Brain Networks in Dystonia

Spasmodic Dysphonia Clinical Trial

Official title:

Brain Networks in Dystonia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03042962
• Other study ID #: 2019P001183
• Secondary ID: R01NS088160
• Status: Completed
• Start date: August 1, 2015
• Est. completion date: May 31, 2022

Study information

• Verified date: October 2023
• Source: Massachusetts Eye and Ear Infirmary
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Task-specific focal dystonias are characterized by selective activation of dystonic movements during performance of highly learned motor tasks, such as writing or playing a musical instrument. To date, there is only limited knowledge about the distinct neural abnormalities that lead to the development of task-specificity in focal dystonias, which affect similar muscle groups but result in different clinical manifestations, such as writer's cramp vs. pianist's dystonia or spasmodic dysphonia vs. singer's dystonia. Our goal is to dissect the pathophysiological mechanisms underlying the phenomenon of task specificity in isolated focal dystonias using multi-level brain network analysis in conjunction with neuropathological examination of postmortem brain tissue from patients with dystonia. Rather than viewing these disorders as interesting curiosities, understanding the biology of task-specific activation of motor programs is central to understanding dystonia.

Description:

Task-specific primary focal dystonias (tsPFDs) are characterized by selective activation of dystonic movements during performance of highly learned motor tasks, such as writing, playing a musical instrument, speaking, or singing. Despite the recent advances in describing the clinical features of dystonia, there is a fundamental gap in understanding the neural abnormalities underlying the development of tsPFDs, which affect the same muscles but result in different clinical manifestations as in writer's cramp vs. pianist's dystonia or spasmodic dysphonia vs. singer's dystonia. Continued existence of this gap is an important problem because it renders us unable to differentiate between primary and secondary brain changes contributing to the tsPFD pathophysiology and to develop novel treatment options targeting disorder-specific brain alterations. The objective of this application is to identify the brain mechanisms underlying the phenomenon of task specificity in two representative groups of patients with writer's cramp vs. musician's hand dystonia and spasmodic dysphonia vs. singer's laryngeal dystonia using a novel approach of combined clinico-behavioral examination, brain network analysis and quantitative neuropathology of postmortem brain tissue. Our central hypothesis is that each tsPFD is characterized by distinct brain abnormalities, which selectively affect the focal segments of brain networks responsible for the performance of the respective motor task. The rationale for the proposed research is that identification of tsPFD-specific brain changes and associated neuropathology will clarify the neural mechanisms (primary vs. secondary) contributing to the clinical manifestation of these disorders and thus explain the phenomenon of tsPFDs. The obtained results are expected to provide strong scientific bases for the next series of studies directed towards identification and validation of novel pharmacological and/or surgical therapies for these patients. The researchers will pursue the following two specific aims: (1) determine distinct features of brain functional network abnormalities underlying task-specificity in different tsPFDs, and (2) establish structural correlates of functional neuroimaging abnormalities in tsPFDs. The proposed research is significant because it is expected to establish scientific evidence that tsPFD is a network disorder with abnormalities following distinct patterns in different tsPFDs and certain abnormalities showing structure-function correlations are associated with underlying neuropathology. By converging the results from multimodal cross-disciplinary studies to a coherent and pathophysiologically meaningful picture, the researchers will be well positioned to identify primary vs. secondary changes in tsPFDs and establish a scientific framework for the development of diagnostic biomarkers and novel treatment options for these disorders.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 141
• Est. completion date: May 31, 2022
• Est. primary completion date: May 31, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 80 Years

Eligibility

Inclusion Criteria:

• Patients will have clinically documented focal dystonia (including spasmodic dysphonia, singer's dystonia, writer's cramp, musician's focal hand dystonia)
• Healthy controls will be healthy volunteers with a negative history of neurological, laryngeal or psychiatric problems
• Age from 21 to 80 years.
• Native English speakers.
• Right-handedness (based on Edinburgh Handedness Inventory).

