Repetitive transcranial magnetic stimulation in cervical dystonia: effect of site and repetition in a randomized pilot trial

Abstract

Dystonia is characterized by abnormal posturing due to sustained muscle contraction, which leads to pain and significant disability. New therapeutic targets are needed in this disorder. The objective of this randomized, sham-controlled, blinded exploratory study is to identify a specific motor system target for non-invasive neuromodulation and to evaluate this target in terms of safety and tolerability in the cervical dystonia (CD) population. Eight CD subjects were given 15-minute sessions of low-frequency (0.2 Hz) repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (MC), dorsal premotor cortex (dPM), supplementary motor area (SMA), anterior cingulate cortex (ACC) and a sham condition with each session separated by at least two days. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) score was rated in a blinded fashion immediately pre- and post-intervention. Secondary outcomes included physiology and tolerability ratings. The mean change in TWSTRS severity score by site was 0.25 ± 1.7 (ACC), -2.9 ± 3.4 (dPM), -3.0 ± 4.8 (MC), -0.5 ± 1.1 (SHAM), and -1.5 ± 3.2 (SMA) with negative numbers indicating improvement in symptom control. TWSTRS scores decreased from Session 1 (15.1 ± 5.1) to Session 5 (11.0 ± 7.6). The treatment was tolerable and safe. Physiology data were acquired on 6 of 8 subjects and showed no change over time. These results suggest rTMS can modulate CD symptoms. Both dPM and MC are areas to be targeted in further rTMS studies. The improvement in TWSTRS scores over time with multiple rTMS sessions deserves further evaluation.

Trial registration: ClinicalTrials.gov NCT01859247.

Fig 1. Consort diagram.

*Prior to enrolment, a randomization schedule was created by random sorting of the five rTMS sites for each subject. All 8 subjects each received rTMS to five separate sites including sham over the course of the trial. (See Table 2 for the randomized order of interventions by subjects).

Fig 2. Scalp and cortical reconstructions.

A) Scalp reconstruction of subject showing scalp locations of TMS hotspot targets by site (green = MC, blue = dPM, orange = SMA, pink = ACC). B)Cortical surface reconstruction of same subject showing same locations targeted (note that the arrows are suspended above the brain as they are marking the scalp locations of stimulation). C)Cortical surface reconstruction showing session to session consistency over targets (light blue = session 1 and red = session 3).

Fig 3. Boxplots of change in TWSTRS severity score by stimulation site showing greatest improvement over dPM and MC.

A box in the boxplot represents first quartile to the third quartile with the median as the centerline. The outliers are represented by circles and the mean value as a cross. Note that the ACC boxplot is collapsed since the first quartile is equal to the third quartile.

Fig 4. Change in TWSTRS severity score as a function of time shown from Session 1 to Session 5.

Individual subject data shown as well as study group mean data shown in blue line. Red line represents historical control data from Comella et al., 2011 [14] showing similar severity scores at Week 8 post-botulinum toxin injection (study Session 1). *p = 0.01.

Fig 5. dPMI expressed as a percentage (MEP amplitude conditioned+test/MEP amplitude test alone *100) from pre-Session 1 and pre-Session 5.

CSP durations shown in msec from pre-Session 1 and pre-Session 5.