Publications by Year: 2013

2013
Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia
Kristina Simonyan, Brian D Berman, Peter Herscovitch, and Mark Hallett. 2013. “Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia.” J Neurosci, 33, 37, Pp. 14705-14.Abstract
Spasmodic dysphonia is a primary focal dystonia characterized by involuntary spasms in the laryngeal muscles during speech production. The pathophysiology of spasmodic dysphonia is thought to involve structural and functional abnormalities in the basal ganglia-thalamo-cortical circuitry; however, neurochemical correlates underpinning these abnormalities as well as their relations to spasmodic dysphonia symptoms remain unknown. We used positron emission tomography with the radioligand [(11)C]raclopride (RAC) to study striatal dopaminergic neurotransmission at the resting state and during production of symptomatic sentences and asymptomatic finger tapping in spasmodic dysphonia patients. We found that patients, compared to healthy controls, had bilaterally decreased RAC binding potential (BP) to striatal dopamine D2/D3 receptors on average by 29.2%, which was associated with decreased RAC displacement (RAC ΔBP) in the left striatum during symptomatic speaking (group average difference 10.2%), but increased RAC ΔBP in the bilateral striatum during asymptomatic tapping (group average difference 10.1%). Patients with more severe voice symptoms and subclinically longer reaction time to initiate the tapping sequence had greater RAC ΔBP measures, while longer duration of spasmodic dysphonia was associated with a decrease in task-induced RAC ΔBP. Decreased dopaminergic transmission during symptomatic speech production may represent a disorder-specific pathophysiological trait involved in symptom generation, whereas increased dopaminergic function during unaffected task performance may be explained by a compensatory adaptation of the nigrostriatal dopaminergic system possibly due to decreased striatal D2/D3 receptor availability. These changes can be linked to the clinical and subclinical features of spasmodic dysphonia and may represent the neurochemical basis of basal ganglia alterations in this disorder.
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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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