Exclusion Criteria:

• Subjects who are incapable of giving an informed consent.
• Pregnant or breastfeeding women until a time when they are no longer pregnant or breastfeeding. All women of childbearing potential will have a urine pregnancy test performed, which must be negative for participation in the imaging studies.
• Subjects with past or present medical history of (a) neurological problems, such as stroke, movement disorders (other than dystonia in the patient groups), brain tumors, traumatic brain injury with loss of consciousness, ataxias, myopathies, myasthenia gravis, demyelinating diseases, alcoholism, drug depend-ence; (b) psychiatric problems, such as schizophrenia, major and/or bipolar depression, obsessive-compulsive disorder; (c) laryngeal problems, such as vocal fold paralysis, paresis, vocal fold nodules and polyps, carcinoma, chronic laryngitis.
• Patients who are not symptomatic due to treatment with botulinum toxin injections into the laryngeal muscles. The duration of positive effects of botulinum toxin vary from patient to patient but lasts on average for 3-4 months. All patients will be evaluated to ensure that they are fully symptomatic prior to entering the study.
• Patients with other forms of dystonia.
• Patients with hereditary forms of dystonia (e.g., DYT1, DYT6, GNAL). If ARSG gene is identified in musician's dystonia patients, it will be used as a nuisance covariate in imaging analysis.
• Patients who have dystonia symptoms at rest in order to avoid the potential confound of dystonic spasms occurring during the scanning.
• To avoid the possibility of confounding effects of drugs acting upon the central nervous system, all study participants will be questioned about any prescribed or over-the-counter medications as part of their initial intake screening. Those patients who receive medication(s) affecting the central nervous system will be excluded from the study.
• The patients will be asked whether they have undergone any head, neck, or hand surgeries, which resulted in changes in regional anatomy or innervation. Because brain, hand and laryngeal surgery may potentially lead to the brain structure and function re-organization, all patients with history of brain, hand and/or laryngeal surgery will be excluded from the study.
• Subjects who have tattoos, ferromagnetic objects in their bodies (e.g., implanted stimulators, surgical clips, prosthesis, artificial heart valve, etc.) that cannot be removed for the purpose of study participation.

Related Conditions & MeSH terms

• Dysphonia
• Dystonia
• Dystonic Disorders
• Musician's Focal Hand Dystonia
• Singer's Dystonia
• Spasmodic Dysphonia
• Writer's Cramp

Intervention

Other:
• MRI
Functional and structural MRI of the brain will be conducted to identify disorder specific neural markers

Procedure:
• Blood draw
Blood samples will be collected, the DNA will be extracted and banked for genetic studies

Locations

Country	Name	City	State
United States	Massachusetts Eye and Ear Infirmary	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Kristina Simonyan	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (19)

Battistella G, Termsarasab P, Ramdhani RA, Fuertinger S, Simonyan K. Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks. Cereb Cortex. 2017 Feb 1;27(2):1203-1215. doi: 10.1093/cercor/bhv313. — View Citation

Bianchi S, Fuertinger S, Huddleston H, Frucht SJ, Simonyan K. Functional and structural neural bases of task specificity in isolated focal dystonia. Mov Disord. 2019 Apr;34(4):555-563. doi: 10.1002/mds.27649. Epub 2019 Mar 6. — View Citation

Blitzer A, Brin MF, Simonyan K, Ozelius LJ, Frucht SJ. Phenomenology, genetics, and CNS network abnormalities in laryngeal dystonia: A 30-year experience. Laryngoscope. 2018 Jan;128 Suppl 1(Suppl 1):S1-S9. doi: 10.1002/lary.27003. Epub 2017 Dec 8. — View Citation

Fuertinger S, Simonyan K. Connectome-Wide Phenotypical and Genotypical Associations in Focal Dystonia. J Neurosci. 2017 Aug 2;37(31):7438-7449. doi: 10.1523/JNEUROSCI.0384-17.2017. Epub 2017 Jul 3. — View Citation

Fuertinger S, Simonyan K. Stability of Network Communities as a Function of Task Complexity. J Cogn Neurosci. 2016 Dec;28(12):2030-2043. doi: 10.1162/jocn_a_01026. Epub 2016 Aug 30. — View Citation

Fuertinger S, Simonyan K. Task-specificity in focal dystonia is shaped by aberrant diversity of a functional network kernel. Mov Disord. 2018 Dec;33(12):1918-1927. doi: 10.1002/mds.97. Epub 2018 Sep 27. — View Citation

Guiry S, Worthley A, Simonyan K. A separation of innate and learned vocal behaviors defines the symptomatology of spasmodic dysphonia. Laryngoscope. 2019 Jul;129(7):1627-1633. doi: 10.1002/lary.27617. Epub 2018 Dec 24. — View Citation

