Publications

2013
Long-term Effect of Sodium Oxybate (Xyrem®) in Spasmodic Dysphonia with Vocal Tremor
Kristina Simonyan and Steven J Frucht. 2013. “Long-term Effect of Sodium Oxybate (Xyrem®) in Spasmodic Dysphonia with Vocal Tremor.” Tremor Other Hyperkinet Mov (N Y), 3.Abstract
BACKGROUND: Symptoms of spasmodic dysphonia (SD) are usually managed successfully with botulinum toxin injections. Vocal tremor (VT), which accompanies SD, has a poor response to this treatment. CASE REPORT: We report a case of a female with SD and VT who became symptom-free for 10 months after the intake of a single dose of sodium oxybate (Xyrem®). The long-term treatment effect correlated with attenuated brain activity in the key regions of dystonic brain network. DISCUSSION: Our case demonstrates that the novel treatment of sodium oxybate may hold promise for SD patients, especially those who have associated VT.
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Primary dystonia: conceptualizing the disorder through a structural brain imaging lens
Ritesh A Ramdhani and Kristina Simonyan. 2013. “Primary dystonia: conceptualizing the disorder through a structural brain imaging lens.” Tremor Other Hyperkinet Mov (N Y), 3.Abstract
BACKGROUND: Dystonia is a hyperkinetic movement disorder characterized by involuntary, repetitive twisting movements. The anatomical structures and pathways implicated in its pathogenesis and their relationships to the neurophysiological paradigms of abnormal surround inhibition, maladaptive plasticity, and impaired sensorimotor integration remain unclear. OBJECTIVE: We review the use of high-resolution structural brain imaging using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) techniques for evaluating brain changes in primary torsion dystonia and their relationships to the pathophysiology of this disorder. METHODS: A PubMed search was conducted to identify relevant literature. RESULTS: VBM and DTI studies produced somewhat conflicting results across different forms of primary dystonia and reported increases, decreases, or both in gray matter volume and white matter integrity. However, despite the discrepancies, these studies are consistent in revealing brain abnormalities in dystonia that extend beyond the basal ganglia and involve the sensorimotor cortex and cerebellum. DISCUSSION: Although limited to date, structural magnetic resonance imaging (MRI) studies combined with functional brain imaging and neurophysiological modalities begin to establish structural-functional relationships at different levels of the abnormal basal ganglia, cortical, and cerebellar networks and provide clues into the pathophysiological mechanisms that underlie primary dystonia. Cross-disciplinary studies are needed for further investigations of the interplay between structural-functional brain abnormalities and environmental and genetic risk factors in dystonia patients.
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Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: a combined PET, fMRI and DTI study
Kristina Simonyan, Peter Herscovitch, and Barry Horwitz. 2013. “Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: a combined PET, fMRI and DTI study.” Neuroimage, 70, Pp. 21-32.Abstract
Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D(2)/D(3) receptor radioligand [(11)C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in both its associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech.
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Striatal dopaminergic dysfunction at rest and during task performance in writer's cramp
Brian D Berman, Mark Hallett, Peter Herscovitch, and Kristina Simonyan. 2013. “Striatal dopaminergic dysfunction at rest and during task performance in writer's cramp.” Brain, 136, Pt 12, Pp. 3645-58.Abstract
Writer's cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer's cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously investigated in writer's cramp. Using positron emission tomography imaging with the D2/D3 antagonist 11C-raclopride, we analysed striatal D2/D3 availability at rest and endogenous dopamine release during sequential finger tapping and speech production tasks in 15 patients with writer's cramp and 15 matched healthy control subjects. Compared with control subjects, patients had reduced 11C-raclopride binding to D2/D3 receptors at rest in the bilateral striatum, consistent with findings in previous studies. During the tapping task, patients had decreased dopamine release in the left striatum as assessed by reduced change in 11C-raclopride binding compared with control subjects. One cluster of reduced dopamine release in the left putamen during tapping overlapped with a region of reduced 11C-raclopride binding to D2/D3 receptors at rest. During the sentence production task, patients showed increased dopamine release in the left striatum. No overlap between altered dopamine release during speech production and reduced 11C-raclopride binding to D2/D3 receptors at rest was seen. Striatal regions where D2/D3 availability at rest positively correlated with disease duration were lateral and non-overlapping with striatal regions showing reduced D2/D3 receptor availability, except for a cluster in the left nucleus accumbens, which showed a negative correlation with disease duration and overlapped with striatal regions showing reduced D2/D3 availability. Our findings suggest that patients with writer's cramp may have divergent responses in striatal dopamine release during an asymptomatic motor task involving the dystonic hand and an unrelated asymptomatic task, sentence production. Our voxel-based results also suggest that writer's cramp may be associated with reduced striatal dopamine release occuring in the setting of reduced D2/D3 receptor availability and raise the possibility that basal ganglia circuits associated with premotor cortices and those associated with primary motor cortex are differentially affected in primary focal dystonias.
