Transcranial Direct Current Stimulation for the Treatment of Focal Hand Dystonia

Abstract

Background

The treatment of Writer’s Cramp, a task-specific focal hand dystonia, needs new approaches. A deficiency of inhibition in the motor cortex might cause Writer’s Cramp. Transcranial direct current stimulation modulates cortical excitability and may provide a therapeutic alternative.

Methods

In this randomized, double-blind, sham-controlled study, we investigated efficacy of cathodal stimulation of contralateral motor cortex in 3-sessions within one week. Assessment over a 2-week period included clinical scales, subjective ratings, kinematic handwriting analysis and neurophysiological evaluation.

Results

Twelve patients with unilateral dystonic Writer’s Cramp were investigated, 6 received transcranial direct current and 6 sham-stimulation. Cathodal transcranial direct current stimulation had no favorable effects on clinical scales, and failed to restore normal handwriting kinematics and cortical inhibition. Subjective worsening remained unexplained leading to premature study termination.

Conclusion

Repeated sessions of cathodal transcranial direct current stimulation of the motor cortex yielded no favorable results supporting a therapeutic potential in Writer’s Cramp.

Background

Writer’s Cramp (WC) is a task-specific focal hand dystonia (FHD) characterized by involuntary muscle spasms, overflow of activity including excessive activity of antagonist muscles, and impaired voluntary motor control during writing. The pathophysiology remains incompletely understood. Evidence points to a deficiency of inhibitory circuits, particularly of the motor cortex.

WC represents a therapeutic challenge. Promising results of deep brain stimulation (DBS) in dystonia and non-invasive brain stimulation, foremost repetitive transcranial magnetic stimulation (rTMS) in WC^1,2 indicate their therapeutic potential.

In transcranial direct current stimulation (tDCS), a direct current is continuously applied by surface electrodes on the head, which contrasts with the electric impulse induced by the short-lasting magnetic field in TMS. The possibility to modulate cortical excitability^3,4 and to promote motor learning in healthy⁵ and functional improvement in Parkinson’s disease⁶ and in stroke⁷ has raised interest in tDCS as an intervention in various brain disorders. Cathodal tDCS decreases excitability of the motor cortex^3,4 and might act on the pathophysiology in WC by compensating for the postulated deficiency in inhibition. Successful trials of low-frequency rTMS^1,2 that is inhibitory suggest a similar mechanism.

In this double-blind, randomized, sham-controlled study, we investigated whether cathodal tDCS of the motor cortex improves WC.

Methods

Adults with primary WC were included. Exclusion criteria were bilateral WC, secondary causes of FHD, generalized dystonia, significant illnesses, pregnancy, epilepsy, substance abuse, metal devices in the head, and Botulinum-toxin injection within 10weeks.

We applied tDCS in 3 sessions within the first study week(Monday-Wednesday-Friday) without concurrent intervention. A battery-driven stimulator, PhoresorII-ModelPM850 (IOMED, Salt Lake City), delivered tDCS through electrodes. Random assignment to tDCS or sham-stimulation was computer-generated.

In the tDCS treatment group, cathodal tDCS(2mA) was delivered for 20 min through 3×3cm electrodes (current density 0.22mA/cm2). We placed the cathode on the primary motor cortex (M1) at the optimal position for motor-evoked potentials(MEPs) in the primarily affected hand muscle(s) that we determined with TMS (Magstim200 TMS-machine, Whitland, Dyfed, UK) with a figure-of-eight(70 mm) coil, and the anode on the contralateral mastoid. In the sham condition, we applied DC(1mA) for 1–2min with anode and cathode over the forehead, short-circuited through skin, generating the same temporary “tingling” without effects on the brain. We set up stimulation out-of-sight of patients and blinded investigators.

Assessment included clinical scales, subjective ratings, kinematic handwriting analysis and neurophysiological evaluation of cortical inhibition at baseline, immediately and a week after the last intervention.

The blinded rater evaluated the severity of WC applying Fahn’s-Arm-Dystonia-Disability-Scale(ADDS)⁸ and the WC-Rating-Scale(WCRS)⁹. In the ADDS, difficulty in various hand activities is scored and the total score-quotient subtracted from 100% representing normal function⁸. The WCRS quantifies WC during handwriting, increasing with severity⁹. Primary outcome measure was the change in disability(ADDS) a week after the last intervention.

After each intervention, patients rated handwriting using a Verbal-Scale with four levels ranging from 0(none) to 3(major improvement) and a Visual-Analog-Scale ranging from 0%(none) to 100%(full recovery).

