***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Our previous studies in Parkinson 's disease have shown that both levodopa and expectancy of receiving levodopa reduce cortical excitability . We design ed this study to evaluate how degree of expectancy and other individual factors modulate placebo response in Parkinson 's patients . Twenty-six Parkinson 's patients were r and omized to 1 of 3 groups : 0 % , 50 % , and 100 % expectancy of receiving levodopa . All subjects received placebo regardless of expectancy group . Subjects completed the NEO-Five Factor Inventory , General Perceived Self-Efficacy Scale , and Perceived Stress Scale . Cortical excitability was measured by the amplitude of motor-evoked potential ( MEP ) evoked by transcranial magnetic stimulation . Objective physical fatigue of extensor carpi radialis before and after placebo levodopa was also measured . Responders were defined as subjects who responded to the placebo levodopa with a decrease in MEP . Degree of expectancy had a significant effect on MEP response ( P < .05 ) . Subjects in the 50 % and 100 % expectancy groups responded with a decrease in MEP , whereas those in the 0 % expectancy group responded with an increase in MEP ( P < .05 ) . Responders tended to be more open to experience than nonresponders . There were no significant changes in objective physical fatigue between the expectancy groups or between responders and nonresponders . Expectancy is associated with changes in cortical excitability . Further studies are needed to examine the relationship between personality and placebo effect in Parkinson 's patients . © 2013 Movement Disorder Society The power of placebos has long been recognized for improving numerous medical conditions such as Parkinson 's disease ( PD ) . Little is known , however , about the mechanism underlying the placebo effect . Using the ability of endogenous dopamine to compete for [11C]raclopride binding as measured by positron emission tomography , we provide in vivo evidence for substantial release of endogenous dopamine in the striatum of PD patients in response to placebo . Our findings indicate that the placebo effect in PD is powerful and is mediated through activation of the damaged nigrostriatal dopamine system Objective : To examine the effect of cost , a traditionally “ inactive ” trait of intervention , as contributor to the response to therapeutic interventions . Methods : We conducted a prospect i ve double-blind study in 12 patients with moderate to severe Parkinson disease and motor fluctuations ( mean age 62.4 ± 7.9 years ; mean disease duration 11 ± 6 years ) who were r and omized to a “ cheap ” or “ expensive ” subcutaneous “ novel injectable dopamine agonist ” placebo ( normal saline ) .  Patients were crossed over to the alternate arm approximately 4 hours later . Blinded motor assessment s in the “ practically defined off ” state , before and after each intervention , included the Unified Parkinson 's Disease Rating Scale motor subscale , the Purdue Pegboard Test , and a tapping task . Measurements of brain activity were performed using a feedback-based visual-motor associative learning functional MRI task . Order effect was examined using stratified analysis . Results : Although both placebos improved motor function , benefit was greater when patients were r and omized first to expensive placebo , with a magnitude halfway between that of cheap placebo and levodopa . Brain activation was greater upon first-given cheap but not upon first-given expensive placebo or by levodopa . Regardless of order of administration , only cheap placebo increased activation in the left lateral sensorimotor cortex and other regions . Conclusion : Expensive placebo significantly improved motor function and decreased brain activation in a direction and magnitude comparable to , albeit less than , levodopa . Perceptions of cost are capable of altering the placebo response in clinical studies . Classification of evidence : This study provides Class III evidence that perception of cost is capable of influencing motor function and brain activation in Parkinson disease Repetitive transcranial magnetic stimulation ( rTMS ) is a valuable probe of brain function . Ever since its adoption as a research tool , there has been great interest regarding its potential clinical role . Presently , it is unclear whether rTMS will have some role as an alternative treatment for neuropsychiatric and neurological disorders such as Parkinson 's disease ( PD ) . To date , studies addressing the contribution of placebo during rTMS are missing . The placebo effect has been shown to be associated either with release of dopamine in the striatum or with changes in brain glucose metabolism . The main objective of this study was to test whether , in patients with PD , the expectation of therapeutic benefit from rTMS , which actually was delivered only as sham rTMS ( placebo-rTMS ) induced changes in striatal [ 11C ] raclopride binding potentials ( BP ) as measured with positron emission tomography ( PET ) .  