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Trial registered on ANZCTR

Registration number

ACTRN12621000417886

Ethics application status

Approved

Date submitted

15/02/2021

Date registered

15/04/2021

Date last updated

15/04/2024

Date data sharing statement initially provided

15/04/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

The effect of multi-day continuous theta-burst stimulation on symptoms of cervical dystonia

Scientific title

The effect of multi-day continuous theta-burst stimulation on symptoms of cervical dystonia in adults

Secondary ID [1]

NIL known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cervical dystonia

Condition category

Condition code

Neurological

Other neurological disorders

Musculoskeletal

Other muscular and skeletal disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Participants will undergo 2 weeks (10 sessions) of continuous theta-burst stimulation (cTBS) to the somatosensory cortex (S1). Participants will be randomised before beginning the trial to receive either the intervention (cTBS) or a sham/placebo in the first block of sessions, and then the opposite form of stimulation in the second block of sessions (i.e., 20 sessions in total, separated into two blocks). The order of stimulation will be counterbalanced amongst participants. A washout period of approximately 2 weeks will separate the two blocks of sessions.
A Magventure Magpro R30 machine will be used to apply cTBS to the S1 bilaterally, which takes approximately 40 seconds each side. The cTBS intervention will consist of three pulses delivered at 50Hz every 200 milliseconds, for a total of 600 pulses.
The first, sixth, and last sessions in the intervention block are expected to take approximately 3 hours, due to the extra outcome measures collected (such as interhemispheric inhibition and single pulse TMS). The rest of the sessions are expected to take less than 30 minutes.
The intervention will take place at Deakin University's Cognitive Neuroscience Unit (Burwood). The intervention will be delivered by a student researcher and the principal investigator, who has over 5 years experience in TMS application.

Intervention code [1]

Treatment: Devices

Comparator / control treatment

Participants will undergo 2 weeks (10 sessions) of sham cTBS to the S1. A Magventure Magpro R30 machine with a sham coil attached will be used to apply the sham cTBS to the S1 bilaterally, taking approximately 40 seconds per side. The first, sixth, and last sessions in the sham/placebo block are expected to take approximately 3 hours, due to the extra outcome measures collected (such as interhemispheric inhibition and single pulse TMS). The rest of the sessions are expected to take less than 30 minutes.
The intervention will take place at Deakin University's Cognitive Neuroscience Unit (Burwood). The intervention will be delivered by a student researcher and the principal investigator, who has over 5 years experience in TMS application.

Control group

Placebo

Outcomes

Primary outcome [1]

Changes to average Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score - clinical rating scale used to measure cervical dystonia symptoms.

Timepoint [1]

The TWSTRS will be measured both before and after the intervention in each session.

Primary outcome [2]

A composite measure which will assess changes to the range of motion, angle, tilt and position of a participants head and neck in space, as measured through a custom-made neck kinematics device.

Timepoint [2]

The range of motion of a participants head and neck will be measured both before and after the intervention in each session.

Secondary outcome [1]

Finger-to-nose dysmetria test, which will be assessed whilst the participant is wearing the neck kinematics device, to measure proprioception.

Timepoint [1]

The dysmetria test will be conducted before and after the intervention in each session.

Secondary outcome [2]

Changes to fMRI data, to determine if there are objective functional or structural changes in a participants brain, after the application of cTBS. The fMRI will be acquired whilst the participant is at rest (no task).

Timepoint [2]

The participant will undergo a scan before and after one block of the intervention..

Secondary outcome [3]

Changes to DWI data (white matter microstructure within the brain), to determine if there are objective structural changes within a participants brain, after the application of cTBS.

Timepoint [3]

A scan will take place before and after one block of the intervention.

Eligibility

Key inclusion criteria

To be included in the study participants must be cervical dystonia patients aged 18 to 85, diagnosed by a physician with cervical dystonia 12 or more months ago. Participants must have had a subjective response to botulinum toxin treatment at some point, with their last botulinum toxin injection 2 or more months ago.

Minimum age

18 Years

Maximum age

85 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Severe head tremor, trauma to head or neck < 12 months prior to onset of dystonia, acquired dystonia (i.e., dystonia as a result of a traumatic brain injury, drug-induced, or as a result of another neurological condition), or pronounced head or neck tremor when lying down with neck supported.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people assessing the outcomes

Intervention assignment

Crossover

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

The projected sample size was guided by similar previous research which examined the effect of multi-day TBS to the cerebellum of cervical dystonia patients (Bradnam et al., 2016; Koch et al., 2014). For a significant difference between pre and post-intervention TWSTRS scores, moderate effect sizes of d=0.31 (Koch et al., 2014) and d=0.42 (Bradnam et al., 2016) were reported. Working under the assumption that lesion network mapping increases efficacy for selection of treatment targets, a large effect size (d=0.8) was estimated for this study. Assuming 80% power (alpha level of 0.05), G*power indicated a sample size of 20 participants will be required.

