DystoniaBoTXNet: Novel Neural Network Biomarker of Botulinum Toxin Efficacy in Isolated Dystonia.

OBJECTIVE: Isolated dystonia is characterized by abnormal, often painful, postures and repetitive movements due to sustained or intermittent involuntary muscle contractions. Botulinum toxin (BoTX) injections into the affected muscles are the first line of therapy. However, there are no objective predictive markers or standardized tests of BoTX efficacy that can be utilized for appropriate candidate selection prior to treatment initiation. METHODS: We developed a deep learning algorithm, DystoniaBoTXNet, which uses a 3D convolutional neural network architecture and raw structural brain magnetic resonance images (MRIs) to automatically discover and test a neural network biomarker of BoTX efficacy in 284 patients with 4 different forms of focal dystonia, including laryngeal dystonia, blepharospasm, cervical dystonia, and writer's cramp. RESULTS: DystoniaBoTXNet identified clusters in superior parietal lobule, inferior and middle frontal gyri, middle orbital gyrus, inferior temporal gyrus, corpus callosum, inferior fronto-occipital fasciculus, and anterior thalamic radiation as components of the treatment biomarker. These regions are known to contribute to both dystonia pathophysiology across a broad clinical spectrum of disorder and the central effects of botulinum toxin treatment. Based on its biomarker, DystoniaBoTXNet achieved an overall accuracy of 96.3%, with 100% sensitivity and 86.1% specificity, in predicting BoTX efficacy in patients with isolated dystonia. The algorithmic decision was computed in 19.2 seconds per case. INTERPRETATION: DystoniaBoTXNet and its treatment biomarker have a high translational potential as an objective, accurate, generalizable, fast, and cost-effective algorithmic platform for enhancing clinical decision making for BoTX treatment in patients with isolated dystonia. ANN NEUROL 2023;93:460-471.

Graph-theoretical insights into the effects of aging on the speech production network.

Speech production relies on the interplay of different brain regions. Healthy aging leads to complex changes in speech processing and production. Here, we investigated how the whole-brain functional connectivity of healthy elderly individuals differs from that of young individuals. In total, 23 young (aged 24.6 ± 2.2 years) and 23 elderly (aged 64.1 ± 6.5 years) individuals performed a picture naming task during functional magnetic resonance imaging. We determined whole-brain functional connectivity matrices and used them to compute group averaged speech production networks. By including an emotionally neutral and an emotionally charged condition in the task, we characterized the speech production network during normal and emotionally challenged processing. Our data suggest that the speech production network of elderly healthy individuals is as efficient as that of young participants, but that it is more functionally segregated and more modularized. By determining key network regions, we showed that although complex network changes take place during healthy aging, the most important network regions remain stable. Furthermore, emotional distraction had a larger influence on the young group's network than on the elderly's. We demonstrated that, from the neural network perspective, elderly individuals have a higher capacity for emotion regulation based on their age-related network re-organization.

Temporal Signature of Task-Specificity in Isolated Focal Laryngeal Dystonia.

BACKGROUND AND OBJECTIVE: Laryngeal dystonia (LD) is focal task-specific dystonia, predominantly affecting speech but not whispering or emotional vocalizations. Prior neuroimaging studies identified brain regions forming a dystonic neural network and contributing to LD pathophysiology. However, the underlying temporal dynamics of these alterations and their contribution to the task-specificity of LD remain largely unknown. The objective of the study was to identify the temporal-spatial signature of altered cortical oscillations associated with LD pathophysiology. METHODS: We used high-density 128-electrode electroencephalography (EEG) recordings during symptomatic speaking and two asymptomatic tasks, whispering and writing, in 24 LD patients and 22 healthy individuals to investigate the spectral dynamics, spatial localization, and interregional effective connectivity of aberrant cortical oscillations within the dystonic neural network, as well as their relationship with LD symptomatology. RESULTS: Symptomatic speaking in LD patients was characterized by significantly increased gamma synchronization in the middle/superior frontal gyri, primary somatosensory cortex, and superior parietal lobule, establishing the altered prefrontal-parietal loop. Hyperfunctional connectivity from the left middle frontal gyrus to the right superior parietal lobule was significantly correlated with the age of onset and the duration of LD symptoms. Asymptomatic whisper in LD patients had not no statistically significant changes in any frequency band, whereas asymptomatic writing was characterized by significantly decreased synchronization of beta-band power localized in the right superior frontal gyrus. CONCLUSION: Task-specific oscillatory activity of prefrontal-parietal circuitry is likely one of the underlying mechanisms of aberrant heteromodal integration of information processing and transfer within the neural network leading to dystonic motor output. © 2023 International Parkinson and Movement Disorder Society.

Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study.

BACKGROUND: Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatment of ET affecting extremities. OBJECTIVE: We conducted a proof-of-concept, open-label phase II study to examine the efficacy and central effects of sodium oxybate in patients with alcohol-responsive ETv. METHODS: All subjects received 1.0 to 1.5 g of oral sodium oxybate and underwent brain functional magnetic resonance imaging. The primary endpoint was the number of patients (% from total) with reduced ETv symptoms by at least 10% at about 40 to 45 minutes after sodium oxybate intake based on the combined visual analog scale score of ETv symptom severity. The secondary endpoint included changes in brain activity after sodium oxybate intake compared to baseline. RESULTS: Sodium oxybate reduced ETv symptoms on average by 40.8% in 92.9% of patients. Drug effects were observed about 40 to 45 minutes after intake, lasting about 3.5 hours, and gradually wearing off by the end of the fifth hour. The central effects of sodium oxybate were associated with normalized activity in the cerebellum, inferior/superior parietal lobules, inferior frontal gyrus, and insula and re-established functional relationships between these regions. CONCLUSIONS: Sodium oxybate showed high efficacy in ETv patients, with a likely central action on disorder pathophysiology. Sodium oxybate may be an effective novel oral drug for treatment of alcohol-responsive ETv patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A microstructural neural network biomarker for dystonia diagnosis identified by a DystoniaNet deep learning platform.

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.

Brain-Computer Interfaces for Treatment of Focal Dystonia.

Task-specificity in isolated focal dystonias is a powerful feature that may successfully be targeted with therapeutic brain-computer interfaces. While performing a symptomatic task, the patient actively modulates momentary brain activity (disorder signature) to match activity during an asymptomatic task (target signature), which is expected to translate into symptom reduction.

Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation.

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 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 classified 95.2% of unaffected relatives as patients rather than healthy controls, substantiating that these neural alterations represent 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 categorized 28.6% of unaffected relative as patients, indicating 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.

The large-scale structural connectome of task-specific focal dystonia.

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.

Neural Representations of the Voice Tremor Spectrum.

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.

Normal Temporal Discrimination in Musician's Dystonia Is Linked to Aberrant Sensorimotor Processing.

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.

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

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.

Polygenic Risk of Spasmodic Dysphonia is Associated With Vulnerable Sensorimotor Connectivity.

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.

Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia.

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.SIGNIFICANCE STATEMENT 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.

Task-specificity in focal dystonia is shaped by aberrant diversity of a functional network kernel.

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.

The Functional Connectome of Speech Control.

In the past few years, several studies have been directed to understanding the complexity of functional interactions between different brain regions during various human behaviors. Among these, neuroimaging research installed the notion that speech and language require an orchestration of brain regions for comprehension, planning, and integration of a heard sound with a spoken word. However, these studies have been largely limited to mapping the neural correlates of separate speech elements and examining distinct cortical or subcortical circuits involved in different aspects of speech control. As a result, the complexity of the brain network machinery controlling speech and language remained largely unknown. Using graph theoretical analysis of functional MRI (fMRI) data in healthy subjects, we quantified the large-scale speech network topology by constructing functional brain networks of increasing hierarchy from the resting state to motor output of meaningless syllables to complex production of real-life speech as well as compared to non-speech-related sequential finger tapping and pure tone discrimination networks. We identified a segregated network of highly connected local neural communities (hubs) in the primary sensorimotor and parietal regions, which formed a commonly shared core hub network across the examined conditions, with the left area 4p playing an important role in speech network organization. These sensorimotor core hubs exhibited features of flexible hubs based on their participation in several functional domains across different networks and ability to adaptively switch long-range functional connectivity depending on task content, resulting in a distinct community structure of each examined network. Specifically, compared to other tasks, speech production was characterized by the formation of six distinct neural communities with specialized recruitment of the prefrontal cortex, insula, putamen, and thalamus, which collectively forged the formation of the functional speech connectome. In addition, the observed capacity of the primary sensorimotor cortex to exhibit operational heterogeneity challenged the established concept of unimodality of this region.

