Codrin Lungu, Laurie Ozelius, David Standaert, Mark Hallett, Beth-Anne Sieber, Christine Swanson-Fisher, Brian D Berman, Nicole Calakos, Jennifer C Moore, Joel S Perlmutter, Sarah E Pirio Richardson, Rachel Saunders-Pullman, Laura Scheinfeldt, Nutan Sharma, Roy Sillitoe, Kristina Simonyan, Philip A Starr, Anna Taylor, Jerrold Vitek, and NINDS Workshop Research Priorities participants and organizers of the on in Dystonia. 2020. “Defining research priorities in dystonia.” Neurology.Abstract
OBJECTIVE: Dystonia is a complex movement disorder. Research progress has been difficult, particularly in developing widely effective therapies. This is a review of the current state of knowledge, research gaps, and proposed research priorities. METHODS: The NIH convened leaders in the field for a 2-day workshop. The participants addressed the natural history of the disease, the underlying etiology, the pathophysiology, relevant research technologies, research resources, and therapeutic approaches and attempted to prioritize dystonia research recommendations. RESULTS: The heterogeneity of dystonia poses challenges to research and therapy development. Much can be learned from specific genetic subtypes, and the disorder can be conceptualized along clinical, etiology, and pathophysiology axes. Advances in research technology and pooled resources can accelerate progress. Although etiologically based therapies would be optimal, a focus on circuit abnormalities can provide a convergent common target for symptomatic therapies across dystonia subtypes. The discussions have been integrated into a comprehensive review of all aspects of dystonia. CONCLUSION: Overall research priorities include the generation and integration of high-quality phenotypic and genotypic data, reproducing key features in cellular and animal models, both of basic cellular mechanisms and phenotypes, leveraging new research technologies, and targeting circuit-level dysfunction with therapeutic interventions. Collaboration is necessary both for collection of large data sets and integration of different research methods.
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.
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.
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.
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.
OBJECTIVE: Our ability to speak is complex, and the role of the central nervous system in controlling speech production is often overlooked in the field of otolaryngology. In this brief review, we present an integrated overview of speech production with a focus on the role of central nervous system. The role of central control of voice production is then further discussed in relation to the potential pathophysiology of spasmodic dysphonia (SD). DATA SOURCES: Peer-review articles on central laryngeal control and SD were identified from PUBMED search. Selected articles were augmented with designated relevant publications. REVIEW METHODS: Publications that discussed central and peripheral nervous system control of voice production and the central pathophysiology of laryngeal dystonia were chosen. RESULTS: Our ability to speak is regulated by specialized complex mechanisms coordinated by high-level cortical signaling, brainstem reflexes, peripheral nerves, muscles, and mucosal actions. Recent studies suggest that SD results from a primary central disturbance associated with dysfunction at our highest levels of central voice control. The efficacy of botulinum toxin in treating SD may not be limited solely to its local effect on laryngeal muscles and also may modulate the disorder at the level of the central nervous system. CONCLUSION: Future therapeutic options that target the central nervous system may help modulate the underlying disorder in SD and allow clinicians to better understand the principal pathophysiology. LEVEL OF EVIDENCE: NA.Laryngoscope, 128:177-183, 2018.
The importance of insula in speech control is acknowledged but poorly understood, partly due to a variety of clinical symptoms resulting from insults to this structure. To clarify its structural organization within the speech network in healthy subjects, we used probabilistic diffusion tractography to examine insular connectivity with three cortical regions responsible for sound processing [Brodmann area (BA) 22], motor preparation (BA 44) and motor execution (laryngeal/orofacial primary motor cortex, BA 4). To assess insular reorganization in a speech disorder, we examined its structural connectivity in patients with spasmodic dysphonia (SD), a neurological condition that selectively affects speech production. We demonstrated structural segregation of insula into three non-overlapping regions, which receive distinct connections from BA 44 (anterior insula), BA 4 (mid-insula) and BA 22 (dorsal and posterior insula). There were no significant differences either in the number of streamlines connecting each insular subdivision to the cortical target or hemispheric lateralization of insular clusters and their projections between healthy subjects and SD patients. However, spatial distribution of the insular subdivisions connected to BA 4 and BA 44 was distinctly organized in healthy controls and SD patients, extending ventro-posteriorly in the former group and anterio-dorsally in the latter group. Our findings point to structural segregation of the insular sub-regions, which may be associated with the different aspects of sensorimotor and cognitive control of speech production. We suggest that distinct insular involvement may lead to different clinical manifestations when one or the other insular region and/or its connections undergo spatial reorganization.