A two-way ANOVA will be conducted, and will explore the relationship between the primary outcome measure (TWSTRS), time, and treatment. The factors will be time and treatment, with two levels to each variable – baseline and post-intervention for time, and sham or cTBS for treatment.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

3/05/2021

Actual

29/03/2022

Date of last participant enrolment

Anticipated

27/09/2024

Actual

Date of last data collection

Anticipated

13/12/2024

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment postcode(s) [1]

3125 - Burwood

Funding & Sponsors

Funding source category [1]

University

Name [1]

Deakin University

Address [1]

221 Burwood Highway
Burwood
VIC 3125

Country [1]

Australia

Funding source category [2]

Charities/Societies/Foundations

Name [2]

Dystonia Coalition

Address [2]

Country [2]

United States of America

Primary sponsor type

University

Name

Deakin University - Australian Government Research Training Program Scholarship

Address

221 Burwood Highway
Burwood
VIC 3125

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Deakin University Human Research Ethics Committee

Ethics committee address [1]

221 Burwood Highway
Burwood
VIC 3125

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

14/04/2021

Approval date [1]

02/03/2022

Ethics approval number [1]

Summary

Brief summary

Dystonia is a neurological disorder causing involuntary muscle contractions, and is thought to be caused by abnormal firing of specific brain networks. There are a number of types of dystonia, each defined by the body region/s that are affected. For example, and relevant to the present application, cervical dystonia (CD) affects the muscles of the neck. The current ‘gold standard’ treatments for CD are the injection of botulinum toxin type A (botox) into the affected muscles, or deep brain stimulation via brain surgery in more severe cases. However, injections only treat patients’ symptoms, rather than the underlying substrate of the disorder, and include side effects such as muscle wasting, while surgery is invasive and can be risky. As such, new treatments for CD are needed. 
Repetitive transcranial magnetic stimulation (rTMS) has shown some promise in patients with CD, however, overall results have not yet been compelling enough to carry rTMS forward as an approved treatment method. rTMS in CD has been hindered by the fact that the particular brain region that should be stimulated is still unknown. This is because previous neuroimaging findings have identified many different brain regions as abnormal in CD. This research will build upon findings by Corp et al. (2019), who demonstrated that the somatosensory cortex is abnormal in CD patients. Thus, this will be the first study to investigate whether a form of rTMS (called continuous theta-burst stimulation, or cTBS) to this brain region can effectively relieve CD symptoms. 
Aim 1 of the project is to investigate whether cTBS is an effective treatment for CD symptoms. It is hypothesised that there will be a significant overall reduction in CD symptoms post-intervention, as measured by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). CD symptoms will also be measured through kinematic testing using a custom-made device to measure head and neck angle, tilt, and position.
Aim 2 of this study is to investigate neurophysiological changes within the somatosensory cortex, due to the application of cTBS. It is hypothesised that there will be significant changes in the excitability of the somatosensory cortex (as measured by IHI) after the application of real cTBS in comparison to sham stimulation. Further, it is hypothesised that there will be a correlation between these changes in excitability, and reductions in CD symptom scores (as measured by the TWSTRS).

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Daniel Corp

Address

Deakin University
Cognitive Neuroscience Unit (CNU)
Building BC, Level 5
221 Burwood Highway
Burwood
VIC 3125

Country

Australia

Phone

+61 3 924 43019

Fax

daniel.corp@deakin.edu.au

Contact person for public queries

Name

Jordan Morrison-Ham

Address

Deakin University
Cognitive Neuroscience Unit (CNU)
Building BC, Level 5
221 Burwood Highway
Burwood
VIC 3125

Country

Australia

Phone

+61 3 924 43019

Fax

jmorriso@deakin.edu.au

Contact person for scientific queries

Name

Jordan Morrison-Ham

Address

Deakin University
Cognitive Neuroscience Unit (CNU)
Building BC, Level 5
221 Burwood Highway
Burwood
VIC 3125

Country

Australia

Phone

+61 3 924 43019

Fax

jmorriso@deakin.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
11009	Informed consent form			jmorriso@deakin.edu.au

Results publications and other study-related documents

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No additional documents have been identified.

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