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Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene
Katja Lohmann, Robert A Wilcox, Susen Winkler, Alfredo Ramirez, Aleksandar Rakovic, Jin-Sung Park, Björn Arns, Thora Lohnau, Justus Groen, Meike Kasten, Norbert Brüggemann, Johann Hagenah, Alexander Schmidt, Frank J Kaiser, Kishore R Kumar, Katja Zschiedrich, Daniel Alvarez-Fischer, Eckart Altenmüller, Andreas Ferbert, Anthony E Lang, Alexander Münchau, Vladimir Kostic, Kristina Simonyan, Marc Agzarian, Laurie J Ozelius, Antonius PM Langeveld, Carolyn M Sue, Marina AJ Tijssen, and Christine Klein. 2013. “Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.” Ann Neurol, 73, 4, Pp. 537-45.Abstract
OBJECTIVE: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.
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2012
Abnormal structure-function relationship in spasmodic dysphonia
Kristina Simonyan and Christy L Ludlow. 2012. “Abnormal structure-function relationship in spasmodic dysphonia.” Cereb Cortex, 22, 2, Pp. 417-25.Abstract
Spasmodic dysphonia (SD) is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. Although recent studies have found abnormal brain function and white matter organization in SD, the extent of gray matter alterations, their structure-function relationships, and correlations with symptoms remain unknown. We compared gray matter volume (GMV) and cortical thickness (CT) in 40 SD patients and 40 controls using voxel-based morphometry and cortical distance estimates. These measures were examined for relationships with blood oxygen level-dependent signal change during symptomatic syllable production in 15 of the same patients. SD patients had increased GMV, CT, and brain activation in key structures of the speech control system, including the laryngeal sensorimotor cortex, inferior frontal gyrus (IFG), superior/middle temporal and supramarginal gyri, and in a structure commonly abnormal in other primary dystonias, the cerebellum. Among these regions, GMV, CT and activation of the IFG and cerebellum showed positive relationships with SD severity, while CT of the IFG correlated with SD duration. The left anterior insula was the only region with decreased CT, which also correlated with SD symptom severity. These findings provide evidence for coupling between structural and functional abnormalities at different levels within the speech production system in SD.