The direct basal ganglia pathway is hyperfunctional in focal dystonia.

See Fujita and Eidelberg (doi:10.1093/brain/awx305) for a scientific commentary on this article. 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 19.6­22.5% in writer's cramp and in right putamen and caudate nucleus by 24.6­26.8% 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 D2 receptors 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.

Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks.

Isolated focal dystonias are a group of disorders with diverse symptomatology but unknown pathophysiology. Although recent neuroimaging studies demonstrated regional changes in brain connectivity, it remains unclear whether focal dystonia may be considered a disorder of abnormal networks. We examined topology as well as the global and local features of large-scale functional brain networks across different forms of isolated focal dystonia, including patients with task-specific (TSD) and nontask-specific (NTSD) dystonias. Compared with healthy participants, all patients showed altered network architecture characterized by abnormal expansion or shrinkage of neural communities, such as breakdown of basal ganglia-cerebellar community, loss of a pivotal region of information transfer (hub) in the premotor cortex, and pronounced connectivity reduction within the sensorimotor and frontoparietal regions. TSD were further characterized by significant connectivity changes in the primary sensorimotor and inferior parietal cortices and abnormal hub formation in insula and superior temporal cortex, whereas NTSD exhibited abnormal strength and number of regional connections. We suggest that isolated focal dystonias likely represent a disorder of large-scale functional networks, where abnormal regional interactions contribute to network-wide functional alterations and may underline the pathophysiology of isolated focal dystonia. Distinct symptomatology in TSD and NTSD may be linked to disorder-specific network aberrations.

Structural Organization of the Laryngeal Motor Cortical Network and Its Implication for Evolution of Speech Production.

The laryngeal motor cortex (LMC) is essential for the production of learned vocal behaviors because bilateral damage to this area renders humans unable to speak but has no apparent effect on innate vocalizations such as human laughing and crying or monkey calls. Several hypotheses have been put forward attempting to explain the evolutionary changes from monkeys to humans that potentially led to enhanced LMC functionality for finer motor control of speech production. These views, however, remain limited to the position of the larynx area within the motor cortex, as well as its connections with the phonatory brainstem regions responsible for the direct control of laryngeal muscles. Using probabilistic diffusion tractography in healthy humans and rhesus monkeys, we show that, whereas the LMC structural network is largely comparable in both species, the LMC establishes nearly 7-fold stronger connectivity with the somatosensory and inferior parietal cortices in humans than in macaques. These findings suggest that important "hard-wired" components of the human LMC network controlling the laryngeal component of speech motor output evolved from an already existing, similar network in nonhuman primates. However, the evolution of enhanced LMC-parietal connections likely allowed for more complex synchrony of higher-order sensorimotor coordination, proprioceptive and tactile feedback, and modulation of learned voice for speech production. SIGNIFICANCE STATEMENT: The role of the primary motor cortex in the formation of a comprehensive network controlling speech and language has been long underestimated and poorly studied. Here, we provide comparative and quantitative evidence for the significance of this region in the control of a highly learned and uniquely human behavior: speech production. From the viewpoint of structural network organization, we discuss potential evolutionary advances of enhanced temporoparietal cortical connections with the laryngeal motor cortex in humans compared with nonhuman primates that may have contributed to the development of finer vocal motor control necessary for speech production.

New Developments in Understanding the Complexity of Human Speech Production.

Speech is one of the most unique features of human communication. Our ability to articulate our thoughts by means of speech production depends critically on the integrity of the motor cortex. Long thought to be a low-order brain region, exciting work in the past years is overturning this notion. Here, we highlight some of major experimental advances in speech motor control research and discuss the emerging findings about the complexity of speech motocortical organization and its large-scale networks. This review summarizes the talks presented at a symposium at the Annual Meeting of the Society of Neuroscience; it does not represent a comprehensive review of contemporary literature in the broader field of speech motor control.

Phenotype- and genotype-specific structural alterations in spasmodic dysphonia.

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. © 2017 International Parkinson and Movement Disorder Society.