Daniel M. Keller, PhD

June 17, 2014

ISTANBUL, Turkey — In what researchers describe as the first randomized trial of repetitive transcranial magnetic stimulation (rTMS) using an H-coil in Parkinson's disease (PD) added on to drug therapy, active stimulation was superior to sham stimulation.

Results suggest improvements in timed tests of motor function, activities of daily living, and quality of life by using active stimulation. Earlier studies with other transcranial magnetic stimulation coils in PD have yielded mixed results, the authors note.

More traditional circular or figure-8 coils produce small and superficial areas of stimulation reaching a depth of 2 to 3 cm. In contrast, the H-coil design results in 3-dimensional summation of magnetic fields, giving a wider area of stimulation and penetrating 5 to 7 cm deep.

Mario Fichera, MD, from the Institute of Experimental Neurology and the neurology department of the Scientific Institute Hospital San Raffaele in Milan, Italy, presented study results here at the 24th Meeting of the European Neurological Society (ENS).

Cortical Dysfunction

Dr. Fichera explained that in PD, besides dysfunction in deep brain structures (including the subthalamic nucleus and substantia nigra), there is also cortical dysfunction, specifically in the dorsolateral prefrontal cortex, the supplementary motor area, and the M1 motor cortex area.

He said rTMS can have long-lasting effects, with frequencies greater than 5 Hz being excitatory and those less than 1 Hz being inhibitory.

The study was double-blind, randomized, and placebo (sham stimulation) controlled. The 2 targets of stimulation were M1 contralateral to the more affected side and the prefrontal (PF) cortex bilaterally.

Participants were younger than age 80 years and had moderate PD so that they were still able to walk (Hoehn and Yahr stage 2 to 4). They had been receiving stable antiparkinsonian and antidepressive therapy for at least 2 months before study entry and had no other major comorbidity.

Treatment consisted of rTMS given 3 times per week for 4 weeks. Stimulation of M1 was at 90% of the resting motor threshold at 10 Hz for 840 pulses. PF stimulation occurred at 100% of the resting motor threshold at 10 Hz for 840 pulses.

The 60 patients were randomly assigned equally into 3 groups. Group 1 received M1 real and PF real stimulation (M1/PF). Group 2 received M1 real and PF sham (M1/sham). Group 3 received placebo treatments (sham/sham). The groups did not significantly differ in age (mean age, 60.4 to 64.2 years), sex distribution (more men than women), disease duration (6 to 8 years), levodopa equivalent daily doses (0.6 to 0.7 g), Hoehn and Yahr stage (stage 2), or disease characteristics.

The primary outcome measures were safety and clinical improvement off drug after the last treatment session vs baseline (T0), expressed as percentage reduction on the Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS OFF) part III. Besides the 3 groups, analysis included a merged group consisting of the M1/PF and M1/sham groups combined.

"We showed that the efficacy of the stimulation was better than the sham stimulation," Dr. Fichera told the audience. Both the M1/PF and the M1/sham groups improved significantly compared with the sham group, and there was no significant difference between these 2 active stimulation groups.

Table. Efficacy of rTMS in Reduction of PD Motor Symptoms

Study Group End vs T0 (% Reduction on MDS-UPDRS OFF) P Value vs Sham
Merged (M1/PF + M1/sham) 27 ± 16 .007
M1/PF 29 ± 15 .010
M1/sham 26 ± 17 .045
Sham 15 ± 17


Dr. Fichera said the merged stimulation group also showed significant improvement on UPDRS part III OFF lateralized subscores for the worse (P = .042) and better (P = .012) sides as well as for tremor over the sham group (P = .011).

There were also improvements on the worse side on the timed tests for hand tapping (P = .041), foot tapping (P = .012), and the 9-hole peg test (P = .003).

Safety was excellent. No serious adverse events or study dropouts occurred, and no adverse effects developed in the placebo group. One patient each experienced activation of ipsilateral peripheral nerve VII during stimulation, requiring a reduction in stimulation intensity of 2% to 3%. Headache in 1 patient at the end of an rTMS session resolved with acetaminophen.

A thoracic symptom occurred once during stimulation and 1 patient had dizziness lasting less than 30 minutes at the end of a session. Two patients in the M1/PF group and 1 in the M1/sham group experienced dyskinesias after the final rTMS session.

Dr. Fichera said other beneficial effects were significant improvements in quality of life, as assessed at the final visit in the merged (P = .014), M1/PF (P = .023), and M1/sham (P = .046) groups vs the sham control. In addition, 1 patient in the M1/PF group had an improvement in blood pressure control, and another in the same group reported an improvement in erectile function.

He advised that a phase 3 trial should be conducted to validate the efficacy seen in this trial and to gauge the duration of the effects.

Empirical Evidence

Session chair Josep Valls-Solé, MD, PhD, a neurologist and neurophysiologist at the Hospital Clinic in Barcelona, Spain, commented to Medscape Medical News, "Evidence-based medicine has not reached yet noninvasive brain stimulation in a way that we are certain. You can say the same with several drugs. But empirically, this works. Now we have to test it with evidence-based medicine."

He noted that the new H-coil is not widely available, so there are not many published or ongoing studies. He praised Dr. Fichera and his group for doing this study and showing that the coil may have efficacy in some PD outcomes, and he added, possibly in some other disorders.

"I think that we have to promote a bit this kind of treatment that is noninvasive and nonpharmacological—so, some hope that we are escaping from toxicity from drugs," Dr. Valls-Solé advised.

He said it is still early and therefore it is unknown what the differences are in the effects of the H-coil compared with other ones. One advantage may be that the H-coil does not heat up. "It perhaps brings up the possibility of sham better than other coils," he suggested.

But the overall cost of this kind of treatment for the personnel to apply it repeatedly and for the equipment itself may limit its availability.

In addition, evidence is only starting to accumulate on its efficacy and the durability of the effect. Retreatment on a regular basis will probably be needed, but Dr. Valls-Solé said that, nonetheless, patients may feel better for a "couple of weeks" after being treated.

The study did not receive any commercial support. Dr. Fichera and Dr. Valls-Solé have disclosed no relevant financial relationships.

24th Meeting of the European Neurological Society (ENS). Abstract OS2104. Presented June 1, 2014.


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