Noninvasive Brain Stimulation for Cervical Dystonia

Official title

The Effect of Noninvasive Brain Stimulation on Symptoms of Cervical Dystonia

Overview

The primary aim of this study is to assess whether continuous theta-burst stimulation (cTBS) can be helpful in reducing symptoms of idiopathic cervical dystonia. This will be a parallel-group, randomised, sham-controlled, double blind clinical trial. Patients and investigators measuring patient symptoms clinical scales will be blinded from allocation group, investigators delivering the intervention will not be blinded, as this is not feasible. Real cTBS will be compared to sham cTBS, with patients allocated to these two groups with a 1:1 recruitment ratio. Bilateral cTBS will be delivered four times daily, over eight days, for a total of 32 bilateral cTBS sessions. The primary outcome is the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). This will be administered at T1 (pre-cTBS), T2 (day 10, following days 2-9 where patients received the intervention), T3 (2 weeks post the final session of cTBS), and T4 (4-5 weeks post the final session of cTBS). Secondary outcomes will be the TWSTRS subscales (severity, disability, pain), Quality of Life scale, Global dystonia severity rating scale (GDS), Fahn Tolosa Marin (FTM) modified (to include only questions relevant to head/neck tremor) tremor scale, kinematic data of patient's movement patterns, motor evoked potentials (MEPs), and resting-state fMRI data (fMRI).

Detailed description

Cervical dystonia (CD) is the most common form of dystonia and is characterised by excessive and involuntary muscle contractions of the muscles in the neck. Whilst botulinum neurotoxin (BoNT) injections to the affected muscles can provide therapeutic relief to CD patients, up to one-third of patients report an inadequate response to treatment. In more severe cases, deep brain stimulation (DBS) of the globus pallidus interna (GPi) or subthalamic nucleus is an effective treatment for CD symptoms, directly and indirectly modulating networks thought to be abnormal in CD. TMS trials have previously been conducted to investigate its potential to ameliorate CD symptoms. These studies have shown limited success, with small sample sizes, and variable results. A major factor limiting the more effective use of TMS in CD is that it is not yet known where to target with TMS, given the many structures implicated in the neurobiology of the disorder. A prior study using lesion network mapping in CD attempted to address this issue by localising a brain network connected to lesions causing CD. Corp, et al. demonstrated that although causal lesions were located throughout the brain, all lesions were functionally connected to a brain network involving positive connectivity to the cerebellum and negative connectivity to the somatosensory cortex (S1). Preliminary work from our group examined the effect of targeting this lesion network mapping-derived S1 cluster using TMS. First, a single session of continuous theta-burst stimulation (cTBS) to the S1 indicated target engagement, as demonstrated by abnormal metabolic response in CD patients, and next, a pilot trial of 10 days of daily cTBS demonstrated a 12% reduction in CD symptoms. The primary aim of this study is to assess whether a higher-dose of (4x daily) cTBS can increase therapeutic effect.

Interventions

• Device Active continuous theta-burst stimulation
  Continuous theta-burst stimulation (cTBS) will be delivered using a Magstim Rapid machine connected to a 70mm cooled coil at 80% of a participants resting motor threshold (RMT). cTBS will consist of three-pulse bursts at 50Hz repeated every 200ms (5Hz) for 40 seconds (600 pulses total) (Huang, Edwards et al. 2005). All cTBS procedures will be conducted bilaterally, with application first over the left hemisphere, before moving to the right (approximately one minute will separate each hemisphere)
• Device Sham continuous theta-burst stimulation
  Sham cTBS procedures will be identical to those in the active cTBS arm but applied using a 70mm sham TMS coil.

Primary outcome measures

• Symptoms of cervical dystonia - TWSTRS total score [Time frame: For a single patient, a minimum of 6 weeks and a maximum of 16 weeks]

Secondary outcome measures (6)

• Symptoms of cervical dystonia - TWSTRS subscales [Time frame: For a single patient, a minimum of 6 weeks and a maximum of 16 weeks]
• Symptoms of cervical dystonia - kinematic recordings [Time frame: For a single patient, 10 days. Pre and post cTBS]
• Motor evoked potentials [Time frame: For a single patient, 10 days. Pre and post cTBS]
• Magnetic resonance imaging [Time frame: For a single patient, 10 days. Pre and post cTBS]
• Fahn Tolosa Marin tremor scale [Time frame: For a single patient, a minimum of 6 weeks and a maximum of 16 weeks]
• Global dystonia severity rating scale [Time frame: For a single patient, a minimum of 6 weeks and a maximum of 16 weeks]

Eligibility criteria

Inclusion criteria

• Aged between 18 and 85 years
• Diagnosis of idiopathic cervical dystonia made by an expert physician
• Last botulinum toxin injection administered at least two months before the start of participation in the study (Albanese, Abbruzzese et al. 2015)

Exclusion criteria

• Head or neck trauma occurring less than 12 months before the onset of dystonia
• Acquired dystonia (e.g., drug-induced, brain lesions or trauma)
• History of major psychiatric disorders (e.g., bipolar disorder, schizophrenia, obsessive-compulsive disorder)
• History of neurological diseases other than CD (e.g., epilepsy, Parkinson's disease)
• Other contraindications for TMS or brain MRI (e.g., metal in the head)
• Pregnant or breastfeeding women
• History of substance abuse or dependence

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Italy · 1 center

• Università Campus Bio-Medico — Roma

Identifiers

NCT: NCT07681284 · NetworkStim 270.25 CET2 cbm

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