Although the concept of left-hemispheric lateralization of neural processes during speech production has been known since the times of Broca, its physiological underpinnings still remain elusive. We sought to assess the modulatory influences of a major neurotransmitter, dopamine, on hemispheric lateralization during real-life speaking using a multimodal analysis of functional MRI, intracranial EEG recordings, and large-scale neural population simulations based on diffusion-weighted MRI. We demonstrate that speech-induced phasic dopamine release into the dorsal striatum and speech motor cortex exerts direct modulation of neuronal activity in these regions and drives left-hemispheric lateralization of speech production network. Dopamine-induced lateralization of functional activity and networks during speaking is not dependent on lateralization of structural nigro-striatal and nigro-motocortical pathways. Our findings provide the first mechanistic explanation for left-hemispheric lateralization of human speech that is due to left-lateralized dopaminergic modulation of brain activity and functional networks.
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.
OBJECTIVE: Laryngeal dystonia (LD) is a functionally specific disorder of the afferent-efferent motor coordination system producing action-induced muscle contraction with a varied phenomenology. This report of long-term studies aims to review and better define the phenomenology and central nervous system abnormalities of this disorder and improve diagnosis and treatment. METHODS: Our studies categorized over 1,400 patients diagnosed with LD over the past 33 years, including demographic and medical history records and their phenomenological presentations. Patients were grouped on clinical phenotype (adductor or abductor) and genotype (sporadic and familial) and with DNA analysis and functional magnetic resonance imaging (fMRI) to investigate brain organization differences and characterize neural markers for genotype/phenotype categorization. A number of patients with alcohol-sensitive dystonia were also studied. RESULTS: A spectrum of LD phenomena evolved: adductor, abductor, mixed, singer's, dystonic tremor, and adductor respiratory dystonia. Patients were genetically screened for DYT (dystonia) 1, DYT4, DYT6, and DYT25 (GNAL)-and several were positive. The functional MRI studies showed distinct alterations within the sensorimotor network, and the LD patients with a family history had distinct cortical and cerebellar abnormalities. A linear discriminant analysis of fMRI findings showed a 71% accuracy in characterizing LD from normal and in characterizing adductor from abductor forms. CONCLUSION: Continuous studies of LD patients over 30 years has led to an improved understanding of the phenomenological characteristics of this neurological disorder. Genetic and fMRI studies have better characterized the disorder and raise the possibility of making objective rather than subjective diagnoses, potentially leading to new therapeutic approaches. Laryngoscope, 128:S1-S9, 2018.
Spasmodic dysphonia (SD), or laryngeal dystonia, is an isolated task-specific dystonia of unknown causes and pathophysiology that selectively affects speech production. Using next-generation whole-exome sequencing in SD patients, we computed polygenic risk score from 1804 genetic markers based on a genome-wide association study in another form of similar task-specific focal dystonia, musician's dystonia. We further examined the associations between the polygenic risk score, resting-state functional connectivity abnormalities within the sensorimotor network, and SD clinical characteristics. We found that the polygenic risk of dystonia was significantly associated with decreased functional connectivity in the left premotor/primary sensorimotor and inferior parietal cortices in SD patients. Reduced connectivity of the inferior parietal cortex was correlated with the age of SD onset. The polygenic risk score contained a significant number of genetic variants lying near genes related to synaptic transmission and neural development. Our study identified a polygenic contribution to the overall genetic risk of dystonia in the cohort of SD patients. Associations between the polygenic risk and reduced functional connectivity of the sensorimotor and inferior parietal cortices likely represent an endophenotypic imaging marker of SD, while genes involved in synaptic transmission and neuron development may be linked to the molecular pathophysiology of this disorder.
