Neuromodulation of Placebo and Nocebo Effects
Phase: NA
Conditions: Pain
Sponsor: Massachusetts General Hospital

 
 
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PROTOCOL TITLE 
 
Neuromodulation of placebo and nocebo effects 
 
IDENTIFIER 
 
NCT03102710 
 
DATE 
 
4/30/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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SPECIFIC AIMS  
Specific Aim 1: Characterize the effect of applying tDCS to the rDLPFC to modulate placebo and 
nocebo effects in healthy subjects 
Hypothesis 1.1: In the sham tDCS group, placebo lidocaine and capsaicin will produce a significant pain rating 
decrease (placebo) and increase (nocebo) respectively, in response to identical heat pain stimuli as compared 
to a within-subject control “neutral” cream. Both effects will be augmented by tDCS enhancement of rDLPFC 
excitability and blunted by tDCS inhibition of rDLPFC excitability.  
Hypothesis 1.2 In the sham tDCS group, placebo treatment will produce fMRI signal increases in regions 
associated with the DPMS including the DLPFC, orbital prefrontal cortex (OPFC), rostral anterior cingulate 
cortex (rACC), periaqueductal gray (PAG), and fMRI signal decreases in pain intensity sensitive regions (insula 
and secondary somatosensory cortex, S2), as compared to the within-subject control in response to identical 
pain stimuli. These changes will increase in the tDCS enhancement cohort and blunt in the inhibition cohort. 
Hypothesis 1.3 In the sham tDCS group, nocebo treatment will produce fMRI signal increases in brain regions 
associated with cognition and anxiety, including DLPFC, hippocampus, and OPFC, along with fMRI signal 
decreases in the areas associated with the affective component of pain (dorsal anterior cingulated cortex 
(dACC) and insula), as compared to the within-subject control neutral cream. These fMRI signal changes will 
be blunted in the tDCS inhibition group and increased in the tDCS enhancement group. 
Specific Aim 2: Characterize how tDCS to rDLPFC can modulate functional connectivity of rDLPFC 
Hypothesis 2: Enhancing rDLPFC excitability will increase resting state functional connectivity (rsFC) between 
the rDLPFC and rACC and insula whereas inhibiting rDLPFC excitability will decrease rsFC between the 
rDLPFC and rACC and insula as compared with sham tDCS. The rsFC between rDLPFC and rACC will be 
associated with placebo effect as indicated by pain rating difference. 
 
STUDY PROCEDURES 
We will recruit healthy subjects for this study. Please see the Protection of Human Subjects section for detailed 
entry criteria for screening and recruitment. In this experiment, subjects will be randomly assigned to three 
groups (26 per group): 1) tDCS enhancement group to increase the excitability of rDLPFC, 2) tDCS inhibition 
group to decrease the excitability of rDLPFC, and 3) sham tDCS group. 
Subjects will participate in five experimental sessions: a training and familiarity session, contextual 
learning/expectancy boost session, two tDCS sessions, and a session combining tDCS and testing for 
placebo/nocebo effects. Sessions 1and 2 will be separated by 2-5 days, sessions 2 and 3 will be separated by 
1-5 days, then sessions 3, 4, and 5 will be applied on consecutive three days. We will measure tDCS effects 
via changes in subjective pain ratings, fMRI signals in response to calibrated heat pain and the rsFC.   
Detailed experimental procedure 
Noxious heat stimuli will be delivered using a PATHWAY system (Medoc Advanced Medical Systems). All 
stimuli will be initiated from a baseline temperature of 32 °C and increased to a target temperature. Each 
stimulus will be presented for 12 seconds, including 2.5 seconds to ramp up to the target temperature and 2.5 
seconds to ramp down to baseline again. Heat stimuli will be applied to the right volar forearm. In sessions 
where tdcs is applied we will administer the tdcs sensation questionnaire to ensure subjects did not 
have any unexpected adverse reactions.  
Randomization Subjects will be randomized into one of three groups using a centrally generated variable-sized 
block design: tDCS enhancement, tDCS inhibition, and sham tDCS groups.  
Session 1 is a training, familiarity, and calibration session. Subjects will be trained to use the Sensory Gracely 
Scale (0-20) [1, 2] to rate pain experiences using the same method as in our previous studies [3, 4]. Subjects 
will first receive an ascending heat stimulus sequence (starting from 38 degrees). The three temperatures that 
each subject rates as approximately 5-6 (mild pain), 10-11(moderate pain) and 14-15 (strong pain) will be 
selected.  Subjects will receive a urine drug test on this day to determine no substance abuse. 
Session 2 is an expectancy manipulation session [3-5]. At the beginning of the session, all subjects will be 
informed that the aim of this study is to use a neuromodulation tool (tDCS) to investigate the analgesic effects 
of lidocaine cream and the hyperalgesic effects of capsaicin cream using a neutral cream as a control. We will 
first apply sham tDCS for 20 minutes, and then apply all 3 creams to different spots on participants’ right volar 
forearm. Subjects will be told that the creams will need about 20 minutes to take effect and that the effect will 
last for more than two hours. In reality, only sham tDCS will be applied, and an inert cream will be used for all 3 

 
 
