OBJECTIVE: To evaluate the hypothesis that individuals with isolated dystonia are at an increased risk for suicidal behavior, we administered an anonymous electronic survey to patients with dystonia, asking them about their history of suicidal ideations and suicide attempt. METHODS: A total of 542 patients with dystonia completed an online 97-question survey, which captured the demographics of suicidal behavior and major psychiatric disorders in these patients. Statistical analyses examined the prevalence of suicidal behavior in patients with dystonia compared to the prevalence of suicidal ideations and attempt in the general global population and assessed the significance of risk associations between suicidality and psychiatric history in these patients. RESULTS: Overall, 32.3% of patients with isolated dystonia reported a lifetime history of suicidal behavior, which was significantly different from the reported rates of suicidal ideation (9.2%) and attempt (2.7%) in the general global population. The prevalence of suicidality was higher in patients with multifocal/segmental and generalized forms of dystonia (range of 46%-50%) compared to patients with focal dystonias (range of 26.1%-33.3%). The highest suicidal ideation-to-attempt ratio of 4:1 was found in patients with generalized dystonia. Suicidality in patients with focal dystonia was significantly associated with their history of depression and anxiety disorders. CONCLUSION: Patients with isolated dystonia have an increased, albeit unrecognized, prevalence of suicidal behavior compared to the general global population. The screening for suicidal risk should be incorporated as part of the clinical evaluation of patients with dystonia to prevent their suicide-induced injury and death.

Importance: In recent years, there have been several meaningful advances in the understanding of the cognitive effects of chronic rhinosinusitis. However, an investigation exploring the potential link between the underlying inflammatory disease and higher-order neural processing has not yet been performed. Objective: To describe the association of sinonasal inflammation with functional brain connectivity (Fc), which may underlie chronic rhinosinusitis-related cognitive changes. Design, Setting, and Participants: This is a case-control study using the Human Connectome Project (Washington University-University of Minnesota Consortium of the Human Connectome Project 1200 release), an open-access and publicly available data set that includes demographic, imaging, and behavioral data for 1206 healthy adults aged 22 to 35 years. Twenty-two participants demonstrated sinonasal inflammation (Lund-Mackay score [LMS] ≥ 10) and were compared with age-matched and sex-matched healthy controls (LMS = 0). These participants were further stratified into moderate (LMS < 14, n = 13) and severe (LMS ≥ 14, n = 9) inflammation groups. Participants were screened and excluded if they had a history of psychiatric disorder and/or neurological or genetic diseases. Participants with diabetes or cardiovascular disease were also excluded, as these conditions may affect neuroimaging quality. The data were accessed between October 2019 and August 2020. Data analysis was performed between May 2020 and August 2020. Main Outcomes and Measures: The primary outcome was the difference in resting state Fc within and between the default mode, frontoparietal, salience, and dorsal attention brain networks. Secondary outcomes included assessments of cognitive function using the National Institutes of Health Toolbox Cognition Battery. Results: A total of 22 patients with chronic rhinosinusitis and 22 healthy controls (2 [5%] were aged 22-25 years, 26 [59%] were aged 26-30 years, and 16 [36%] were aged 31-35 years; 30 [68%] were men) were included in the analysis. Participants with sinonasal inflammation showed decreased Fc within the frontoparietal network, in a region involving bilateral frontal medial cortices. This region demonstrated increased Fc to 2 nodes within the default-mode network and decreased Fc to 1 node within the salience network. The magnitude of these differences increased with inflammation severity (dose dependent). There were no significant associations seen on cognitive testing. Conclusions and Relevance: In this case-control study, participants with sinonasal inflammation showed decreased brain connectivity within a major functional hub with a central role in modulating cognition. This region also shows increased connectivity to areas that are activated during introspective and self-referential processing and decreased connectivity to areas involved in detection and response to stimuli. Future prospective studies are warranted to determine the applicability of these findings to a clinical chronic rhinosinusitis population.

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in the prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine-learning classification of 95.2% of unaffected relatives together with patients rather than healthy controls substantiated these neural alterations as the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine-learning categorization of 28.6% of unaffected relative as patients indicated their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials.

OBJECTIVES: Voice tremor is a common movement disorder that manifests as involuntary oscillations of laryngeal muscles, leading to rhythmic alterations in voice pitch and loudness. Differential diagnosis of essential tremor of voice (ETv) is often challenging and includes dystonic tremor of voice (DTv), which is characterized by irregular, isometric contractions of laryngeal muscles during dystonic activity. Although clinical characteristics of voice tremor are well described, the pathophysiology underlying its heterogeneous phenomenology remains limited. METHODS: We used a multimodal approach of functional magnetic resonance imaging for assessment of brain activity during symptomatic speech production, high-resolution magnetic resonance imaging for the examination of cortical thickness and gray matter volume, and diffusion-weighted imaging for evaluation of white matter integrity to identify disorder-specific neural alterations and their relationships with the symptomatology of ETv and DTv. RESULTS: We found a broad overlap between cortical alterations in ETv and DTv, involving sensorimotor regions responsible for the integration of multisensory information during speech production, such as primary sensorimotor, inferior/superior parietal, and inferior temporal cortices. In addition, ETv and DTv showed unique patterns of abnormalities in regions controlling speech motor preparation, which were localized in the cerebellum in ETv and the premotor cortex, insula, and superior temporal gyrus in DTv. Neural alterations in superior parietal and inferior temporal cortices were correlated with ETv severity, whereas changes in the left premotor cortex were associated with DTv severity. CONCLUSIONS: Our findings point to the pathophysiological spectrum underlying ETv and DTv and favor a more heterogeneous rather than dichotomous diagnostic classification of these voice tremor disorders. © 2020 International Parkinson and Movement Disorder Society.