Cognitive impairment in Parkinson's disease (PD) is related to the reorganization of brain topology. Although drug challenge studies have proven how levodopa treatment can modulate functional connectivity in brain circuits, the role of chronic dopaminergic therapy on cognitive status and functional connectivity has never been investigated. We sought to characterize brain functional topology in mid-stage PD patients under chronic antiparkinson treatment and explore the presence of correlation between reorganization of brain architecture and specific cognitive deficits. We explored networks topology and functional connectivity in 16 patients with PD and 16 matched controls through a graph theoretical analysis of resting state-functional MRI data, and evaluated the relationships between network metrics and cognitive performance. PD patients showed a preserved small-world network topology but a lower clustering coefficient in comparison with healthy controls. Locally, PD patients showed lower degree of connectivity and local efficiency in many hubs corresponding to functionally relevant areas. Four disconnected subnetworks were also identified in regions responsible for executive control, sensory-motor control and planning, motor coordination and visual elaboration. Executive functions and information processing speed were directly correlated with degree of connectivity and local efficiency in frontal, parietal and occipital areas. While functional reorganization appears in both motor and cognitive areas, the clinical expression of network imbalance seems to be partially compensated by the chronic levodopa treatment with regards to the motor but not to the cognitive performance. In a context of reduced network segregation, the presence of higher local efficiency in hubs regions correlates with a better cognitive performance.
Isolated focal dystonia is a debilitating movement disorder of unknown pathophysiology. Early studies in focal dystonias have pointed to segregated changes in brain activity and connectivity. Only recently has the notion that dystonia pathophysiology may lie in abnormalities of large-scale brain networks appeared in the literature. Here, we outline a novel concept of functional connectome-wide alterations that are linked to dystonia phenotype and genotype. Using a neural community detection strategy and graph theoretical analysis of functional MRI data in human patients with the laryngeal form of dystonia (LD) and healthy controls (both males and females), we identified an abnormally widespread hub formation in LD, which particularly affected the primary sensorimotor and parietal cortices and thalamus. Left thalamic regions formed a delineated functional community that highlighted differences in network topology between LD patients with and without family history of dystonia. Conversely, marked differences in the topological organization of parietal regions were found between phenotypically different forms of LD. The interface between sporadic genotype and adductor phenotype of LD yielded four functional communities that were primarily governed by intramodular hub regions. Conversely, the interface between familial genotype and abductor phenotype was associated with numerous long-range hub nodes and an abnormal integration of left thalamus and basal ganglia. Our findings provide the first comprehensive atlas of functional topology across different phenotypes and genotypes of focal dystonia. As such, this study constitutes an important step toward defining dystonia as a large-scale network disorder, understanding its causative pathophysiology, and identifying disorder-specific markers.The architecture of the functional connectome in focal dystonia was analyzed in a large population of patients with laryngeal dystonia. Breaking with the empirical concept of dystonia as a basal ganglia disorder, we discovered large-scale alterations of neural communities that are significantly influenced by the disorder's clinical phenotype and genotype.
Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research tomography with the radioligand 11C-NNC-112 to examine striatal dopamine D1 receptor function in two independent groups of patients, writer’s cramp and laryngeal dystonia, compared to healthy controls. We found that availability of dopamine D1 receptors was significantly increased in bilateral putamen by 19.6–22.5% in writer’s cramp and in right putamen and caudate nucleus by 24.6–26.8% in laryngeal dystonia (all P ≤ 0.009). This suggests hyperactivity of the direct basal ganglia pathway in focal dystonia. Our findings paralleled abnormally decreased dopaminergic function via the indirect basal ganglia pathway and decreased symptom-induced phasic striatal dopamine release in writer’s cramp and laryngeal dystonia. When examining topological distribution of dopamine D1 and D2 receptor abnormalities in these forms of dystonia, we found abnormal separation of direct and indirect pathways within the striatum, with negligible, if any, overlap between the two pathways and with the regions of phasic dopamine release. However, despite topological disorganization of dopaminergic function, alterations of dopamine D1 and D2 receptors were somatotopically localized within the striatal hand and larynx representations in writer’s cramp and laryngeal dystonia, respectively. This finding points to their direct relevance to disorder-characteristic clinical features. Increased D1 receptor availability showed significant negative correlations with dystonia duration but not its severity, likely representing a developmental endophenotype of this disorder. In conclusion, a comprehensive pathophysiological mechanism of abnormal basal ganglia function in focal dystonia is built upon upregulated dopamine D1 receptors that abnormally increase excitation of the direct pathway, downregulated dopamine D2receptors that abnormally decrease inhibition within the indirect pathway, and weakened nigro-striatal phasic dopamine release during symptomatic task performance. Collectively, these aberrations of striatal dopaminergic function underlie imbalance between direct and indirect basal ganglia pathways and lead to abnormal thalamo-motor-cortical hyperexcitability in dystonia.