesophageal reflux, and neck trauma, all of which influence sensory feedback from the larynx, represent extrinsic risk factors, likely triggering the manifestation of SD symptoms, and (2) neural alterations in the regions necessary for sensorimotor preparation and integration are influenced by an extrinsic risk in susceptible individuals. CONCLUSIONS: These findings provide evidence for the extrinsic risk in SD development and demonstrate the link with alterations in the sensorimotor preparatory network that collectively contribute to the multifactorial pathophysiology of SD.

BACKGROUND: Task-specific focal dystonias selectively affect movements during the production of highly learned and complex motor behaviors. Manifestation of some task-specific focal dystonias, such as musician's dystonia, has been associated with excessive practice and overuse, whereas the etiology of others remains largely unknown. OBJECTIVES: In this study, we aimed to examine the neural correlates of task-specific dystonias in order to determine their disorder-specific pathophysiological traits. METHODS: Using multimodal neuroimaging analyses of resting-state functional connectivity, voxel-based morphometry and tract-based spatial statistics, we examined functional and structural abnormalities that are both common to and distinct between four different forms of task-specific focal dystonias. RESULTS: Compared to the normal state, all task-specific focal dystonias were characterized by abnormal recruitment of parietal and premotor cortices that are necessary for both modality-specific and heteromodal control of the sensorimotor network. Contrasting the laryngeal and hand forms of focal dystonia revealed distinct patterns of sensorimotor integration and planning, again involving parietal cortex in addition to inferior frontal gyrus and anterior insula. On the other hand, musician's dystonia compared to nonmusician's dystonia was shaped by alterations in primary and secondary sensorimotor cortices together with middle frontal gyrus, pointing to impairments of sensorimotor guidance and executive control. CONCLUSION: Collectively, this study outlines a specialized footprint of functional and structural alterations in different forms of task-specific focal dystonia, all of which also share a common pathophysiological framework involving premotor-parietal aberrations. © 2019 International Parkinson and Movement Disorder Society.

The basal ganglia are a complex subcortical structure that is principally involved in the selection and implementation of purposeful actions in response to external and internal cues. The basal ganglia set the pattern for facilitation of voluntary movements and simultaneous inhibition of competing or interfering movements. In addition, the basal ganglia are involved in the control of a wide variety of non-motor behaviors, spanning emotions, language, decision making, procedural learning, and working memory. This review presents a comparative overview of classic and contemporary models of basal ganglia organization and functional importance, including their increased integration with cortical and cerebellar structures.

OBJECTIVE: Spasmodic dysphonia (SD) is a neurological disorder characterized by involuntary spasms in the laryngeal muscles. It is thought to selectively affect speaking; other vocal behaviors remain intact. However, the patients' own perspective on their symptoms is largely missing, leading to partial understanding of the full spectrum of voice alterations in SD. METHODS: A cohort of 178 SD patients rated their symptoms on the visual analog scale based on the level of effort required for speaking, singing, shouting, whispering, crying, laughing, and yawning. Statistical differences between the effort for speaking and the effort for other vocal behaviors were assessed using nonparametric Wilcoxon rank-sum tests within the overall SD cohort as well as within different subgroups of SD. RESULTS: Speech production was found to be the most impaired behavior, ranking as the most effortful type of voice production in all SD patients. In addition, singing required nearly similar effort as speaking, ranking as the second most altered vocal behavior. Shouting showed a range of variability in its alterations, being especially difficult to produce for patients with adductor form, co-occurring voice tremor, late onset of disorder, and familial history of dystonia. Other vocal behaviors, such as crying, laughing, whispering, and yawning, were within the normal ranges across all SD patients. CONCLUSION: Our findings widen the symptomatology of SD, which has predominantly been focused on selective speech impairments. We suggest that a separation of SD symptoms is rooted in selective aberrations of the neural circuitry controlling learned but not innate vocal behaviors. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018.