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Combined laryngeal inflammation and trauma mediate long-lasting immunoreactivity response in the brainstem sensory nuclei in the rat
Kristina Simonyan, Xin Feng, Victor M Henriquez, and Christy L Ludlow. 2012. “Combined laryngeal inflammation and trauma mediate long-lasting immunoreactivity response in the brainstem sensory nuclei in the rat.” Front Integr Neurosci, 6, Pp. 97.Abstract
Somatosensory feedback from the larynx plays a critical role in regulation of normal upper airway functions, such as breathing, deglutition, and voice production, while altered laryngeal sensory feedback is known to elicit a variety of pathological reflex responses, including persistent coughing, dysphonia, and laryngospasm. Despite its clinical impact, the central mechanisms underlying the development of pathological laryngeal responses remain poorly understood. We examined the effects of persistent vocal fold (VF) inflammation and trauma, as frequent causes of long-lasting modulation of laryngeal sensory feedback, on brainstem immunoreactivity in the rat. Combined VF inflammation and trauma were induced by injection of lipopolysaccharide (LPS) solution and compared to VF trauma alone from injection of vehicle solution and to controls without any VF manipulations. Using a c-fos marker, we found significantly increased Fos-like immunoreactivity (FLI) in the bilateral intermediate/parvicellular reticular formation (IRF/PCRF) with a trend in the left solitary tract nucleus (NTS) only in animals with combined LPS-induced VF inflammation and trauma. Further, FLI in the right NTS was significantly correlated with the severity of LPS-induced VF changes. However, increased brainstem FLI response was not associated with FLI changes in the first-order neurons of the laryngeal afferents located in the nodose and jugular ganglia in either group. Our data indicate that complex VF alterations (i.e., inflammation/trauma vs. trauma alone) may cause prolonged excitability of the brainstem nuclei receiving a direct sensory input from the larynx, which, in turn, may lead to (mal)plastic changes within the laryngeal central sensory control.
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Commentary on "Bilateral cerebellar stroke presenting with acute dysphonia and late palatal tremor"
Kristina Simonyan and Andrew Blitzer. 2012. “Commentary on "Bilateral cerebellar stroke presenting with acute dysphonia and late palatal tremor".” Mov Disord, 27, 3, Pp. 348. Full text.pdf
Dopamine regulation of human speech and bird song: a critical review
Kristina Simonyan, Barry Horwitz, and Erich D Jarvis. 2012. “Dopamine regulation of human speech and bird song: a critical review.” Brain Lang, 122, 3, Pp. 142-50.Abstract
To understand the neural basis of human speech control, extensive research has been done using a variety of methodologies in a range of experimental models. Nevertheless, several critical questions about learned vocal motor control still remain open. One of them is the mechanism(s) by which neurotransmitters, such as dopamine, modulate speech and song production. In this review, we bring together the two fields of investigations of dopamine action on voice control in humans and songbirds, who share similar behavioral and neural mechanisms for speech and song production. While human studies investigating the role of dopamine in speech control are limited to reports in neurological patients, research on dopaminergic modulation of bird song control has recently expanded our views on how this system might be organized. We discuss the parallels between bird song and human speech from the perspective of dopaminergic control as well as outline important differences between these species.
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2011
Laryngeal motor cortex and control of speech in humans
Kristina Simonyan and Barry Horwitz. 2011. “Laryngeal motor cortex and control of speech in humans.” Neuroscientist, 17, 2, Pp. 197-208.Abstract
Speech production is one of the most complex and rapid motor behaviors, and it involves a precise coordination of more than 100 laryngeal, orofacial, and respiratory muscles. Yet we lack a complete understanding of laryngeal motor cortical control during production of speech and other voluntary laryngeal behaviors. In recent years, a number of studies have confirmed the laryngeal motor cortical representation in humans and have provided some information about its interactions with other cortical and subcortical regions that are principally involved in vocal motor control of speech production. In this review, the authors discuss the organization of the peripheral and central laryngeal control based on neuroimaging and electrical stimulation studies in humans and neuroanatomical tracing studies in nonhuman primates. It is hypothesized that the location of the laryngeal motor cortex in the primary motor cortex and its direct connections with the brain stem laryngeal motoneurons in humans, as opposed to its location in the premotor cortex with only indirect connections to the laryngeal motoneurons in nonhuman primates, may represent one of the major evolutionary developments in humans toward the ability to speak and vocalize voluntarily.
