Abstract
Tremor, affecting a dystonic body part, is a frequent feature of adult-onset dystonia. However, our understanding of dystonic tremor pathophysiology remains ambiguous as its interplay with the main co-occurring disorder, dystonia, is largely unknown. We used a combination of functional MRI, voxel-based morphometry and diffusion-weighted imaging to investigate similar and distinct patterns of brain functional and structural alterations in patients with dystonic tremor of voice (DTv) and isolated spasmodic dysphonia (SD). We found that, compared to controls, SD patients with and without DTv showed similarly increased activation in the sensorimotor cortex, inferior frontal (IFG) and superior temporal gyri, putamen and ventral thalamus, as well as deficient activation in the inferior parietal cortex and middle frontal gyrus (MFG). Common structural alterations were observed in the IFG and putamen, which were further coupled with functional abnormalities in both patient groups. Abnormal activation in left putamen was correlated with SD onset; SD/DTv onset was associated with right putaminal volumetric changes. DTv severity established a significant relationship with abnormal volume of the left IFG. Direct patient group comparisons showed that SD/DTv patients had additional abnormalities in MFG and cerebellar function and white matter integrity in the posterior limb of the internal capsule. Our findings suggest that dystonia and dystonic tremor, at least in the case of SD and SD/DTv, are heterogeneous disorders at different ends of the same pathophysiological spectrum, with each disorder carrying a characteristic neural signature, which may potentially help development of differential markers for these two conditions.
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References
Basho, S., Palmer, E. D., Rubio, M. A., Wulfeck, B., & Muller, R. A. (2007). Effects of generation mode in fMRI adaptations of semantic fluency: paced production and overt speech. Neuropsychologia, 45(8), 1697–1706. doi:10.1016/j.neuropsychologia.2007.01.007.
Berardelli, A., Rothwell, J. C., Day, B. L., & Marsden, C. D. (1985). Pathophysiology of blepharospasm and oromandibular dystonia. Brain, 108 (Pt 3), 593–608.
Burton, M. W., Locasto, P. C., Krebs-Noble, D., & Gullapalli, R. P. (2005). A systematic investigation of the functional neuroanatomy of auditory and visual phonological processing. NeuroImage, 26(3), 647–661. doi:10.1016/j.neuroimage.2005.02.024.
Casanova, R., Srikanth, R., Baer, A., Laurienti, P. J., Burdette, J. H., Hayasaka, S., et al. (2007). Biological parametric mapping: a statistical toolbox for multimodality brain image analysis. NeuroImage, 34(1), 137–143. doi:10.1016/j.neuroimage.2006.09.011.
Cerasa, A., Nistico, R., Salsone, M., Bono, F., Salvino, D., Morelli, M., et al. (2014). Neuroanatomical correlates of dystonic tremor: a cross-sectional study. Parkinsonism & Related Disorders, 20(3), 314–317. doi:10.1016/j.parkreldis.2013.12.007.
Crosson, B., Benefield, H., Cato, M. A., Sadek, J. R., Moore, A. B., Wierenga, C. E., et al. (2003). Left and right basal ganglia and frontal activity during language generation: contributions to lexical, semantic, and phonological processes. Journal of the International Neuropsychological Society, 9(7), 1061–1077. doi:10.1017/S135561770397010X.
Defazio, G., Conte, A., Gigante, A. F., Fabbrini, G., & Berardelli, A. (2015). Is tremor in dystonia a phenotypic feature of dystonia? American academy of neurology(84), 1053–1059.
Deuschl, G., Bain, P., & Brin, M. (1998). Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Movement Disorders, 13 Suppl 3, 2–23.
Elble, R. (2013). Defining Dystonic Tremor. Current Neuropharmacology, 11, 48–52.
Gurey, L. E., Sinclair, C. F., & Blitzer, A. (2013). A new paradigm for the management of essential vocal tremor with botulinum toxin. Laryngoscope, 123(10), 2497–2501. doi:10.1002/lary.24073.
Haslinger, B., Erhard, P., Dresel, C., Castrop, F., Roettinger, M., & Ceballos-Baumann, A. O. (2005). "Silent event-related" fMRI reveals reduced sensorimotor activation in laryngeal dystonia. Neurology, 65(10), 1562–1569. doi:10.1212/01.wnl.0000184478.59063.db.
Helmich, R. C., Toni, I., Deuschl, G., & Bloem, B. R. (2013). The pathophysiology of essential tremor and parkinson’s tremor. Current Neurology and Neuroscience Reports, 13(9), 378. doi:10.1007/s11910-013-0378-8.
Husain, F. T., Fromm, S. J., Pursley, R. H., Hosey, L. A., Braun, A. R., & Horwitz, B. (2006). Neural bases of categorization of simple speech and nonspeech sounds. Human Brain Mapping, 27(8), 636–651. doi:10.1002/hbm.20207.
Jankovic, J., Leder, S., Warner, D., & Schwartz, K. (1991). Cervical dystonia: clinical findings and associated movement disorders. Neurology, 41(7), 1088–1091.
