Expectation modulates the effect of deep brain stimulation on motor and cognitive function in tremor-dominant Parkinson's disease

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.

Figure 1. Impact of expectation on resting tremor.

Power at tremor frequency (mean and standard error of the mean) in tremor-dominant Parkinson's disease patients treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN). Upper row: Power of tremor in placebo responders in the placebo (open bars) and control condition ([grey bars] n = 8, Fig. 1A) and in nocebo responders in the nocebo (black bars) and control condition (n = 5; Fig. 1B) on antiparkinsonian medication. Lower row: Power of tremor in placebo responders (n = 7, Fig. 1C) in the placebo and control condition and in nocebo responders in the nocebo and control condition (n = 2, Fig. 1D) off antiparkinsonian medication.

Figure 2. Impact of expectation on verbal fluency in nocebo responders.

Performance in verbal fluency of tremor-dominant Parkinson's disease patients showing a nocebo response in tremor: Number of words (mean and standard error of the mean) produced in the semantic category change test in the nocebo condition (black bars) and the control condition (grey bars) in 5 patients on deep brain stimulation of the subthalamic nucleus and on antiparkinsonian medication. * p<0.05.

Figure 3. Expectation Rating.

Mean and standard error of the mean for the expectation rating under the three conditions (placebo, nocebo, control) when the same Parkinson's disease patients were on (n = 24 [Fig. 3A]) and off antiparkinsonian medication (n = 24 [Fig. 3B]). On a numeric rating scale patients' expectations regarding the effect of deep brain stimulation of the subthalamic nucleus on motor symptoms were assessed. +5 indicates expectation of strong improvement, −5 indicates expectation of strong impairment while 0 represents expectation of no change of motor function. ** p<0.01; *** p<0.001