The placebo and nocebo effect is believed to be mediated by both cognitive and conditioning mechanisms, although little is known about their role in different circumstances. In this study, we first analyzed the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients and found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. We also measured the effects of opposing verbal suggestions on hormonal secretion and found that verbally induced expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones. However, if a preconditioning was performed with sumatriptan, a 5-HT_1B/1Dagonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given. These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo responses are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.

Placebo administration is known to affect the brain both in pain and in Parkinson disease. Here we show that placebo treatment caused reduced activity in single neurons in the subthalamic nucleus of placebo-responsive Parkinsonian patients. These changes in activity were tightly correlated with clinical improvement; no decrease in activity occurred when the clinical placebo response was absent.

OBJECTIVE To investigate the relation between the variation of the parameters of stimulation and the clinical effectiveness in parkinsonian patients treated with deep brain stimulation of the subthalamic nucleus (STN), to provide information on the electrical parameter setting and the mechanism of action of deep brain stimulation. METHODS Ten patients with Parkinson's disease bilaterally implanted in the STN were studied. For every patient the intensity of the stimulus necessary to obtain the disappearance of contralateral wrist rigidity (required clinical effect, RCE) and the side effect threshold in 20 different conditions of stimulation, coupling four pulse width values (60, 120, 210, 450 μs) with five rate values (10, 50, 90, 130, 170 Hz) were determined. All the patients were tested after a 12 hour withdrawal of antiparkinsonian drugs, and the clinical evaluation was double blind. RESULTS In all the patients it was impossible to obtain the RCE using 10 and 50 Hz stimulus rates. For all the other stimulus rate values, the intensity-pulse width curves (IPWCs) for the RCE and for the side effect threshold showed a hyperbolic trend. For every pulse width value, increasing the rate from 90 to 130 and to 170 Hz progressively decreased the intensity of the stimulus necessary to reach the RCE, but the differences were not significant. Within the same rate value, the progressive reduction of the stimulus intensity necessary to obtain the RCE, obtained with the lengthening of the pulse width was significant (p<0.05) only comparing 60 with 210 μs and 60 with 450 μs. CONCLUSIONS The findings give some useful indications for the electrical parameter setting in deep brain stimulation of the STN, and some information about the mechanism of action of deep brain stimulation.

Objectives: Bilateral chronic high frequency stimulation of the subthalamic nucleus (STN), through the stereotactical placement of stimulating electrodes, effectively improves the motor symptoms of severe Parkinson's disease. Intraoperative neurophysiological and clinical monitoring techniques (neuronal electrical activity recording and intraoperative stimulation) may improve and refine the localisation of the nucleus. The objective of this work was to compare the preoperative CT and MRI localisation with the intraoperative neurophysiological identification of STN. The relation between the localisation of the STN and the position of the most effective contact of the permanent quadripolar electrode at a 3 month and 1 year follow up was also studied. Methods: Fourteen consecutive parkinsonian patients were submitted to bilateral implant for STN stimulation. All the patients underwent a standard MRI and stereotactic CT to obtain, by image fusion and localisation software, the stereotactical coordinates of STN. The STN extension and boundaries were identified by a semimicrorecording of the neuronal electrical activity. The definitive quadripolar electrode was positioned to locate at least two contacts within the STN recording area. Intraoperative macrostimulation was performed to confirm the correct position of the electrode. Postoperative clinical evaluation of the effects of stimulation was checked for each contact of the quadripolar electrode testing the improvement on contralateral rigidity to select the best contact. This evaluation was repeated at 3 months and 1 year after surgery. Results: In 35.7% of the procedures it was necessary to perform more than one track to get a recording of neuronal activity consistent with STN. The mean position of the central point of all the 28 STN recording areas in respect of the AC-PC line midpoint was 2.7 mm posterior (SD 0.7), 3.8 mm inferior (SD 1.1), and 11.6 mm lateral (SD 0.9), and the mean distance between the anatomical target and the central point of the STN as defined by intraoperative recording was 0.5 mm (SD 0.5) on the anteroposterior plane, 0.7 mm (SD 0.7) on the lateral plane, and 0.9 mm (SD 0.6) on the vertical plane. At 1 year the mean position of the central point of the most effective contact of the electrode in respect of the AC-PC line midpoint was 1.7 mm posterior (SD 0.9), 1.7 mm inferior (SD 1.5), and 12.3 mm lateral (SD 0.9). Conclusion: The results highlight the role of the intraoperative recording to get a more accurate localisation of the STN in surgery for Parkinson's disease, allowing the identification of the boundaries and of the extension of the nucleus. The most effective contact of the quadripolar electrode was always in the upper part of the STN recording area or immediately above it, suggesting a role of this region in the clinical effectiveness of the STN electrical stimulation.