Mechanistic Studies on Video-guided Acupuncture Imagery Treatment of Knee Pain
Phase: NA
Conditions: Osteoarthritis, Knee
Sponsor: Massachusetts General Hospital

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Title: Mechanistic Studies on Video-guided Acupuncture 
Imagery Treatment of Knee Pain 
 
Clinical trial ID: NCT03261505 
Date: 02/28/23 

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I. BACKGROUND AND SIGNIFICANCE 
Knee osteoarthritis (OA) is a common disorder among the elderly population in the U.S. that 
often leads to disability over time. About 27 million adults (more than 50% of arthritis cases in 
the U.S.) report being diagnosed with OA by their doctor. As life expectancy increases, so does 
the number of people suffering from joint disease [1]. 
Despite the high prevalence of OA, treatment of OA is far from satisfactory [1, 2]. 
Pharmacological treatment of knee OA is often ineffective and has unwanted, sometimes 
dangerous, side effects [2, 3]. Developing a cost-effective complementary treatment for OA 
would have a high clinical impact. 
Imagery is a commonly used therapeutic method for many disorders such as chronic pain [4-7] 
and stroke [8-10]. Yet, the underlying mechanism remains unclear. Studies suggest that in 
addition to directly perceiving one's environment, individuals spend considerable time 
recollecting and/or imagining experiences [11-13]. A large body of literature suggests that 
common brain areas are activated during direct and vicarious (observational) experiences [14]. 
For example, observing others' experience of pain can activate a similar network as is activated 
when one directly experiences pain [11, 15-22]. Furthermore, investigators have found that 
imagined painful scenarios from a first-person perspective can be more vivid, less difficult, and 
less disembodied than scenarios imagined from a third-person perspective [11, 23] and can 
produce stronger fMRI signal increases at the secondary somatosensory cortex (S2) and insula 
[23]. 
As an invasive treatment, acupuncture involves needle insertion and manipulation. Literature 
suggests that deqi (sensations evoked by acupuncture needle manipulation such as soreness, 
aching, and dull pain) are crucial for treatment effects [24-26]. To the extent that these 
acupuncture sensations can be elicited by watching a video of acupuncture treatment and 
imagining the treatment, one would expect that brain activity changes would be produced that 
overlap with those changes produced by real acupuncture needle manipulation. Indeed, this has 
been demonstrated by a previous brain imaging study in which investigators found that 
visualizing images of acupuncture needle stimulation [27] produced overlapping fMRI signal 
changes in the brain at the anterior insula (AI), middle cingulate cortex (MCC)/dorsal anterior 
cingulate cortex (dACC), and periaqueductal grey (PAG). 
Taken together, these findings provide a solid foundation for VGAIT. Most importantly, applying 
powerful brain imaging tools to explore the neuroscience of mind-body interaction and then 
testing its treatment effect in a patient population may elucidate how the mind can alter 
perception [11] and thereby reshape pain experience to achieve a therapeutic effect. 
 
II. SPECIFIC AIMS 
The aim of this proposal is to investigate brain response and connectivity changes evoked by 
video-guided acupuncture imagery treatment (VGAIT) and verum and sham acupuncture in 
patient populations to elucidate the underlying brain mechanisms of mind-body interaction, 
imagery, and acupuncture. 
Specific Aim 1: Characterize and compare the brain response evoked by VGAIT, a VGAIT 
control condition, and real and sham acupuncture in chronic pain patients. 
Hypothesis 1.1 VGAIT and real acupuncture will produce overlapping fMRI signal increases in 
AI, MCC/dACC, and PAG as compared to control and sham acupuncture. Real acupuncture will 
produce greater fMRI signal increases at primary somatosensory cortex (S1) compared to 
VGAIT in OA patients. 

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Hypothesis 1.2: Pain intensity ratings of the OA patients will be reduced after about one month 
of VGAIT and real acupuncture treatment; fMRI signal increases at AI, MCC/dACC, and PAG 
evoked by treatment will be associated with knee pain intensity reduction after about one month 
treatment. 
Specific Aim 2: Characterize and compare the modulation effects of different treatments 
on resting state functional connectivity (rsFC) in chronic pain patients. 
Hypothesis 2.1: After treatment, the PAG rsFC with ACC/MPFC will be significantly enhanced 
in the VGAIT and real acupuncture groups, compared to the control condition and sham 
acupuncture groups. 
Hypothesis 2.2: The PAG-ACC/MPFC rsFC increase will be significantly associated with 
corresponding knee pain intensity reduction. 
 
