Study Purpose
This study will investigate the use of an experimental research device called transcranial direct current stimulation (tDCS). tDCS is a way to stimulate the brain with potential therapeutic benefits. It works by either increasing or decreasing brain excitability. This is done by delivering a current to the outside of the head. This weak electrical current then passes through the skull and modulates the underlying brain tissue. Genetic factors may contribute to the effectiveness of this intervention; therefore, a saliva sample will be collected to assess the status of two genes: Brain derived neurotrophic factor (BDNF) and apolipoprotein E4. Our purpose is to determine the best location of stimulation for tDCS that improves the symptoms and quality of life in people with CD. The results of this study will help to identify alternative interventions for people with cervical dystonia. Brain excitability will be measured using an additional form of non-invasive brain stimulation, specifically by a device called a transcranial magnetic stimulator. By applying a magnetic field to the outside of the head, electrical currents are produced within the brain that can transiently affect brain activity and be recorded though electrodes on your skin. Using this procedure, different areas of the brain can be studied to gain a greater understanding of the brain physiology in patients with cervical dystonia.
Procedures
Intervention: Briefly, non-invasive brain stimulation can be delivered safely and painlessly via different mechanisms with the goal of either exciting or inhibiting the underlying brain issue. In focal dystonia, as indicated above, there is thought to be a lack of inhibition, thus settings are typically used to increase inhibition. Transcranial direct current stimulation (tDCS) is one device that has been shown to be safe and effective at modulating excitation and inhibition in humans and has been used extensively in a variety of research applications for over 10 years. In addition to the potential physiologic benefit of altering excitability, tDCS is a particularly practical technique for use in people with CD, because it does not require one's head to remain still, thus not applying additional stress to the impaired neck.
An investigator will deliver tDCS using a constant current of 2 milliamps (mA) using a direct current stimulator (TCT Research Limited, Hong Kong) via two 35 cm2 saline soaked sponge electrodes. Treatment is 1x/day for 4 days. Electrode placement will be at one of four locations referenced in terms of dystonic head-turn resting position (i.e. if head turns to the left, the primary muscles involved are on the left, so contralateral M1 would be the right hemisphere): 1) Bilateral M1 with cathode to contralateral M1 and anode to ipsilateral M1, 15 minutes (Goal: decrease contralateral M1 excitability); 2) Cerebellum with anode to ipsilateral cerebellum with cathode to ipsilateral side of face, 15 minutes (Goal: increase ipsilateral cerebellum activation which exerts inhibitory effect on motor circuits); 3) M1+cerebellum: M1 will first be 'primed' with anode on contralateral M1, cathode on face, for 10 min, followed immediately by 15 min of cerebellar stimulation as in #2. (Goal: prime the contralateral M1 with increased excitability to engage a potentially larger effect from the following ipsilateral cerebellar stimulation that will be excited to exert inhibitory effect on the motor circuits including M1); or 4) Sham stimulation: electrode placement will be same as M1. Sham tDCS will be applied by ramping down current intensity to 0 after 30 seconds following standard practice for sham tDCS (Gandiga et al. 2006).
Pre-testing (Day1) will occur 10 weeks post standard care (SC) visit, so the participant will be near most impaired level of functioning prior to 12 week visit for botulinum (BTX) injection. tDCS will be delivered on day 1 and each subsequent day for 4 days. Posttesting will occur on Day5 and then 1 week later prior to SC visit (follow up- day 12). The primary endpoint of interest is follow up at one week.
Cortical Excitability Testing: Before and after intervention, single-pulse TMS will be delivered with a figure of eight coil (90 mm wing diameter) (MagStim Co., Whitland, Dyfed, Wales), positioned over M1. The 'hotspot' over the M1 contralateral to the direction of dystonic head turn will be used to collect motor evoked potentials (MEPs) in cervical muscles (upper trapezius) ipsilateral to head turn will be located and marked on the scalp. Various measures will be collected according to established methods to assess cortical excitability by single and paired pulse TMS.
Clinical assessment: Severity of CD will be assessed before and after the intervention. Behavioral measures will be administered by an investigator, blinded to intervention and will be assessed pre and post each intervention and at follow up. The primary endpoint of interest is the Craniocervical Dystonia Questionnaire CDQ-24. This primary outcome was selected because it is a patient-rated, disease-specific assessment of quality of life, which we feel should be the primary issue of concern. Secondary measures are TWSTRS and visual analog scale.
CDQ-24: The CDQ-24 contains 24 items with 5 subscales: stigma, emotional well-being, pain, activities of daily living and social/family life. Internal consistency and reliability is satisfactory for all sub-scales and total score with good sensitivity and high test/retest reliability (Muller, 2004).
TWSTRS. Toronto Western Spasmodic Torticollis Rating Scale is an outcome measure used to rate severity, disability and pain in CD (Consky et al., 1990). TWSTRS utilizes three sub-scores of physician-based severity (0-35), patient-based disability (0-30) and pain (0-20) with higher scores indicating greater severity of symptoms. Inter-observer reliability is excellent (rs=99) and good for disability and pain measurements (r˃0.88). The global severity scale was moderate (rs=0.63)(Salvia et al., 2006). TWSTRS exam will be videotaped for posthoc assessment by investigator blinded to group and testing period.
Visual Analog Scale (VAS). At the end of each intervention session participants will be asked to rate the ease of movement and perceived pain during cervical rotation in the contralateral direction to their head turn using VAS for self-assessment.
Adverse reactions. Adverse reactions will be recorded using established reporting forms.
Genetic Testing: At the last session, a saliva sample will be collected for genetic screening for BDNF and apolipoprotein E4 polymorphisms. We will collect approximately 2 ml (less than one-half teaspoon) of saliva by asking the subject to spit into a tube. It may take up to 30 minutes to provide a saliva sample, however, most people typically require less time (approximately 5 minutes). Collection of saliva using Oragene Discover is non-invasive and there are no anticipated personal risks of injury.
