circosThe research focus of the Simonyan Laboratory is two-fold: identification of the central mechanisms responsible for speech production and elucidation of the pathophysiology of neurological voice and speech disorders. 
 
Our earlier contributions involved identification of the extensive projection system of the laryngeal motor cortex in the rhesus monkey using neuroanatomical tract tracing. Using multimodal neuroimaging, our laboratory later played a central role in i) identification of the laryngeal motocortical representation in humans; ii) defining the functional connectome of speech production, and iii) elucidation of the mechanisms of dopaminergic neurotransmission during speaking, as well as those underlying left-hemispheric lateralization of speech networks. We are currently focused on examining temporal characteristics of laryngeal motocortical activity and the modulatory role of different neurotransmitters on neural networks controlling speech production. To this end, we are developing multi-compartmental neural population models to test specific hypotheses about speech motor control, which have remained extremely challenging to address due to either invasiveness of the applied methods or technical limitations.
 
Our contributions to the understanding of the pathophysiology of neurological speech disorders include a comprehensive mapping of brain functional, structural and dopaminergic alterations as well as identification of neuropathological changes in spasmodic dysphonia (laryngeal dystonia) and voice tremor. We demonstrated that focal dystonia is a disorder of large-scale functional neural networks, where abnormal regional interactions may contribute to network-wide alterations. We also established that abnormal sensory discrimination thresholds in patients with focal dystonias represent a common endophenotypic trait of this disorder. We further showed that clinically and genetically distinct forms of spasmodic dysphonia can be accurately classified based on cortical sensorimotor abnormalities, the latter serving as potential objective diagnostic markers for this disorder. Our laboratory described the first spasmodic dysphonia patient with a causative DYT25 (GNAL) mutation and determined the polygenic risk of focal dystonia. Most recently, we delineated the first effective use of a novel oral medication, sodium oxybate (Xyrem®), in patients with spasmodic dysphonia and voice tremor.
 
The Simonyan laboratory currently uses multi-modal neuroimaging, machine learning, and neural population modeling to determine and validate phenotype- and genotype-specific neural markers of dystonia as well as the endophenotypic markers of its development. We are also working on the identification of the primary neural determinants of clinical response to sodium oxybate in patients with dystonia and tremor as a potential new therapeutic option. Another goal is to delineate abnormal neurotransmission in dystonia, which would ultimately help identify other novel pharmacological targets. We are applying several genetic strategies, including next-generation sequencing in dystonia families and singleton cases as well as genome-wide association studies in isolated populations, in order to identify new genes and risk factors of spasmodic dysphonia.
 