Placebo-rTMS induced a significant bilateral reduction in [ 11C ] raclopride BP in dorsal and ventral striatum as compared to the baseline condition . This reduction BP is indicative of an increase in dopamine neurotransmission . The changes in [ 11C ] raclopride binding were more evident in the hemisphere contralateral to the more affected side supporting the hypothesis that the more severe the symptoms , the greater the drive for symptom relief , and therefore the placebo response . This is the first study addressing the placebo contribution during rTMS . While our results seem to confirm earlier evidence that expectation induces dopaminergic placebo effects , they also suggest the importance of placebo-controlled studies for future clinical trials involving brain stimulation techniques OBJECTIVE Administration of placebo can result in a clinical response indistinguishable from that seen with active antidepressant treatment . Functional brain correlates of this phenomenon have not been fully characterized . METHOD Changes in brain glucose metabolism were measured by using positron emission tomography in hospitalized men with unipolar depression who were administered placebo  as part of an inpatient imaging study of fluoxetine . Common and unique response effects to administration of placebo or fluoxetine were assessed after a 6-week , double-blind trial . RESULTS Placebo response was associated with regional metabolic increases involving the prefrontal , anterior cingulate , premotor , parietal , posterior insula , and posterior cingulate and metabolic decreases involving the subgenual cingulate , parahippocampus , and thalamus . Regions of change overlapped those seen in responders administered active fluoxetine . Fluoxetine response , however , was associated with additional subcortical and limbic changes in the brainstem , striatum , anterior insula , and hippocampus , sources of efferent input to the response-specific regions identified with both agents . CONCLUSIONS The common pattern of cortical glucose metabolism increases and limbic-paralimbic metabolism decreases in placebo and fluoxetine responders suggests that facilitation of these changes may be necessary for depression remission , regardless of treatment modality . Clinical improvement in the group receiving placebo as part of an inpatient study is consistent with the well-recognized effect that altering the therapeutic environment may significantly contribute to reducing clinical symptoms . The additional subcortical and limbic metabolism decreases seen uniquely in fluoxetine responders may convey additional advantage in maintaining long-term clinical response and in relapse prevention CONTEXT Expectations play a central role in the mechanism of the placebo effect . In Parkinson disease ( PD ) , the placebo effect is associated with release of endogenous dopamine in both nigrostriatal and mesoaccumbens projections , yet the factors that control this dopamine release are undetermined . OBJECTIVE To determine how the strength of expectation of clinical improvement influences the degree of striatal dopamine release in response to placebo in patients with moderate PD . DESIGN R and omized , repeated- measures study with perceived expectation as the independent between-subjects variable . SETTING University of British Columbia Hospital , Vancouver , British Columbia , Canada . Patients Thirty-five patients with mild to moderate PD undergoing levodopa treatment . Intervention Verbal manipulation was used to modulate the expectations of patients , who were told that they had a particular probability ( 25 % , 50 % , 75 % , or 100 % ) of receiving active medication when they in fact received placebo . MAIN OUTCOME MEASURES The dopaminergic response to placebo was measured using [11C]raclopride positron emission tomography .  The clinical response was also measured ( Unified Parkinson Disease Rating Scale ) and subjective responses were ascertained using patient self-report . RESULTS Significant dopamine release occurred when the declared probability of receiving active medication was 75 % , but not at other probabilities . Placebo-induced dopamine release in all regions of the striatum was also highly correlated with the dopaminergic response to open administration of active medication . Whereas response to prior medication was the major determinant of placebo-induced dopamine release in the motor striatum , expectation of clinical improvement was additionally required to drive dopamine release in the ventral striatum . CONCLUSIONS The strength of belief of improvement can directly modulate dopamine release in patients with PD . Our findings demonstrate the importance of uncertainty and /or salience over and above a patient 's prior treatment response in regulating the placebo effect and have important implication s for the interpretation and design of clinical trials Background : A recent well-conducted meta- analysis showed that placebo effect is associated with a possible small benefit for subjective outcomes , but has no significant effects on objective outcomes . Objective : Herein , we aim ed