III. SUBJECT SELECTION 
Inclusion/exclusion criteria for patients with knee OA: 
125 male and female patients aged 40-75 with a diagnosis of knee osteoarthritis and pain will 
be recruited for the experiment. A written informed consent form or REDCap eConsent will be 
obtained in all cases. 
Inclusion Criteria: 
a) Volunteers 40-75 years of age 
b) Meet the Classification Criteria of the American College of Rheumatology for osteoarthritis of 
the right and/or left knee for at least the past 3 months, as determined by the referring physician 
c) Ability to read and understand English; English can be a second language provided that the 
patient feels he or she can understand all the questions used in the assessment measures. 
Exclusion Criteria: 
a) Any interventional procedure for knee pain, including corticosteroid injections (within 2 
months [28, 29]) to the knee 
b) Prior acupuncture treatment for any condition within the past year 
c) The intent to undergo surgery during the time of involvement in the study 
d) Presence of any illness, medication use, or condition that is judged by the principal 
investigator to interfere with the trial. For example: skin irritations around the knee such as 
psoriasis, bleeding disorders or anticoagulant use that would be contraindications for 
acupuncture, diabetes due to the increased possibility of sensitivity to heat pain, or substance 
abuse. Use of opiates or other medications is allowable if the participant has been taking a 
stable dosage of the medication for at least one month. Per the judgment of the principal 
investigator, we may perform a urine toxicology screen to verify a patient’s medication status 
during Session 1. A positive drug test is not exclusionary unless it contradicts the patient’s self- 
report or indicates the presence of illegal substances. 
e) Knee pain due to other causes such as inflammation or malignancy, other pain disorders that 
may refer pain to the leg, OA of ipsilateral hip, diagnosis of RA 
f) Non-ambulatory status. Assistive devices such as walkers/canes are allowable given that 
patients do not require assistance with said device. 
g) History of a chronic disease that, in the investigator’s judgment, precludes participation in the 
study because of a heightened potential for adverse outcome (e.g., asthma or claustrophobia) 

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h) Presence of any contraindications to fMRI scanning (e.g., cardiac pacemaker, metal implants, 
fear of closed spaces, pregnancy) 
 
IV. SUBJECT RECRUITMENT 
Knee osteoarthritis subjects and healthy controls will be recruited from Research Patient Data 
Registry (RPDR), a clinical data registry that gathers medical records from many Partners 
HealthCare hospitals (Massachusetts General Hospital (MGH) and Brigham and Women’s 
Hospital (BWH)). The possible participants identified through RPDR will be contacted through 
mailed letters or patient gateway letters and targeted announcements. Contingency plans will 
include advertising through email, web, and bulletin board announcements posted within our 
hospital network community and pain centers / clinics in Boston area. Our team has extensive 
experience in recruiting Knee OA patients and if necessary, auxiliary backup methods such as 
Craigslist, posters, newspapers, and public transportation advertisements will be adopted. 
As part of obtaining informed consent, one of the study investigators will review all study 
procedures to be sure patients are aware of and in agreement with participating in a complete 
experiment. This will happen during a telephone screening as well as the beginning of their first 
study visit. Sufficient funds have been budgeted to cover the costs of recruiting and screening 
additional participants as it is expected that some patients will not pass all the screening criteria 
described in above. 
 
V. STUDY PROCEDURES 
Detailed experimental procedure 
Subject recruitment 125 patients with knee OA will be recruited. Please see the Protection of 
Human Subjects and Other Attachment sections for more detailed inclusion criteria for the 
screening and recruitment methods. In addition, we will recruit a cohort of age- and gender- 
matched non-pain control subjects (n=50); identical imaging and other assessments (when 
applicable) will be assessed one time only. For both knee OA and control, we will also add the 
MoCA and blood sample measurements, since both of these measurements will be additional 
measurements added to parent grant, it will not influence the integrity of the original aims. 
Randomization Patients who pass the screening will be randomized into one of the four groups 
using a centrally generated, variable-sized block design. 
Endpoints 
Primary outcomes 
The primary outcome will be blood oxygen level (BOLD) response (fMRI signal) differences 
evoked by VGAIT and VGAIT control. 
Secondary outcomes 
Secondary outcomes will include 1) PAG resting state functional connectivity differences before 
and after one month of treatment; 2) KOOS Score [30] (we will focus on KOOS pain subscale 
score based on previous studies [2, 31-33]) and other clinical outcomes (see below for details); 
and 3) QST [1, 34]. All clinical outcomes will be measured at baseline and after the last 
treatment. 
PAG-ACC/mPFC resting state functional connectivity will be assessed by calculating Pearsons’ 
correlation between the fMRI scan time courses of the PAG and ACC / MPFC using the CONN 
toolbox [35], while the subject is resting in the fMRI scanner prior to beginning the treatment and 
again immediately after the treatment. In short, preprocessing of resting state fMRI data will 

