The present study confirms earlier evidence of a diffuse striatal dopamine release in PD in response to placebo (de la Fuente-Fernandez et al., 2001
). While the expectation of therapeutic benefit from rTMS certainly played a major role in this effect, a possible contribution from TMS-induced sensory experience is also very likely. The latter, indeed, either by increasing, indirectly, patient’s expectation (Kaptchuk et al., 2000
; Tsuji and Akamatsu, 2003
) or by inducing some dopamine release itself (Nieoullon et al., 1977
) could have enhanced the placebo contribution.
The neuroanatomical localization of our findings suggests that placebo rTMS is able to activate in PD patients the same brain network activated by other placebo and active dopaminergic drugs (de la Fuente-Fernandez et al., 2001
), thus supporting the notion of a shared neuronal network (Petrovic et al., 2002
). The bilateral changes in [11
C] raclopride BP involving the dorsal and ventral striatum suggest that both nigrostriatal and mesolimbic dopaminergic pathways were involved in placebo-rTMS. This striatal neuronal network is different from the corticostriatal activation described, in our previous studies, in healthy subjects (Strafella et al., 2001
) and in PD patients (Strafella et al., 2005
) in which rTMS induced only a focal release of dopamine in the ipsilateral dorsal striatum.
In the present study, the bilateral striatal reduction in BP ranged from 7.9% to 13.4%; this is greater than the reported 7% test–retest reliability of this method (Wang et al., 1999
While placebo-rTMS induced in all patients a significant biochemical response in the striatum (), only four PD patients perceived a certain degree of clinical benefit. This discrepancy is not a novel finding and has also been reported, previously, in placebo studies involving either caffeine (Kaasinen et al., 2004
) or apomorphine (de la Fuente-Fernandez et al., 2001
). It has been suggested that the possible role of dopamine in mediating expectation and coding uncertainty could be crucial for this phenomenon (de la Fuente-Fernandez and Stoessl, 2002
; de la Fuente-Fernandez et al., 2004
; Kaasinen et al., 2004
; Fiorillo et al., 2003
). Indeed, dopamine neurons have long been implicated with reward mechanisms, involving either expectation of reward (tonic activation) or reward itself (phasic activation) (Wise and Rompre, 1989
; Schultz, 1998
; Fiorillo et al., 2003
). In addition, dopaminergic neurons have also been shown to specifically code uncertainty, and the level of sustained dopaminergic activity is highest when uncertainty is highest (i.e. 50% chance of receiving active/placebo treatment) (Fiorillo et al., 2003
). Therefore, the higher the probability of reward (i.e. clinical benefit), the greater the expectation and consequently the placebo effect (de la Fuente-Fernandez et al., 2004
). Thus, in our study, the expectation of a clinical benefit along with the uncertainty of receiving treatment (active vs. placebo rTMS) may have played a significant contribution to the striatal biochemical response.
Previous reports have shown that the degree of placebo-induced dopamine release in the dorsal striatum seems to be related to the degree of perceived improvement by the patient (de la Fuente-Fernandez et al., 2001
) while placebo induces a similar amount of dopamine release in the ventral striatum regardless of the degree of perceived improvement (de la Fuente-Fernandez et al., 2002a
). In our study, while our findings were consistent with those reports with regard to the ventral striatum, we did not observe significant differences in [11
C] raclopride BP in the dorsal striatum between the group of patients who perceived the clinical benefit and the group who did not. A number of reasons could explain this difference. The first explanation could be simply the small number of patients or the confounding factor represented by the TMS-induced sensory experience which could also have contributed to some dopamine release. However, other factors could also be involved. Indeed, differences in the magnitude of the placebo response are not unknown among different clinical trials in PD (Shetty et al., 1999
; Goetz et al., 2000
; Freed et al., 2001
). These differences in magnitude have been described to be in relation to either differences in patient group characteristics, amount of information provided or previous medication exposure, all of which could influence the amount of expectation and therefore the perception of clinical benefit (de la Fuente-Fernandez and Stoessl, 2002
; de la Fuente-Fernandez et al., 2002b
). All these factors could also have played a role in the observed lack of difference in [11
C] raclopride BP in the dorsal striatum between our two groups of patients.
An interesting observation was represented by the fact that changes in [11
C] raclopride binding were clearly more evident in the hemisphere contralateral to the more affected side (). This asymmetry seems to support the hypothesis that the more severe the symptoms the greater the drive for symptom relief and therefore the placebo response. It is worth noting that a larger cluster of change in binding in the more affected hemisphere was also observed in our previous rTMS study involving PD patients (Strafella et al., 2005
). We claimed that because of the more advanced loss of re-uptake sites released dopamine diffuses out to more distant regions and possibly interacts with larger areas of the receptor population in the dopamine-denervated striatum (Zigmond et al., 1990
). Thus, it cannot be excluded that this could also play a role in our present study.
It should be noted that a reduction in BP was also observed in the thalamus (), which was similar to what it has also been described in previous placebo studies involving expectation (Kaasinen et al., 2004
To date, it is unclear whether rTMS could have some role as alternative treatment for neuropsychiatric and neurological disorders. This study was designed to provide some insights into the unexplored contribution of some of the confounding elements (i.e. expectation, sensory experience) of rTMS when applied in a clinical setting, and it has clearly demonstrated the importance of placebo-controlled studies for future clinical trials involving brain stimulation techniques. Indeed, the placebo rTMS-induced changes in brain dopaminergic neurotransmission similar to the one activated also by other placebo and active dopaminergic drugs (de la Fuente-Fernandez et al., 2001
) seem to support the notion of a shared neuronal network (Petrovic et al., 2002