The vagus nerve is the 10th of the 12 pairs of cranial nerves and is a part of the parasympathetic nervous system. It originates in the medulla oblongata and is comprised of sensory and motor neurons that innervate the peripheral nervous system. The vagus nerve exits the central nervous system at the vagal ganglia and spreads to the rest of the body. Among other functions, the vagus nerve supplies the laryngopharynx and other structures in the neck via afferent and efferent nerve branches. These branches are composed of different fibers that have their origins in different vagal nuclei in the medulla and are responsible for phonation, gastrointestinal reflexes, swallowing, air passing, and cardiac function.

Isolated dystonia is a neurological disorder of heterogeneous pathophysiology, which causes involuntary muscle contractions leading to abnormal movements and postures. Its diagnosis is remarkably challenging due to the absence of a biomarker or gold standard diagnostic test. This leads to a low agreement between clinicians, with up to 50% of cases being misdiagnosed and diagnostic delays extending up to 10.1 y. We developed a deep learning algorithmic platform, DystoniaNet, to automatically identify and validate a microstructural neural network biomarker for dystonia diagnosis from raw structural brain MRIs of 612 subjects, including 392 patients with three different forms of isolated focal dystonia and 220 healthy controls. DystoniaNet identified clusters in corpus callosum, anterior and posterior thalamic radiations, inferior fronto-occipital fasciculus, and inferior temporal and superior orbital gyri as the biomarker components. These regions are known to contribute to abnormal interhemispheric information transfer, heteromodal sensorimotor processing, and executive control of motor commands in dystonia pathophysiology. The DystoniaNet-based biomarker showed an overall accuracy of 98.8% in diagnosing dystonia, with a referral of 3.5% of cases due to diagnostic uncertainty. The diagnostic decision by DystoniaNet was computed in 0.36 s per subject. DystoniaNet significantly outperformed shallow machine-learning algorithms in benchmark comparisons, showing nearly a 20% increase in its diagnostic performance. Importantly, the microstructural neural network biomarker and its DystoniaNet platform showed substantial improvement over the current 34% agreement on dystonia diagnosis between clinicians. The translational potential of this biomarker is in its highly accurate, interpretable, and generalizable performance for enhanced clinical decision-making.

The emerging view of dystonia is that of a large-scale functional network disorder, in which the communication is disrupted between sensorimotor cortical areas, basal ganglia, thalamus, and cerebellum. The structural underpinnings of functional alterations in dystonia are, however, poorly understood. Notably, it is unclear whether structural changes form a larger-scale dystonic network or rather remain focal to isolated brain regions, merely underlying their functional abnormalities. Using diffusion-weighted imaging and graph theoretical analysis, we examined inter-regional white matter connectivity of the whole-brain structural network in two different forms of task-specific focal dystonia, writer's cramp and laryngeal dystonia, compared to healthy individuals. We show that, in addition to profoundly altered functional network in focal dystonia, its structural connectome is characterized by large-scale aberrations due to abnormal transfer of prefrontal and parietal nodes between neural communities and the reorganization of normal hub architecture, commonly involving the insula and superior frontal gyrus in patients compared to controls. Other prominent common changes involved the basal ganglia, parietal and cingulate cortical regions, whereas premotor and occipital abnormalities distinctly characterized the two forms of dystonia. We propose a revised pathophysiological model of focal dystonia as a disorder of both functional and structural connectomes, where dystonia form-specific abnormalities underlie the divergent mechanisms in the development of distinct clinical symptomatology. These findings may guide the development of novel therapeutic strategies directed at targeted neuromodulation of pathophysiological brain regions for the restoration of their structural and functional connectivity.

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.

OBJECTIVES: Alterations in sensory discrimination are a prominent nonmotor feature of dystonia. Abnormal temporal discrimination in focal dystonia is considered to represent its mediational endophenotype, albeit unclear pathophysiological correlates. We examined the associations between the visual temporal discrimination threshold (TDT) and brain activity in patients with musician's dystonia, nonmusician's dystonia, and healthy controls. METHODS: A total of 42 patients and 41 healthy controls participated in the study. Between-group differences in TDT z scores were computed using inferential statistics. Statistical associations of TDT z scores with clinical characteristics of dystonia and resting-state functional brain activity were examined using nonparametric rank correlations. RESULTS: The TDT z scores of healthy controls were significantly different from those of patients with nonmusician's dystonia, but not of patients with musician's dystonia. Healthy controls showed a significant relationship between normal TDT levels and activity in the inferior parietal cortex. This relationship was lost in all patients. Instead, TDT z scores in musician's dystonia established additional correlations with activity in premotor, primary somatosensory, ventral extrastriate cortices, inferior occipital gyrus, precuneus, and cerebellum, whereas nonmusician's dystonia showed a trending correlation in the lingual gyrus extending to the cerebellar vermis. There were no significant relationships between TDT z scores and dystonia onset, duration, or severity. CONCLUSIONS: TDT assessment as an endophenotypic marker may only be relevant to nonmusician forms of dystonia because of the lack of apparent alterations in musician's dystonia. Compensatory adaptation of neural circuitry responsible for TDT processing likely adjusted the TDT performance to the behaviorally normal levels in patients with musician's dystonia, but not nonmusician's dystonia. © 2020 International Parkinson and Movement Disorder Society.