Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation

Abstract

Parkinson's disease (PD) is among the disorders in which the placebo effect can play a significant role. [1][2][3][4] Functional imaging studies have demonstrated that this effect is related to dopamine release in the striatum. 5 This dopamine release appears to be linked to expectation of reward (i.e., clinical benefit), which is in turn mediated by dopamine release in the ventral striatum.Since the initial description of high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) for the treatment of severe PD in 1995, 6 many centers have reported efficacy and the safety of this procedure. 7-10 Despite its clinical success, the mechanism underlying the effects of STN DBS in PD remains unknown. 11 Only two previous studies have been published describing the role played by expectation in the outcome of movement velocity in parkinsonian patients treated with effective STN DBS. 12,13 The objective of this study is to determine whether the degree to which patients with Parkinson's disease expect therapeutic benefit from STN DBS influences the magnitude of their improved motor response. PATIENTS AND METHODS This study was approved by the University of British Columbia Clinical Research Ethics Board (C98-0404).Ten patients with idiopathic Parkinson's disease who had received bilateral STN DBS were enrolled in the study. Disabling motor fluctuations with severe bradykinesia and dyskinesias secondary to the chronic use of antiparkinsonian medication were the main indications for surgery. There were two women and eight men whose mean age was 61 years (range, 42-78 years). The mean duration of the symptoms before surgery was 14 years (range, 6 -23 years). All underwent microelectrode-guided placement of bilateral deep brain stimulation electrodes (model 3389; Medtronic, Minneapolis, MN) in the subthalamic nuclei, connected to an implantable pulse generator below the left clavicle (Kinetra, model 7428; Medtronic). The stimulation parameters and reduced level of medications were then optimized over several months. At the moment of the study, the mean dose of L-dopa and dopamine agonist in the form of L-dopa equivalents that the patients were receiving was 690 mg (range, 200 -1,300 mg). Patients were then tested for this study after a 12-hour period of no antiparkinsonian medications and no stimulation. Four consecutive Unified Parkinson's Disease Rating Scale (UPDRS) scores were performed in the following conditions: stimulator OFF and patient aware that the stimulation was OFF; stimulator OFF and patient unaware whether the stimulation was ON or OFF; stimulator ON, patient aware; stimulator ON, patient blind. The four conditions were randomly assigned. The stimulator remained OFF or was switched OFF for 10 minutes after each evaluation. The patients were evalu-

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

“…This result differs from the findings of previous studies where a modulation of bradykinesia by expectation was reported [18][19][20][21]; yet in those studies either exclusively hypokinetic-rigid or a mixture of hypokinetic-rigid and tremor-dominant PD patients were analyzed suggesting that placebo and nocebo responses mainly manifest on symptoms of predominant relevance to the patients, that is, tremor in the patients of the present study. Moreover, although expectations regarding the effect of STN-DBS were not exclusively induced with respect to tremor but also regarding motor symptoms in general, patients may have specifically focused their expectation on tremor rather than on other symptoms such as bradykinesia.…”

“…On group level, expectation did not significantly affect resting tremor in the patients of the present study. This finding is in agreement with a study by Mercado et al [19] who did not observe a modulation of tremor using a different paradigm to manipulate patients' expectation regarding STN-DBS. However, given the relatively small number of placebo and nocebo responders in the present study, the lack of statistical significance on group level is not surprising.…”

“…For example, the administration of placebo drugs which PD patients expect to be a potent antiparkinsonian medication induces a substantial dopamine release in the striatum and alterations in the firing rate of single neurons in the STN associated with improvement in rigidity [15][16][17]. Furthermore, the therapeutic effect of STN-DBS on bradykinesia can be modulated by verbally induced opposite expectations regarding the effect of STN-DBS with improvement following positive expectation and impairment in consequence of negative expectation [18][19][20][21]. Interestingly, a modulation of verbal fluency has been described in relation to expectation-induced placebo responses in bradykinesia in PD patients treated with STN-DBS [21].…”

“…While it has been repeatedly shown that bradykinesia and rigidity are responsive to verbally induced expectation [15,[18][19][20][21], research regarding its effect on resting tremor in PD patients treated with STN-DBS is scarce. Given evidence of a worsening of resting tremor in PD patients performing cognitive tasks or during mental stress [22], it is of clinical relevance to investigate whether the therapeutic effect of STN-DBS on tremor can also be modulated by patients' expectations.…”

The History and Future of Deep Brain Stimulation

“…Without the patient or the evaluating physician knowing in which group they are, some of the systems can be left off for some specified period of time in a crossover design. Given the strength of the placebo effect in patients with movement disorders and psychiatric disease, [33][34][35] this is an …”