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creams. The cream will be a fragrance-free moisturizing lotion dyed three different colors (blue for “Lidocaine,” 
pink for “Capsaicin,” and white for neutral). 
After this scripted explanation, 9 unique regions of the subject's arm will be demarcated for each stimulus. We 
will draw a 3x3 grid comprised of 2 cm x 2 cm squares on the subject's right volar forearm, starting the grid at 
the subject's elbow crease. (If the volar portion of the arm is not wide enough to accommodate the 6 cm width 
required, we will draw one 1x3 column on the radial, lateral portion of the forearm.)  The creams will then be 
applied with each cream spread onto a unique set of 3 adjacent squares (i.e. one cream for each row). The 
row placement of the neutral control cream, placebo Lidocaine and Capsaicin creams will be randomized 
between subjects.  
Using methods similar to those of previous studies [5, 6], subjects will then be told that to test the hyperalgesia 
effect of capsaicin and the analgesia effect of the lidocaine, 6 identical pain stimuli will be applied to each of 
the nine spots. However, in reality, to boost subjects’ expectancy, 6 moderate stimuli will be given to each of 
the neutral control cream spots, 6 mild stimuli will be applied on placebo Lidocaine cream spots, and 6 high 
stimuli will be applied on nocebo Capsaicin cream spots. The location of the placebo, nocebo and control rows 
will be randomized across subjects to balance the experimental design. Subjects will be asked to rate their 
expectancy of both the analgesic effect of lidocaine cream and the hyperalgesic effect of capsaicin using a 0-
10 scale (with 0 indicating a very negative expectation of “does not work at all” and 10 indicating a very positive 
expectation of “very effective”) before the pain stimulus is applied and again how much they expected the 
cream reduced or enhanced their pain afterward. The Gracely Sensory and Affective Scale will be used to rate 
experienced pain during the stimulation afterward. 
Session 3 is the first tDCS session. Right before and after tDCS, resting state fMRI data will be collected.  
Session 4 is the second tDCS session with no fMRI scan involved.  
Session 5 is the third tDCS and placebo / nocebo test session. At the beginning of the Session, subjects will be 
told that the Session 2 procedure will be repeated in the fMRI scanner. As in Session 2, the 3 different creams 
(in reality all one inert cream) will be administered to each row of squares, with “lidocaine” and “capsaicin” 
cream administered to the same rows as determined in Session 2. Then, tDCS will be applied based on 
subjects’ randomization. The resting state fMRI data will be collected before and after tDCS.  
After that, calibrated pain will be applied during the fMRI scan. Since this session will test the placebo/nocebo 
effect, we will only administer different heat stimuli to the 3 regions in the most lateral column of the 9 x 9 grid. 
Then, subjects will be asked to rate their expectancy of both the analgesia effect of lidocaine cream and the 
hyperalgesic effect of capsaicin using a 0-10 scale. After that, we will administer the same moderate stimulus 
to all remaining regions with all 3 creams. Our outcome measurement will be the subjective pain ratings and 
fMRI signal changes to identical calibrated heat pain. 
At the end of the experiment, subjects will be debriefed by a licensed physician or by the Principal Investigator, 
Jian Kong. We will inform them that in this study, only inert cream and sham tDCS (in session 2 or in sham 
tDCS group) was used, and that we changed the heat pain temperature at session 2. We will also emphasize 
that the experience of this study should not influence their impression of lidocaine / capsaicin or their interest in 
choosing these drugs as a potential therapeutic method.  
Transcranial direct current stimulation (tDCS) administration 
Twenty minutes of tDCS at 2mA will be applied by the StarStim system. For the rDLPFC excitability inhibition 
group, the cathodal electrode will be placed over F4 and the anodal electrode above the left orbit. For the 
rDLPFC excitability enhancement group, the anodal electrode will be placed over F4 and the cathodal 
electrode above the left orbit. Stimulation will start and finish with a 15 second gradual current ramp up and 
ramp down to decrease subjects’ discomfort. For sham tDCS treatment, stimulation will be applied only at 
ramp periods at the beginning and end of sham stimulation to mimic the somatosensory effect of real tDCS for 
15 s. As in a previous study [7], the electrodes will be placed at the same positions for the real tDCS (half 
rDLPFC enhancement position, half rDLPFC inhibition position).  
 
fMRI data acquisition 
The MRI scan will be performed using a 3 Tesla Siemens MRI System equipped for Echo Planar Imaging 
using a 32 channel head coil. fMRI data will be acquired using gradient echo T2*-weighted sequence 
(TR/TE=2000/30 msec, flip angle=90º, slice thickness=3 mm). The scans will include pre-tDCS resting state (8 
minutes) and post-tDCS resting state (8 minutes) scans during the application of heat pain stimuli to different 
spots.  For pain stimuli at each spot, a paradigm used in our previous study [8] will be applied, which include 

 
 
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anticipation, pain and pain rating, each pain sequence at one spot lasts about 5 minutes (Figure 6). A high-
resolution 3D MPRAGE sequence with 1 mm3 isotropic resolution will also be collected for anatomic 
localization of the fMRI signal changes. tDCS (20 minutes) will be applied in the scanner as our tDCS device is 
MRI compatible.  
 
 
Reference 
 
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