Dystonia is a neurological disorder characterized by involuntary, repetitive movements. Although the precise mechanisms of dystonia development remain unknown, the diversity of its clinical phenotypes is thought to be associated with multifactorial pathophysiology, which is linked not only to alterations of brain organization, but also environmental stressors and gene mutations. This chapter will present an overview of the pathophysiology of isolated dystonia through the lens of applications of major neuroimaging methodologies, with links to genetics and environmental factors that play a prominent role in symptom manifestation.

Oral medications for the treatment of dystonia are not established. Currently, symptoms of focal dystonia are managed with botulinum toxin injections into the affected muscles. However, the injection effects are short-lived and not beneficial for all patients. We recently reported significant clinical improvement of symptoms with novel investigational oral drug, sodium oxybate, in patients with the alcohol-responsive form of laryngeal focal dystonia. Understanding the mechanism of action of this promising oral agent holds a strong potential for the development of a scientific rationale for its use in dystonia. Therefore, to determine the neural markers of sodium oxybate effects, which may underlie dystonic symptom improvement, we examined brain activity during symptomatic speech production before and after drug intake in patients with laryngeal dystonia and compared to healthy subjects. We found that sodium oxybate significantly attenuated hyperfunctional activity of cerebellar, thalamic and primary/secondary sensorimotor cortical regions. Drug-induced symptom improvement was correlated with decreased-to-normal levels of activity in the right cerebellum. These findings suggest that sodium oxybate shows direct modulatory effects on disorder pathophysiology by acting upon abnormal neural activity within the dystonic network.

OBJECTIVES: Task-specific focal dystonia selectively affects the motor control during skilled and highly learned behaviors. Recent data suggest the role of neural network abnormalities in the development of the pathophysiological dystonic cascade. METHODS: We used resting-state functional MRI and analytic techniques rooted in network science and graph theory to examine the formation of abnormal subnetwork of highly influential brain regions, the functional network kernel, and its influence on aberrant dystonic connectivity specific to affected body region and skilled motor behavior. RESULTS: We found abnormal embedding of sensorimotor cortex and prefrontal thalamus in dystonic network kernel as a hallmark of task-specific focal dystonia. Dependent on the affected body region, aberrant functional specialization of the network kernel included regions of motor control management in focal hand dystonia (writer's cramp, musician's focal hand dystonia) and sensorimotor processing in laryngeal dystonia (spasmodic dysphonia, singer's laryngeal dystonia). Dependent on skilled motor behavior, the network kernel featured altered connectivity between sensory and motor execution circuits in musician's dystonia (musician's focal hand dystonia, singer's laryngeal dystonia) and abnormal integration of sensory feedback into motor planning and executive circuits in non-musician's dystonia (writer's cramp, spasmodic dysphonia). CONCLUSIONS: Our study identified specific traits in disorganization of large-scale neural connectivity that underlie the common pathophysiology of task-specific focal dystonia while reflecting distinct symptomatology of its different forms. Identification of specialized regions of information transfer that influence dystonic network activity is an important step for future delineation of targets for neuromodulation as a potential therapeutic option of task-specific focal dystonia. © 2018 International Parkinson and Movement Disorder Society.

Despite the wealth of genetic information available, mechanisms underlying pathological effects of disease-associated mutations in components of G protein-coupled receptor (GPCR) signaling cascades remain elusive. In this study, we developed a scalable approach for the functional analysis of clinical variants in GPCR pathways along with a complete analytical framework. We applied the strategy to evaluate an extensive set of dystonia-causing mutations in G protein Gαolf. Our quantitative analysis revealed diverse mechanisms by which pathogenic variants disrupt GPCR signaling, leading to a mechanism-based classification of dystonia. In light of significant clinical heterogeneity, the mechanistic analysis of individual disease-associated variants permits tailoring personalized intervention strategies, which makes it superior to the current phenotype-based approach. We propose that the platform developed in this study can be universally applied to evaluate disease mechanisms for conditions associated with genetic variation in all components of GPCR signaling.