Kinematic analysis of handwriting was computed^10,11. Patients wrote for 20sec on a digitizing-tablet (WACOM-IntuosA4, 430×300mm) with high spatial (0.05mm) and temporal resolution (200Hz sampling-rate). The program computes the kinematic profile from velocity and acceleration of stylus movement in x-/y-directions¹². Following kinematic variables discriminated handwriting in WC from controls (unpublished). Mean positive stroke duration (time for an upward-stroke), the number of inversions in velocity (NIV) and acceleration (NIA; number of velocity and acceleration peaks during a single stroke that inversely measures smoothness of handwriting) and co-efficient of variation (CV) of mean peak velocity (measures variability in the velocity profile of consecutive strokes) were increased in WC and frequency of strokes and percentage of strokes with number of inversions equal to one (measures handwriting consistency) were decreased. In addition, velocity was included. We discarded the measurement of vertical pressure on the tablet, because the recordable maximum of 4Newton was often exceeded. This invalidated the movement score composed of kinematic variables including pressure that was the initial primary outcome measure.

We determined Short Intra-Cortical Inhibition(SICI) in the motor cortex in a paired-pulse paradigm with a 3ms inter-stimulus interval(ISI) between sub-threshold conditioning(80%-rest motor threshold[RMT]) and the supra-threshold test TMS-pulse (120%-RMT) targeting M1-area of the primarily affected muscle¹³. We calculated SICI as ratio of paired-pulse to test MEP-amplitudes. We determined RMT to the nearest 1% of the stimulator output required to elicit an MEP of ≥ 50μV in ≥ 5/10 trials.

The NIH Institutional-Review-Board approved the registered study (ClinicalTrials.gov:NCT00106782) and its premature termination. All participants gave written informed consent.

Statistical Analysis

Full-factorial repeated-measures-ANOVAs were applied with between-subjects factor for treatment(Treatment) and within-subjects factor for time(Time). Omnibus main effects and interactions were examined post-hoc using Bonferroni-adjusted simple effects tests within the context of ANOVA-ANCOVA. A-priori comparisons were made as specified. Levene’s test was used to verify the homogeneity of variance assumption and Shapiro-Wilk’s test and standardized residuals were examined to verify the normality assumption. Independent t-test or Wilcoxon-ranked-sum-test, and Fisher’s exact test, whichever appropriate, were applied to compare groups on demographic and clinical findings. Significance was evaluated at p<.05, two-tailed. Bonferroni’s procedure corrected for multiple comparisons. We used SPSS-Version17.0.1.

Results

We performed an interim-analysis because two patients receiving tDCS reported short-lasting worsening of handwriting after their last intervention, but we could not substantiate clinical deterioration, or changes in kinematics and neurophysiology. Since deleterious effects of cathodal stimulation could not be excluded and preliminary results were not favorable, we opted to terminate the study. We had enrolled twelve patients (4women, mean age 57.1 ± 6.6 years, range 44–67) with dystonic WC (mean duration, 13.3 ± 5.9 years, range 4–20) of the dominant hand (all right-handed but one), randomly assigned to tDCS(n=6) or sham stimulation(n=6; Figure 1). Demographics and clinical findings at baseline did not differ between groups. No patient was taking drugs for WC. All had received Botulinum-toxin, but only seven responded.

Figure 1.

Flow diagram of patients with Writer’s Cramp (WC) enrolled in this therapeutic study (http://www.consort-statement.org).

Cathodal tDCS had no effects on disability(ADDS) and severity of WC(WCRS; Table 1). Even more, those receiving sham-stimulation reported more improvement than those with tDCS in the verbal scale (1.1±0.27 versus 0.3±0.3, p=0.001), while not significantly in the VAS (22.8±11.4 versus 14.0±14.2, p=0.26).

Table 1.

Clinical scales, kinematics of handwriting and neurophysiology at baseline (mean ± standard error), immediately after and 1 week after the last tDCS or sham intervention (adjusted mean ± standard error). tDCS group: upper value, sham group: lower value. d: Cohen’s d – effect sizes

