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Spinocerebellar degeneration is an inherited or acquired neurodegenerative disorder characterised by steadily progressive cerebellar ataxia, dysarthria, and gait disturbance. These symptoms restrict daily activities. However, no satisfactory therapy has been established. Transcranial magnetic stimulation (TMS), originally introduced to the medical field to evaluate the function of the CNS, is recently becoming a therapeutic tool for neuropsychiatric disorders, such as major depression1 and Parkinson's disease.2 We also reported the efficacy of TMS for inherited spinocerebellar degeneration.3 We now report here a placebo controlled trial of TMS over the cerebellum for patients with spinocerebellar degeneration.
Seventy four patients with spinocerebellar degeneration gave written informed consent to participate in this study, which was approved by the ethics committee of Tohoku University. No patient had a history of seizures or any abnormalities established by EEG. They also had no orthopaedic problems. Thirty nine patients, aged from 27 to 76 years (19 men and 20 women), were assigned to active stimulation, and the other 35 patients, aged from 38 to 76 years (25 men and 11 women), were assigned to sham stimulation. They were divided based on the date when they were admitted to our hospitals. The age, disease duration (unpaired t test), disease type (χ2 test), and disease severity (unpaired t test) were matched between the two groups. Disease types were divided into two groups, cerebellar type (sporadic and hereditary cortical cerebellar atrophy including spinocerebellar atrophy (SCA) 6) and olivopontocerebellar atrophy (OPCA) type (sporadic OPCA, SCA1, SCA3, etc). Transcranial magnetic stimulation over the cerebellum was administered at almost the same time in the evening once a day for 21 consecutive days. A Magstim 200 (Magstim, Wales, UK), a transcranial magnetic stimulator with a 14 cm circular coil, was used. The stimulus coil was placed tangentially (active stimulation) or vertically (sham stimulation) over the scalp and centred on the inion, 4 cm lateral to the right of the inion, and 4 cm lateral to the left of the inion. The site order of delivery was always the same, first the right, then the centre, and then the left repeatedly 10 times in the same order. Ten pulses (the interpulse interval was about 6 seconds, which depended on the time that the Magstim 200 needed to be fully charged; five were counter clockwise and five were clockwise) were delivered on each region. The duration of each stimulus pulse was 0.1 ms. The stimulator output was adjusted to 100% of the maximum output capacity, which was about 2.5 times the motor threshold of the participants. We measured the motor threshold by stimulating the hand area of the left cortex using a 14 cm circular coil and recording the motor evoked potentials from the right first dorsal interosseous muscle while the hands were relaxed. The average threshold was 39.4 (SD 3.8)%.
We evaluated their truncal ataxia according to the time required for a 10 m walk (10 m time), the number of steps for a 10 m walk (10 m steps), and the number of practicable steps on a walk with the feet in the tandem position (tandem steps). Standing capacities (0, able to stand on one foot more than 15 seconds; 1, able to stand with the feet in the tandem position; 2, able to stand with the feet together; 3, able to stand with the heels together; 4, able to stand with the feet less than 10 cm apart; 5, able to stand with feet more than 10 cm apart; 6, unable to stand without support) and walking capacities (0, normal; 1, almost normal but unable to run; 2, able to walk without support, but clearly abnormal; 3, able to walk without support but with considerable staggering; 4, able to walk with a handrail; 5, able to walk with considerable support; 6, unable to walk, even with accompanying person) were also evaluated. The evaluation was done by the patients' physicians, who did not participate in this study. We measured the regional brain blood flow by consecutive single photon emission computed tomography (SPECT) using technetium-99m ethyl cystinate dimer before and after the 3 week TMS trial in 28 patients in the active stimulation group. We put the regions of interest on the bilateral frontal lobes, temporal lobes, occipital lobes, putamina, cerebellar hemispheres and pontine base. Quantitative blood flow in each region of interest was calculated from qualitative axial SPECT images by the application of Patlak plot graphical analysis.4 The examiners were blind to the manner of TMS.
All participants completed the 3 week TMS trial without any adverse effects. One patient was fearful and needed a reduction in the stimulus intensity to 80% of the maximum output. Before the TMS trial, there were no differences in 10 m time, 10 m steps, tandem steps, standing capacities, and walking capacities in both groups (Mann-Whitney U test). Comparing between active and sham stimulation after 3 week TMS, active stimulation was significantly more effective in 10 m time (p<0.05), 10 m steps (p<0.05), tandem steps (p<0.005), and standing capacities (p<0.05) (Mann-Whitney U test, table 1 ). However, 10 m time (p<0.05), 10 m steps (p<0.05), and standing capacities (p<0.05) were significantly improved in the sham stimulation group (Wilcoxon signed rank test, *table 1). The cerebellar type of spinocerebellar degeneration was significantly more sensitive to TMS than the OPCA type in 10 m time (p<0.05), tandem steps (p<0.05), and standing capacities (p<0.01) (Mann-Whitney U test, table 1). After the 3 week TMS trial, the mean regional brain blood flow significantly increased in the cerebellum and pons from 52.52 (SEM 2.12) ml/100 g/min to 58.54 (SEM 1.89) ml/100 g/min (p<0.005), and from 34.38 (SEM 2.21) ml/100 g/min to 39.68 (SEM 1.34) ml/100 g/min (p<0.05), respectively (paired t test). The regional brain blood flow in the cerebral cortices did not show any change.
In this study, we found a significant alleviation of truncal ataxia in patients with spinocerebellar degeneration treated by active TMS. Although placebo or training effects were demonstrated in 10 m time, 10 m steps, and standing capacities (* table 1), the effects of active stimulation were far beyond those of sham stimulation. With our method, active stimulation evoked the contraction of nuchal and shoulder muscles. However, sham stimulation produced the same noise as that of active stimulation, and some scalp sensation. Patients did not know the difference between active and sham stimulation because no patients had experienced active stimulation previously. Therefore, patients having sham stimulation did not notice that they were receiving inactive stimulation. Our results showed that the disease type was important for the effect of TMS. We matched not only the age, disease duration, and disease severity of both groups but also the type of disease. We considered this study to be placebo controlled. Therefore, TMS over the cerebellum actually alleviates truncal ataxia in patients with spinocerebellar degeneration.
Although we do not yet know the mechanism by which TMS works, we are very much interested in the increase in cerebellar blood flow after TMS. This finding suggests that TMS over the cerebellum may activate the decreased cerebellar function. This effect may be caused by direct stimulation to the cerebellum as we used the maximum strength of stimulation at 2.5 times the motor threshold. Another possibility is that sensory input from the contracted muscles by TMS might occur.
After the TMS trial we continued TMS in some patients. Patients receiving TMS once or twice a week kept their improved condition at least for 6 months, but patients receiving TMS every 2 weeks returned to their baseline in 2 weeks. Therefore, we think that the effects of TMS with our method are maintained for about 1 week. We conclude that TMS over the cerebellum is a promising treatment for spinocerebellar degeneration.
This work was financially supported by the Magnetic Health Science Foundation.