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Neuroanatomical changes due to hearing loss and chronic tinnitus: a combined VBM and DTI study
Fatima T Husain, Roberto E Medina, Caroline W Davis, Yvonne Szymko-Bennett, Kristina Simonyan, Nathan M Pajor, and Barry Horwitz. 2011. “Neuroanatomical changes due to hearing loss and chronic tinnitus: a combined VBM and DTI study.” Brain Res, 1369, Pp. 74-88.Abstract
Subjective tinnitus is the perception of sound in the absence of an external source. Tinnitus is often accompanied by hearing loss but not everyone with hearing loss experiences tinnitus. We examined neuroanatomical alterations associated with hearing loss and tinnitus in three groups of subjects: those with hearing loss with tinnitus, those with hearing loss without tinnitus and normal hearing controls without tinnitus. To examine changes in gray matter we used structural MRI scans and voxel-based morphometry (VBM) and to identify changes in white matter tract orientation we used diffusion tensor imaging (DTI). A major finding of our study was that there were both gray and white matter changes in the vicinity of the auditory cortex for subjects with hearing loss alone relative to those with tinnitus and those with normal hearing. We did not find significant changes in gray or white matter in subjects with tinnitus and hearing loss compared to normal hearing controls. VBM analysis revealed that individuals with hearing loss without tinnitus had gray matter decreases in anterior cingulate and superior and medial frontal gyri relative to those with hearing loss and tinnitus. Region-of-interest analysis revealed additional decreases in superior temporal gyrus for the hearing loss group compared to the tinnitus group. Investigating effects of hearing loss alone, we found gray matter decreases in superior and medial frontal gyri in participants with hearing loss compared to normal hearing controls. DTI analysis showed decreases in fractional anisotropy values in the right superior and inferior longitudinal fasciculi, corticospinal tract, inferior fronto-occipital tract, superior occipital fasciculus, and anterior thalamic radiation for the hearing loss group relative to normal hearing controls. In attempting to dissociate the effect of tinnitus from hearing loss, we observed that hearing loss rather than tinnitus had the greatest influence on gray and white matter alterations.
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2010
Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study
Kristina Simonyan and Christy L Ludlow. 2010. “Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study.” Cereb Cortex, 20, 11, Pp. 2749-59.Abstract
Spasmodic dysphonia (SD) is a task-specific focal dystonia of unknown pathophysiology, characterized by involuntary spasms in the laryngeal muscles during speaking. Our aim was to identify symptom-specific functional brain activation abnormalities in adductor spasmodic dysphonia (ADSD) and abductor spasmodic dysphonia (ABSD). Both SD groups showed increased activation extent in the primary sensorimotor cortex, insula, and superior temporal gyrus during symptomatic and asymptomatic tasks and decreased activation extent in the basal ganglia, thalamus, and cerebellum during asymptomatic tasks. Increased activation intensity in SD patients was found only in the primary somatosensory cortex during symptomatic voice production, which showed a tendency for correlation with ADSD symptoms. Both SD groups had lower correlation of activation intensities between the primary motor and sensory cortices and additional correlations between the basal ganglia, thalamus, and cerebellum during symptomatic and asymptomatic tasks. Compared with ADSD patients, ABSD patients had larger activation extent in the primary sensorimotor cortex and ventral thalamus during symptomatic task and in the inferior temporal cortex and cerebellum during symptomatic and asymptomatic voice production. The primary somatosensory cortex shows consistent abnormalities in activation extent, intensity, correlation with other brain regions, and symptom severity in SD patients and, therefore, may be involved in the pathophysiology of SD.
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Brainstem pathology in spasmodic dysphonia
Kristina Simonyan, Christy L Ludlow, and Alexander O Vortmeyer. 2010. “Brainstem pathology in spasmodic dysphonia.” Laryngoscope, 120, 1, Pp. 121-4.Abstract
Spasmodic dysphonia (SD) is a primary focal dystonia of unknown pathophysiology, characterized by involuntary spasms in the laryngeal muscles during speech production. We examined two rare cases of postmortem brainstem tissue from SD patients compared to four controls. In the SD patients, small clusters of inflammation were found in the reticular formation surrounding solitary tract, spinal trigeminal, and ambigual nuclei, inferior olive, and pyramids. Mild neuronal degeneration and depigmentation were observed in the substantia nigra and locus coeruleus. No abnormal protein accumulations and no demyelination or axonal degeneration were found. These neuropathological findings may provide insights into the pathophysiology of SD.
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2009
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.
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2008
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.
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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.
