Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: the contribution of expectation

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a valuable probe of brain function. Ever since its adoption as a research tool, there has been great interest regarding its potential clinical role. Presently, it is unclear whether rTMS will have some role as an alternative treatment for neuropsychiatric and neurological disorders such as Parkinson's disease (PD). To date, studies addressing the contribution of placebo during rTMS are missing. The placebo effect has been shown to be associated either with release of dopamine in the striatum or with changes in brain glucose metabolism. The main objective of this study was to test whether, in patients with PD, the expectation of therapeutic benefit from rTMS, which actually was delivered only as sham rTMS (placebo-rTMS) induced changes in striatal [11C] raclopride binding potentials (BP) as measured with positron emission tomography (PET). Placebo-rTMS induced a significant bilateral reduction in [11C] raclopride BP in dorsal and ventral striatum as compared to the baseline condition. This reduction BP is indicative of an increase in dopamine neurotransmission. The changes in [11C] raclopride binding were more evident in the hemisphere contralateral to the more affected side supporting the hypothesis that the more severe the symptoms, the greater the drive for symptom relief, and therefore the placebo response. This is the first study addressing the placebo contribution during rTMS. While our results seem to confirm earlier evidence that expectation induces dopaminergic placebo effects, they also suggest the importance of placebo-controlled studies for future clinical trials involving brain stimulation techniques.

Fig. 1

Placebo rTMS-induced dopamine release: axial, coronal and sagittal sections of the statistical parametric map of the change in [¹¹C] raclopride BP, overlaid upon the average MRI of all subjects in stereotaxic space, at the level of the dorsal (A) and ventral (B) striatum. The left and right hemispheres display, respectively, the more affected and less affected side.

Fig. 2

[¹¹C] raclopride binding potentials (baseline and following placebo-rTMS), from the dorsal and ventral striatum of the more affected hemisphere, extracted from a volume of interest centered at the x, y and z coordinates of the statistical peak revealed by the parametric map (*P = 0.001; ^§P < 0.001).

Fig. 3

Individual [¹¹C] raclopride binding potentials (baseline and following placebo-rTMS) from the putamen of the more affected hemisphere for each PD patient.

Fig. 4

On the top, the figure displays the percentage changes in [¹¹C] raclopride BP at the level of caudate, putamen and ventral striatum of the more affected (black bars) and less affected (gray bars) hemisphere (*P = 0.03). On the bottom, the figure displays the size (mm³) of the significant cluster of dopamine release in the dorsal and ventral striatum for the more affected (black bars) and less affected (gray bars) hemisphere.

Fig. 5

Percentage changes in [¹¹C] raclopride BP at the level of caudate, putamen and ventral striatum of the patients that perceived a clinical benefit (black bars) and the group who did not (gray bars).