Research Article: Expectation Modulates the Effect of Deep Brain Stimulation on Motor and Cognitive Function in Tremor-Dominant Parkinson’s Disease

Date Published: December 2, 2013

Publisher: Public Library of Science

Author(s): Ariane Keitel, Stefano Ferrea, Martin Südmeyer, Alfons Schnitzler, Lars Wojtecki, Oscar Arias-Carrion.

http://doi.org/10.1371/journal.pone.0081878

Abstract

Expectation contributes to placebo and nocebo responses in Parkinson’s disease (PD). While there is evidence for expectation-induced modulations of bradykinesia, little is known about the impact of expectation on resting tremor. Subthalamic nucleus (STN) deep brain stimulation (DBS) improves cardinal PD motor symptoms including tremor whereas impairment of verbal fluency (VF) has been observed as a potential side-effect. Here we investigated how expectation modulates the effect of STN-DBS on resting tremor and its interaction with VF. In a within-subject-design, expectation of 24 tremor-dominant PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Resting tremor was recorded by accelerometry and bradykinesia of finger tapping and diadochokinesia were assessed by a 3D ultrasound motion detection system. VF was quantified by lexical and semantic tests. In a subgroup of patients, the effect of STN-DBS on tremor was modulated by expectation, i.e. tremor decreased (placebo response) or increased (nocebo response) by at least 10% as compared to the control condition while no significant effect was observed for the overall group. Interestingly, nocebo responders in MedON were additionally characterized by significant impairment in semantic verbal fluency. In contrast, bradykinesia was not affected by expectation. These results indicate that the therapeutic effect of STN-DBS on tremor can be modulated by expectation in a subgroup of patients and suggests that tremor is also among the parkinsonian symptoms responsive to placebo and nocebo interventions. While positive expectations enhanced the effect of STN-DBS by further decreasing the magnitude of tremor, negative expectations counteracted the therapeutic effect and at the same time exacerbated a side-effect often associated with STN-DBS. The present findings underscore the potency of patients’ expectation and its relevance for therapeutic outcomes.

Partial Text

In Parkinson’s disease (PD), dopamine replacement therapy and deep brain stimulation (DBS) of the subthalamic nucleus (STN) are well established and effective treatments for the cardinal symptoms resting tremor, bradykinesia and rigidity [1]–[3]. Although both treatments generally lead to improvement in motor symptoms, tremor is usually more effectively supressed by STN-DBS as compared to dopamine replacement therapy (for a review see [4]). Moreover, while STN-DBS does not affect overall cognitive function [5], [6], adverse effects of therapeutic STN-DBS have been reported for verbal fluency [7]–[9].

In brief, expectation did not significantly affect resting tremor on group level but modulated the effect of STN-DBS on resting tremor in a subgroup of patients. Furthermore, verbal fluency was adversely affected in patients showing a nocebo response in resting tremor. On the other hand, bradykinesia of proximal and distal movements was not significantly modulated by expectation. Descriptive data of the results are presented in Table 1.

The main findings of the present study are that the therapeutic effect of STN-DBS on resting tremor was modulated by verbally induced expectation in a subgroup of PD patients and that negative expectation regarding the STN-DBS effect on motor function also adversely affected verbal fluency in patients showing a nocebo response in resting tremor.

Taken together, the results of the present study provide evidence that the therapeutic effect of STN-DBS on resting tremor can be modulated by expectation in a subgroup of patients. Moreover, the present findings indicate that tremor is among the parkinsonian symptoms responsive to placebo and nocebo interventions – although less so than other cardinal symptoms. While positive expectations enhanced the effect of STN-DBS by further decreasing the magnitude of resting tremor, negative expectations did not only counteract the therapeutic effect of STN-DBS by increasing the amplitude of tremor, but additionally exacerbated impairment in verbal fluency, a side-effect often associated with therapeutic STN-DBS. This suggests that – at least in a subgroup of patients – negative expectations can undermine the therapeutic effect even of very efficacious treatments such as STN-DBS while at the same time exacerbating side-effects. However, given the relatively small size of responders and the exploratory descriptive approach, future studies are needed to substantiate the findings of the present study and to elucidate the prerequisites and patient-associated factors which contribute to responsiveness to placebo and nocebo interventions in PD. Nevertheless, the present results underscore the potency of patients’ expectation and thus its relevance for therapeutic outcomes and should consequently be considered in the context of patient-physician interaction.

 

Source:

http://doi.org/10.1371/journal.pone.0081878