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Recent Publications

Functional but not structural networks of the human laryngeal motor cortex show left hemispheric lateralization during syllable but not breathing production
Kristina Simonyan, John Ostuni, Christy L Ludlow, and Barry Horwitz. 2009. “Functional but not structural networks of the human laryngeal motor cortex show left hemispheric lateralization during syllable but not breathing production.” J Neurosci, 29, 47, Pp. 14912-23.Abstract
The laryngeal motor cortex (LMC) is indispensible for the vocal motor control of speech and song production. Patients with bilateral lesions in this region are unable to speak and sing, although their nonverbal vocalizations, such as laughter and cry, are preserved. Despite the importance of the LMC in the control of voluntary voice production in humans, the literature describing its connections remains sparse. We used diffusion tensor probabilistic tractography and functional magnetic resonance imaging-based functional connectivity analysis to identify LMC networks controlling two tasks necessary for speech production: voluntary voice as repetition of two different syllables and voluntary breathing as controlled inspiration and expiration. Peaks of activation during all tasks were found in the bilateral ventral primary motor cortex in close proximity to each other. Functional networks of the LMC during voice production but not during controlled breathing showed significant left-hemispheric lateralization (p < 0.0005). However, structural networks of the LMC associated with both voluntary voice production and controlled breathing had bilateral hemispheric organization. Our findings indicate the presence of a common bilateral structural network of the LMC, upon which different functional networks are built to control various voluntary laryngeal tasks. Bilateral organization of functional LMC networks during controlled breathing supports its indispensible role in all types of laryngeal behaviors. Significant left-hemispheric lateralization of functional networks during simple but highly learned voice production suggests the readiness of the LMC network for production of a complex voluntary behavior, such as human speech.
Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study
Kristina Simonyan, Fernanda Tovar-Moll, John Ostuni, Mark Hallett, Victor F Kalasinsky, Michael R Lewin-Smith, Elisabeth J Rushing, Alexander O Vortmeyer, and Christy L Ludlow. 2008. “Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study.” Brain, 131, Pt 2, Pp. 447-59.Abstract
Spasmodic dysphonia is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although the clinical symptoms are well characterized, the pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in these patients as determined by a combined approach of diffusion tensor imaging (DTI) and postmortem histopathology. We used DTI to identify brain changes and to target those brain regions for neuropathological examination. DTI showed right-sided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/corticospinal tract in 20 spasmodic dysphonia patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus and cerebellar white and grey matter in the patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions, containing calcium, phosphorus and iron, in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus and cerebellum in the postmortem brain tissue from one patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization, limited only to the corticobulbar/corticospinal tract and its main input/output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of spasmodic dysphonia (r = 0.509, P = 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of this disorder.
Sensory stimulation activates both motor and sensory components of the swallowing system
Soren Y Lowell, Christopher J Poletto, Bethany R Knorr-Chung, Richard C Reynolds, Kristina Simonyan, and Christy L Ludlow. 2008. “Sensory stimulation activates both motor and sensory components of the swallowing system.” Neuroimage, 42, 1, Pp. 285-95.Abstract
Volitional swallowing in humans involves the coordination of both brainstem and cerebral swallowing control regions. Peripheral sensory inputs are necessary for safe and efficient swallowing, and their importance to the patterned components of swallowing has been demonstrated. However, the role of sensory inputs to the cerebral system during volitional swallowing is less clear. We used four conditions applied during functional magnetic resonance imaging to differentiate between sensory, motor planning, and motor execution components for cerebral control of swallowing. Oral air pulse stimulation was used to examine the effect of sensory input, covert swallowing was used to engage motor planning for swallowing, and overt swallowing was used to activate the volitional swallowing system. Breath-holding was also included to determine whether its effects could account for the activation seen during overt swallowing. Oral air pulse stimulation, covert swallowing and overt swallowing all produced activation in the primary motor cortex, cingulate cortex, putamen and insula. Additional regions of the swallowing cerebral system that were activated by the oral air pulse stimulation condition included the primary and secondary somatosensory cortex and thalamus. Although air pulse stimulation was on the right side only, bilateral cerebral activation occurred. On the other hand, covert swallowing minimally activated sensory regions, but did activate the supplementary motor area and other motor regions. Breath-holding did not account for the activation during overt swallowing. The effectiveness of oral-sensory stimulation for engaging both sensory and motor components of the cerebral swallowing system demonstrates the importance of sensory input in cerebral swallowing control.
Human brain activation during phonation and exhalation: common volitional control for two upper airway functions
Torrey MJ Loucks, Christopher J Poletto, Kristina Simonyan, Catherine L Reynolds, and Christy L Ludlow. 2007. “Human brain activation during phonation and exhalation: common volitional control for two upper airway functions.” Neuroimage, 36, 1, Pp. 131-43.Abstract
Phonation is defined as a laryngeal motor behavior used for speech production, which involves a highly specialized coordination of laryngeal and respiratory neuromuscular control. During speech, brief periods of vocal fold vibration for vowels are interspersed by voiced and unvoiced consonants, glottal stops and glottal fricatives (/h/). It remains unknown whether laryngeal/respiratory coordination of phonation for speech relies on separate neural systems from respiratory control or whether a common system controls both behaviors. To identify the central control system for human phonation, we used event-related fMRI to contrast brain activity during phonation with activity during prolonged exhalation in healthy adults. Both whole-brain analyses and region of interest comparisons were conducted. Production of syllables containing glottal stops and vowels was accompanied by activity in left sensorimotor, bilateral temporoparietal and medial motor areas. Prolonged exhalation similarly involved activity in left sensorimotor and temporoparietal areas but not medial motor areas. Significant differences between phonation and exhalation were found primarily in the bilateral auditory cortices with whole-brain analysis. The ROI analysis similarly indicated task differences in the auditory cortex with differences also detected in the inferolateral motor cortex and dentate nucleus of the cerebellum. A second experiment confirmed that activity in the auditory cortex only occurred during phonation for speech and did not depend upon sound production. Overall, a similar central neural system was identified for both speech phonation and voluntary exhalation that primarily differed in auditory monitoring.

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