to investigate the immediate effects of two different types of placebo [ placebo pill and sham transcranial magnetic stimulation ( TMS ) ] in Parkinson ’s disease ( PD ) patients and compared them to the st and ard treatment ( levodopa ) in a proper r and omized , double-blind , crossover clinical trial . Methods : PD patients received three different interventions on different days : levodopa , placebo pill , and sham TMS . The motor function was assessed using simple and choice reaction time , Unified Parkinson ’s Disease Rating Scale ( UPDRS ) , finger tapping , Purdue Pegboard test , time to button up , walking time and supination-pronation . The subjective motor function was measured by a visual analogue scale ( VAS ) . Results : The results showed that there was a significant motor function in the motor function only after the treatment with levodopa , but not after treatment with placebo pills or sham TMS . However , patients reported a similar subjective improvement in motor function indexed by VAS following these three treatments . Conclusion : These results suggest that placebo interventions in PD may have an immediate subjective sensation of improvement but result in no significant objective motor changes compared with levodopa treatment . Although physiological changes are possible after a placebo intervention , our findings suggest that the acute placebo effect in PD may be the result of the subjective change in the motor rating only Repetitive transcranial magnetic stimulation ( rTMS ) has been used as a potential therapeutic tool in Parkinson 's disease ( PD ) . However , the therapeutic value and /or the placebo effect of rTMS on PD remain to be eluci date d. To investigate the therapeutic value and /or placebo effect of rTMS in PD , we compared the motor section of unified PD rating scale ( UPDRS III ) and the amount of extracellular dopamine concentration using [ (11)C ] raclopride PET before and after two sessions of rTMS in 9 PD patients . During a consecutive 2 days while off-medication , two series of 15 trains of 5 Hz-frequency rTMS ( intensity , 90 % of the resting motor threshold ) were applied to the h and area of more severely symptomatic motor cortex ( MC ) . After unilateral rTMS of MC , mean raclopride binding potentials ( BPs ) were reduced not only in putaminal and cau date areas on the stimulated side ( -4.9 % and -6.5 % , respectively ) ( P > 0.05 ) but also in putaminal and cau date areas of nonstimulated hemispheres ( -6.6 % , P > 0.05 and -12.1 % , P = 0.049 , respectively ) . UPDRS III scores were significantly decreased ( 35.0 + /- 14.1 to 32.0 + /- 13.4 , P = 0.049 ) . A reduction of raclopride BP in nonstimulated ventral striatum by unilateral rTMS supports the placebo response during rTMS To study the efficacy of 0.2-Hz repetitive transcranial magnetic stimulation ( rTMS ) on Parkinson 's disease ( PD ) , 85 patients with PD were enrolled into three groups : 1 ) . motor cortical , 2 ) . occipital , and 3 ) . sham stimulation . A round coil was centered over the vertex in motor cortical stimulation , and over the inion in occipital stimulation . In one session , 100 stimuli of 0.2-Hz rTMS at an intensity of 1.1 times active motor threshold ( AMT ) were given . In sham stimulation , electric currents were given with electrodes fixed on the head to mimic the sensation in real stimulation . Each session was carried out once a week for the first 8 weeks . The Unified Parkinson Disease Rating Scale ( UPDRS ) , Hamilton Rating Scale for Depression ( HRSD ) and subjective score ( visual analogue scale ) were assessed . There were no significant differences in clinical features among the three groups . Total and motor score of UPDRS were improved to the same extent by rTMS over Cz , inion , and sham stimulation . HRSD was improved by rTMS over Cz and sham stimulation in the same manner . Subjective score was not significantly improved by any methods of stimulation . 0.2-Hz rTMS at an intensity of 1.1 x AMT has only a placebo effect on PD . Our realistic sham stimulation maneuver must produce powerful placebo effects as a real stimulation Using the ability of [11C]raclopride to compete with dopamine for D(2)/D(3 ) 
    Output:
    
The lessons learned from these studies are threefold : ( i ) motor improvement is dependent on the activation of the entire nigrostriatal pathway induced by dopamine release in the dorsal striatum ; ( ii ) the magnitude of placebo-induced effects is modulated by an expectancy of improvement , which is in turn related to the release of dopamine within the ventral striatum ; ( iii ) the functioning of the neural pathways underlying the placebo response can be tuned by prior exposure and learning strategies .
In conclusion , although the neural network underlying the placebo effect in PD has been largely confirmed and accepted , what remains to be established is how , when , and where the expectation of reward ( mediated by the ventral striatum ) interacts with the primary motor system ( mediated by the dorsal striatum ) to induce clinical improvement in motor symptoms .