Klein, D., Zatorre, R. J., Milner, B., Meyer, E., & Evans, A. C. (1994). Left putaminal activation when speaking a second language: evidence from PET. Neuroreport, 5(17), 2295–2297.
Krienen, F. M., & Buckner, R. L. (2009). Segregated fronto-cerebellar circuits revealed by intrinsic functional connectivity. Cerebral Cortex, 19(10), 2485–2497. doi:10.1093/cercor/bhp135.
Lee, M. S., Lee, S. B., & Kim, W. C. (1996). Spasmodic dysphonia associated with a left ventrolateral putaminal lesion. Neurology, 47(3), 827–828.
Lin, C. Y., Louis, E. D., Faust, P. L., Koeppen, A. H., Vonsattel, J. P., & Kuo, S. H. (2014). Abnormal climbing fibre-purkinje cell synaptic connections in the essential tremor cerebellum. Brain, 137(Pt 12), 3149–3159. doi:10.1093/brain/awu281.
Louis, E. D. (2014). ‘Essential tremor’ or ‘the essential tremors’: is this one disease or a family of diseases? Neuroepidemiology, 42(2), 81–89. doi:10.1159/000356351.
Louis, E. D., Lee, M., Babij, R., Ma, K., Cortes, E., Vonsattel, J. P., et al. (2014). Reduced purkinje cell dendritic arborization and loss of dendritic spines in essential tremor. Brain, 137(Pt 12), 3142–3148. doi:10.1093/brain/awu314.
Marsden, C. D. (1984). Motor disorders in basal ganglia disease. Human Neurobiology, 2(4), 245–250.
Middleton, F. A., & Strick, P. L. (1997). Cerebellar output channels. International Review of Neurobiology, 41, 61–82.
Moser, D., Baker, J. M., Sanchez, C. E., Rorden, C., & Fridriksson, J. (2009). Temporal order processing of syllables in the left parietal lobe. The Journal of Neuroscience, 29(40), 12568–12573. doi:10.1523/JNEUROSCI.5934-08.2009.
Munchau, A., Schrag, A., Chuang, C., MacKinnon, C. D., Bhatia, K. P., Quinn, N. P., et al. (2001). Arm tremor in cervical dystonia differs from essential tremor and can be classified by onset age and spread of symptoms. Brain, 124(Pt 9), 1765–1776.
Neychev, V. K., Gross, R. E., Lehericy, S., Hess, E. J., & Jinnah, H. A. (2011). The functional neuroanatomy of dystonia. Neurobiology of Disease, 42(2), 185–201. doi:10.1016/j.nbd.2011.01.026.
Nicoletti, V., Cecchi, P., Frosini, D., Pesaresi, I., Fabbri, S., Diciotti, S., et al. (2015). Morphometric and functional MRI changes in essential tremor with and without resting tremor. Journal of Neurology, 262(3), 719–728. doi:10.1007/s00415-014-7626-y.
Nistico, R., Pirritano, D., Salsone, M., Valentino, P., Novellino, F., Condino, F., et al. (2012). Blink reflex recovery cycle in patients with dystonic tremor: a cross-sectional study. Neurology, 78(17), 1363–1365. doi:10.1212/WNL.0b013e3182518316.
Noppeney, U., & Price, C. J. (2002). Retrieval of visual, auditory, and abstract semantics. NeuroImage, 15(4), 917–926. doi:10.1006/nimg.2001.1016.
O’Reilly, J. X., Beckmann, C. F., Tomassini, V., Ramnani, N., & Johansen-Berg, H. (2010). Distinct and overlapping functional zones in the cerebellum defined by resting state functional connectivity. Cerebral Cortex, 20(4), 953–965. doi:10.1093/cercor/bhp157.
Paulesu, E., Goldacre, B., Scifo, P., Cappa, S. F., Gilardi, M. C., Castiglioni, I., et al. (1997). Functional heterogeneity of left inferior frontal cortex as revealed by fMRI. Neuroreport, 8(8), 2011–2017.
Pinto, A. D., Lang, A. E., & Chen, R. (2003). The cerebellothalamocortical pathway in essential tremor. Neurology, 60(12), 1985–1987.
Ramdhani, R. A., & Simonyan, K. (2013). Primary dystonia: conceptualizing the disorder through a structural brain imaging lens. Tremor Other Hyperkinet Mov (N Y), 3.
Rodd, J. M., Davis, M. H., & Johnsrude, I. S. (2005). The neural mechanisms of speech comprehension: fMRI studies of semantic ambiguity. Cerebral Cortex, 15(8), 1261–1269. doi:10.1093/cercor/bhi009.
Rosen, H. J., Ojemann, J. G., Ollinger, J. M., & Petersen, S. E. (2000). Comparison of brain activation during word retrieval done silently and aloud using fMRI. Brain and Cognition, 42(2), 201–217. doi:10.1006/brcg.1999.1100.
Sachs, O., Weis, S., Zellagui, N., Sass, K., Huber, W., Zvyagintsev, M., et al. (2011). How different types of conceptual relations modulate brain activation during semantic priming. Journal of Cognitive Neuroscience, 23(5), 1263–1273. doi:10.1162/jocn.2010.21483.