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2007
Functional neuroanatomy of human voluntary cough and sniff production
Kristina Simonyan, Ziad S Saad, Torrey MJ Loucks, Christopher J Poletto, and Christy L Ludlow. 2007. “Functional neuroanatomy of human voluntary cough and sniff production.” Neuroimage, 37, 2, Pp. 401-9.Abstract
Cough and sniff are both spontaneous respiratory behaviors that can be initiated voluntarily in humans. Disturbances of cough may be life threatening, while inability to sniff impairs the sense of smell in neurological patients. Cortical mechanisms of voluntary cough and sniff production have been predicted to exist; however, the localization and function of supramedullary areas responsible for these behaviors are poorly understood. We used functional magnetic resonance imaging to identify the central control of voluntary cough and sniff compared with breathing. We determined that both voluntary cough and sniff require a widespread pattern of sensorimotor activation along the Sylvian fissure convergent with voluntary breathing. Task-specific activation occurred in a pontomesencephalic region during voluntary coughing and in the hippocampus and piriform cortex during voluntary sniffing. Identification of the localization of cortical activation for cough control in humans may help potential drug development to target these regions in patients with chronic cough. Understanding the sensorimotor sniff control mechanisms may provide a new view on the cerebral functional reorganization of olfactory control in patients with neurological disorders.
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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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2005
Afferent cortical connections of the motor cortical larynx area in the rhesus monkey
K Simonyan and U Jürgens. 2005. “Afferent cortical connections of the motor cortical larynx area in the rhesus monkey.” Neuroscience, 130, 1, Pp. 133-49.Abstract
The present study describes the cortical input into the motor cortical larynx area. The retrograde tracer horseradish peroxidase-conjugated wheat germ agglutinin was injected into the electrophysiologically identified motor cortical larynx area in three rhesus monkeys (Macaca mulatta). Retrogradely labeled cells were found in the surrounding premotor cortex (areas 6V and 6D), primary motor cortex (area 4), primary somatosensory cortex (areas 3, 1 and 2), anterior and posterior secondary somatosensory cortex and the probable homologue of Broca's area (areas 44 and 45); furthermore, labeling was found in the supplementary motor area, anterior and posterior cingulate cortex (areas 24 and 23), prefrontal and orbital frontal cortex (areas 8A, 46V, 47/12L, 47/12O, 13), agranular, dysgranular and granular insula as well as in the cortex within the upper bank of the middle third of the superior temporal sulcus (area TPO). The majority of these regions are reciprocally connected with the motor cortical larynx area [Brain Res 949 (2000) 23]. The laryngeal motor cortical input is discussed in relation to the connections of other motor cortical areas and its role in vocal control.
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Afferent subcortical connections into the motor cortical larynx area in the rhesus monkey
K Simonyan and U Jürgens. 2005. “Afferent subcortical connections into the motor cortical larynx area in the rhesus monkey.” Neuroscience, 130, 1, Pp. 119-31.Abstract
In three rhesus monkeys (Macaca mulatta), the inferior motor cortex was explored by electrical stimulation for sites yielding vocal fold adduction. The retrograde tracer wheat germ-agglutinin-conjugated horseradish peroxidase was injected into the effective sites. Within the forebrain, retrogradely labeled cells were found in the claustrum, basal nucleus of Meynert, substantia innominata, extended amygdala, lateral and posterior hypothalamic area, field H of Forel, and a number of thalamic nuclei with the strongest labeling in the nuclei ventralis lateralis, ventralis posteromedialis, including its parvocellular part, medialis dorsalis and centrum medianum, and weaker labeling in the nuclei ventralis anterior, ventralis posterolateralis, intermediodorsalis, paracentralis, parafascicularis and pulvinaris anterior. In the midbrain, labeling was found in the deep mesencephalic nucleus, ventral tegmental area, and substantia nigra. In the lower brainstem, labeled cells were found in the pontine reticular formation, median and dorsal raphe nuclei, medial parabrachial nucleus, and locus coeruleus. The findings are discussed in terms of the possible role of these structures in voluntary vocal control.
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