tDCS sham	Baseline	after last intervention	p/d	1 week after last intervention	p/d
Clinical scales
ADDS	52.5 ± 8.9	59.8 ± 4.1	0.67	59.6 ± 2.0	0.14
	66.0 ± 7.9	62.4 ± 4.1	0.29	64.2 ± 2.0	1.07
WCRS	9.3 ± 1.7	11.5 ± 1.1	0.38	10.8 ± 1.3	0.38
	14.0 ± 2.7	10.0 ± 1.0	0.77	9.1 ± 1.1	0.77
Kinematics of handwriting
Frequency of strokes (Hz)	3.4 ± 0.14	3.3 ± 0.17	0.4	3.6 ± 0.19	0.24
	3.0 ± 0.14	3.1 ± 0.17	0.59	3.3 ± 0.19	0.83
NIV	1.22 ± 0.08	1.24 ± 0.06	0.13	1.21 ± 0.04	0.051
	1.42 ± 0.08	1.37 ± 0.06	1.12	1.35 ± 0.04	1.5
Velocity (mm/sec)	62.2 ± 4.8	63.6 ± 6.1	0.74	70.1 ± 6.2	0.55
	55.9 ± 4.8	66.6 ± 6.1	0.23	64.5 ± 6.2	0.42
positive stroke duration (msec)	150.5 ± 9.3	160.5 ± 14.3	0.82	155.6 ± 13.3	0.87
	157.6 ± 9.3	165.4 ± 14.3	0.16	158.6 ± 13.3	0.11
NIA	2.05 ± 0.11	2.09 ± 0.15	0.49	1.87 ± 0.14	0.30
	2.14 ± 0.11	2.25 ± 0.15	0.48	2.09 ± 0.14	0.73
CV of Peak velocity	0.493 ± 0.045	0.423 ± 0.034	0.98	0.435 ± 0.026	0.99
	0.448 ± 0.045	0.420 ± 0.034	0.04	0.436 ± 0.026	0.02
NIO (%)	81.6 ± 3.9	80.3 ± 4.3	0.96	82.8 ± 3.6	0.65
	78.6 ± 3.9	80.6 ± 4.3	0.04	80.3 ± 3.6	0.31
Neurophysiology
Inhibition (SICI; %)	54.7 ± 10.2	57.7 ± 10.2	0.73	60.7 ± 4.6	0.53
	66.4 ± 11.2	63.3 ± 11.5	0.30	65.3 ± 5.1	0.54

ADDS Arm Dystonia Disability Scale ¹¹, CV coefficient of variation, NIA number of inversions in the acceleration profile, NIO percentage of strokes with number of inversions equal to one, NIV number of inversions in the velocity profile, SICI Short Intra-Cortical Inhibition, WCRS Writer’s Cramp Rating Scale ¹²

Cathodal tDCS had no effects on kinematics, but we found a trend to a decrease of NIV in the sham group (p=0.051, uncorrected) indicating smoother handwriting. Cathodal tDCS did not modulate Short Intra-Cortical Inhibition. All experienced short-lasting “tingling”, but no pain or other adverse events.

Discussion

In this controlled study, cathodal stimulation of the motor cortex yielded no favorable effects on disability and severity of dystonic WC, and failed to restore normal kinematics of handwriting and cortical inhibition. Sham-stimulated patients even reported a significantly better improvement contrasting with the subjective worsening with tDCS, which remained unexplained and constituted the reason for the premature study termination. These findings are consistent with the lack of beneficial effects of a single-session of cathodal tDCS on FHD in guitarists¹⁴ and extend knowledge by demonstrating ineffectiveness of repeated interventions.

There is evidence for abnormal plasticity considered maladaptive in dystonia contributing to the pathogenesis. This could explain the progressive development and the protracted improvement with DBS along with changes in physiology over months¹⁵. Therefore, prolonged stimulation may be required to induce effects. These could be adverse with cathodal stimulation which need to be excluded prior to future trials. Prolonged controlled trials are feasible with newer programmable DC-stimulators allowing interventions at-home.

The maladaptive plasticity in WC could cause irreversible changes and might have impeded efficacy of tDCS as the failure of inhibitory cathodal stimulation to decrease cortical excitability suggested¹⁶. The variable response of WC to Botulinum-toxin may reflect this heterogeneity in pathophysiology which remains incompletely understood. Structural abnormalities in the sensorimotor cortex¹⁷ could underlie maladaptive plasticity and explain why stimulatory interventions fail. These structural¹⁷ and functional¹⁸ abnormalities in the primary motor cortex provided rationale for targeting by non-invasive brain stimulation with beneficial effects. Inhibitory 1Hz-rTMS of motor¹ and 0.2Hz-rTMS of pre-motor cortex² reportedly restored intra-cortical inhibition and reduced impairment. The discrepancy in therapeutic efficacy could result from differences in mechanisms of action. In contrast to pulsed stimulation in rTMS, continuous direct current of tDCS modulates membrane excitability and induces shifts in cortical excitability. But, this increase in cortical excitability with anodal stimulation lacks the swiftness to generate an action potential^{3, 4} while cathodal stimulation decreases excitability³. The mechanism of action beyond immediate physiological effects remains unknown. There is evidence to suggest that tDCS spreads widely beyond stimulation site with effects in pre-motor cortex areas and basal ganglia¹⁹, where functional abnormalities are found¹⁸.

The sample size was small, but the absence of changes in kinematics and neurophysiology, which represent complementary aspects of WC²⁰, argues against a therapeutic potential of the present cathodal tDCS protocol. Anodal or other patterns of DC-stimulation and possibly longer-lasting treatment might be more potent. A promising approach could be combining tDCS with a behavioral therapy. Behavioral therapies in FHD^12,21 were found effective to regain fine motor control and involve re-learning of writing and fine hand movements. Since anodal tDCS enhances motor learning in healthy⁵ and in various brain disorders including PD⁶ and stroke⁷, a combination of tDCS and behavioral therapy could carry a therapeutic potential.