Shaikh, A. G., Zee, D. S., & Jinnah, H. A. (2015). Oscillatory head movements in cervical dystonia: dystonia, tremor, or both? Movement Disorders, 30(6), 834–842. doi:10.1002/mds.26231.
Sidtis, J. J. (2012). Performance-based connectivity analysis: a path to convergence with clinical studies. NeuroImage, 59(3), 2316–2321. doi:10.1016/j.neuroimage.2011.09.037.
Simonyan, K., & Ludlow, C. L. (2010). Abnormal activation of the primary somatosensory cortex in spasmodic dysphonia: an fMRI study. Cerebral Cortex, 20(11), 2749–2759. doi:10.1093/cercor/bhq023.
Simonyan, K., & Ludlow, C. L. (2012). Abnormal structure-function relationship in spasmodic dysphonia. Cerebral Cortex, 22(2), 417–25. doi: 10.1093/cercor/bhr120.
Simonyan, K., Tovar-Moll, F., Ostuni, J., Hallett, M., Kalasinsky, V. F., Lewin-Smith, M. R., et al. (2008). Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study. Brain, 131(Pt 2), 447–459. doi:10.1093/brain/awm303.
Simonyan, K., Ostuni, J., Ludlow, C. L., & Horwitz, B. (2009). Functional but not structural networks of the human laryngeal motor cortex show left hemispheric lateralization during syllable but not breathing production. The Journal of Neuroscience, 29(47), 14912–14923. doi:10.1523/JNEUROSCI.4897-09.2009.
Simonyan, K., Berman, B. D., Herscovitch, P., & Hallett, M. (2013). Abnormal striatal dopaminergic neurotransmission during rest and task production in spasmodic dysphonia. The Journal of Neuroscience, 33(37), 14705–14714. doi:10.1523/JNEUROSCI.0407-13.
Termsarasab, P., Ramdhani, R. A., Battistella, G., Rubien-Thomas, E., Choy, M., Farwell, I. M., et al. (2016). Neural correlates of abnormal sensory discrimination in laryngeal dystonia. Neurologic Clinics, 10, 18–26. doi:10.1016/j.nicl.2015.10.016.
Tinazzi, M., Fasano, A., Di Matteo, A., Conte, A., Bove, F., Bovi, T., et al. (2013). Temporal discrimination in patients with dystonia and tremor and patients with essential tremor. Neurology, 80(1), 76–84. doi:10.1212/WNL.0b013e31827b1a54.
White, L. J., Klein, A. M., Hapner, E. R., Delgaudio, J. M., Hanfelt, J. J., Jinnah, H. A., et al. (2011). Coprevalence of tremor with spasmodic dysphonia: a case-control study. Laryngoscope, 121(8), 1752–1755. doi:10.1002/lary.21872.
Wildgruber, D., Ackermann, H., & Grodd, W. (2001). Differential contributions of motor cortex, basal ganglia, and cerebellum to speech motor control: effects of syllable repetition rate evaluated by fMRI. NeuroImage, 13(1), 101–109. doi:10.1006/nimg.2000.0672.
Acknowledgments
We thank Amanda Pechman, BA, Ian M. Farwell, MSG, and Heather Alexander, BA, for help with patient recruitment and data acquisition.
Author contributions
KS designed the study; DNK, GB, ERT, MC collected the data; DNK, GB, VK, ERT, MC, AR and KS analyzed the data; DNK wrote the first draft of the manuscript; KS, GB, VK, ERT, MC and AR revised and critiqued the paper.
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Diana N. Kirke declares that she has no conflict of interest. Diana N. Kirke was supported by a research fellowship grant from the Foundation for Surgery Reg Worcester Research Fellowship Scholarship, Royal Australasian College of Surgeons.
Giovanni Battistella declares that he has no conflict of interest.
Veena Kumar declares that she has no conflict of interest.
Estee Rubien-Thomas declares that she has no conflict of interest.
Melissa Choy declares that she has no conflict of interest.
Anna Rumbach declares that she has no conflict of interest.
Kristina Simonyan declares that she has no conflict of interest. Kristina Simonyan received grants from National Institute on Deafness and Other Communication Disorders, National Institutes of Health (R01DC011805, R01DC012434, R01DC007658), National Institute of Neurological Disorders and Stroke, National Institutes of Health (R01NS088160). Kristina Simonyan serves on the Medical and Scientific Advisory Council of the Dystonia Medical Research Foundation.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Informed consent was obtained from all individual participants included in the study.
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This study was funded by the National Institute on Deafness and Other Communication Disorders, National Institutes of Health (grant number R01DC012545) to KS. DNK was supported by a research fellowship grant from the Foundation for Surgery Reg Worcester Research Fellowship Scholarship, Royal Australasian College of Surgeons.
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Kirke, D.N., Battistella, G., Kumar, V. et al. Neural correlates of dystonic tremor: a multimodal study of voice tremor in spasmodic dysphonia. Brain Imaging and Behavior 11, 166–175 (2017). https://doi.org/10.1007/s11682-016-9513-x
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DOI: https://doi.org/10.1007/s11682-016-9513-x