Hanekamp S, Simonyan K. The large-scale structural connectome of task-specific focal dystonia. Hum Brain Mapp. 2020 Aug 15;41(12):3253-3265. doi: 10.1002/hbm.25012. Epub 2020 Apr 20. — View Citation

Killian O, McGovern EM, Beck R, Beiser I, Narasimham S, Quinlivan B, O'Riordan S, Simonyan K, Hutchinson M, Reilly RB. Practice does not make perfect: Temporal discrimination in musicians with and without dystonia. Mov Disord. 2017 Dec;32(12):1791-1792. doi: 10.1002/mds.27185. Epub 2017 Oct 27. No abstract available. — View Citation

Lungu C, Ozelius L, Standaert D, Hallett M, Sieber BA, Swanson-Fisher C, Berman BD, Calakos N, Moore JC, Perlmutter JS, Pirio Richardson SE, Saunders-Pullman R, Scheinfeldt L, Sharma N, Sillitoe R, Simonyan K, Starr PA, Taylor A, Vitek J; participants and organizers of the NINDS Workshop on Research Priorities in Dystonia. Defining research priorities in dystonia. Neurology. 2020 Mar 24;94(12):526-537. doi: 10.1212/WNL.0000000000009140. Epub 2020 Feb 25. — View Citation

Maguire F, Reilly RB, Simonyan K. Normal Temporal Discrimination in Musician's Dystonia Is Linked to Aberrant Sensorimotor Processing. Mov Disord. 2020 May;35(5):800-807. doi: 10.1002/mds.27984. Epub 2020 Jan 13. — View Citation

Mor N, Simonyan K, Blitzer A. Central voice production and pathophysiology of spasmodic dysphonia. Laryngoscope. 2018 Jan;128(1):177-183. doi: 10.1002/lary.26655. Epub 2017 May 23. — View Citation

Rittiner JE, Caffall ZF, Hernandez-Martinez R, Sanderson SM, Pearson JL, Tsukayama KK, Liu AY, Xiao C, Tracy S, Shipman MK, Hickey P, Johnson J, Scott B, Stacy M, Saunders-Pullman R, Bressman S, Simonyan K, Sharma N, Ozelius LJ, Cirulli ET, Calakos N. Fun — View Citation

Simonyan K, Ackermann H, Chang EF, Greenlee JD. New Developments in Understanding the Complexity of Human Speech Production. J Neurosci. 2016 Nov 9;36(45):11440-11448. doi: 10.1523/JNEUROSCI.2424-16.2016. — View Citation

Simonyan K, Barkmeier-Kraemer J, Blitzer A, Hallett M, Houde JF, Jacobson Kimberley T, Ozelius LJ, Pitman MJ, Richardson RM, Sharma N, Tanner K; The NIH/NIDCD Workshop on Research Priorities in Spasmodic Dysphonia/Laryngeal Dystonia. Laryngeal Dystonia: Multidisciplinary Update on Terminology, Pathophysiology, and Research Priorities. Neurology. 2021 May 25;96(21):989-1001. doi: 10.1212/WNL.0000000000011922. Epub 2021 Apr 15. — View Citation

Simonyan K. Neuroimaging Applications in Dystonia. Int Rev Neurobiol. 2018;143:1-30. doi: 10.1016/bs.irn.2018.09.007. Epub 2018 Oct 23. — View Citation

Simonyan K. Recent advances in understanding the role of the basal ganglia. F1000Res. 2019 Jan 30;8:F1000 Faculty Rev-122. doi: 10.12688/f1000research.16524.1. eCollection 2019. — View Citation

Valeriani D, Simonyan K. A microstructural neural network biomarker for dystonia diagnosis identified by a DystoniaNet deep learning platform. Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26398-26405. doi: 10.1073/pnas.2009165117. Epub 2020 Oct 1. — View Citation

Worthley A, Simonyan K. Suicidal Ideations and Attempts in Patients With Isolated Dystonia. Neurology. 2021 Mar 16;96(11):e1551-e1560. doi: 10.1212/WNL.0000000000011596. Epub 2021 Jan 27. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of brain structural and functional changes	Identify imaging alterations responsible for task specificity in dystonia. Identify changes in brain activity and gray and white matter in patients with task-specific dystonia	5 years

External Links

•   NIH grant description