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include co-registration, motion correction, normalization to MNI stereotactic space, and spatial 
smoothing with an 8 mm Gaussian kernel. Functional connectivity analysis for individual 
subjects will be carried out using the PAG as a seed. Specifically, the average time course of 
the PAG will be obtained and correlation analysis will be performed in a voxel-wise way to 
generate a functional connectivity map for PAG. The resulting correlation coefficient map will be 
converted into a Fisher-Z map using Fisher's r-to-z transformation to improve the normality, and 
then will be entered into the group analysis. Group analysis will be performed using CONN 
toolbox [35]. A full factorial module in SPM 12 will be performed to compare the PAG rsFC 
changes before and after about one month of VGAIT, VGAIT control, real and sham treatments. 
Blindness During data acquisition, all study personnel except the administering acupuncturist 
will be blinded with respect to treatment conditions. Patients will also be blind to acupuncture 
modality (real or sham) they receive till end of the study, a study investigator will debrief the 
subject and explain the rational of blindness. 
Experimental procedure 
Session 1 will be a behavioral session to train subjects for QST responses, and reduce 
anticipatory anxiety to treatments. Subjects will complete a set of clinical and psychometric 
measurements. Recently, EEG has been applied to investigate both acupuncture [36] and 
chronic pain [37]. We will thus collect approximately 12 minutes of resting state EEG for 
exploratory analyses to test 1) if different treatment can modulate the power spectrum of 
different EEG frequency bands and 2) if power spectrum of different EEG frequency bands at 
baseline can be used to predict treatment response. 
Then, based on the randomization, they will be introduced to different treatments. Those who 
are randomized to the real acupuncture and VGAIT groups will receive real acupuncture 
treatment (about 5 minutes); the procedure will be videotaped for those in the VGAIT group. For 
those in the sham acupuncture group, sham acupuncture will be introduced. For those in the 
VGAIT control touching group, we will explain the situation and videotape the touching exposure 
process. For those in the VGAIT and VGAIT control groups, we will explain the potential 
underlying mechanism of how imagery treatment works and inform them that the more vividly 
they can imagine treatment based on the video, the better the result will be. Subjects will then 
be introduced to the MGH Acupuncture Sensation Scale (MASS) to report their sensations as 
described below. 
Blood marker test Using a method described in a previous study [38], peripheral blood 
samples for circulating markers will be collected by venipuncture in EDTA tubes. The samples 
(about 10 mL) will be immediately placed on ice and centrifuged for acquisition of plasma within 
one hour. The aliquots will then be stored at −80 °C for subsequent batch testing at baseline, 
week 4, week 8, and the 3 follow-up sessions. We will examine inflammatory mediators such as 
interleukins (ILs including IL-1alph and beta , IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, and IL-10), IFN-γ, 
and tumor necrosis factor (TNF) via multiplex immunoassays using Luminex, as well as highly 
sensitive C-reactive protein (hsCRP), TNF-α programmed death 1 (PD-1), prostaglandin E2, and 
BDNF via Enzyme Linked Immuno Assay (ELISA). All tests will be administered at the Clinical 
Research Center at the Massachusetts General Hospital that will provide all proposed test. 
Clinical and psychometric measurements All clinical assessments will be completed by 
patients during their first visit (session 1) and during their last visit (session 8). Question 6 (pain 
rating now, 0-10 scale) of the BPI and ERS will be repeated at the beginning and end of all fMRI 
scan sessions. The MASS will be administered after all treatments. The complete KOOS and 
BPI will be administered during patients’ first and final study visits. 
Knee Injury and Osteoarthritis Outcomes Score (KOOS): The KOOS is a 35-item self- 
administered survey of pain and function in knee OA patients [30]. It contains the WOMAC 

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items (Western Ontario and McMaster Universities Osteoarthritis Index) and additional items for 
pain and functional ratings. It may be more sensitive to subtle improvements in function than the 
WOMAC [39]. KOOS is comprised of 5 subscales: 1) pain, 2) other symptoms, 3) function in 
daily living (ADL), 4) function in sport and recreation, and 5) knee-related quality of life (QOL). 
Each subscale allows for calculation of a normalized score, with 0 denoting the most extreme 
symptoms/pain and 100 denoting no symptoms/pain [30]. Based on previous studies [2, 31-33], 
we will focus on the KOOS pain subscale. 
Brief Pain Inventory (BPI): The BPI is a 15-item questionnaire rating pain location, intensity, 
relief, and quality, as well as pain-related quality of life, and it has been validated in many pain 
studies [40, 41]. 
Beck Depression Inventory (BDI): The 21-item BDI has shown good sensitivity and specificity 
for major depression in chronic pain patients [42, 43]. BDI scores greater than 20 will be 
considered high for depression symptoms [42]. 
MGH Acupuncture Sensation Scale (MASS): The MASS includes 12 descriptors of common 
acupuncture sensations: soreness, aching, deep pressure, heaviness, fullness/distension, 
tingling, numbness, sharp pain, dull pain, warmth, cold, and throbbing with one supplementary 
row at the end of the descriptors for subjects to describe their perceptions in their own words 
[25]. We have developed an EPrime script that allows us to collect subject MASS ratings while 
they are in the scanner, using a projector and a button response system. 
Betts’ Questionnaire upon Mental Imagery (BQMI): We will use the BQMI to measure the 
imagery vividness of VGAIT in this study. The BQMI consists of 35 items. Each item of image 
vividness is rated on a 7-point scale, and the procedure is undertaken with the eyes open. 
Expectations for Relief Scale (ERS): The ERS is a 0-10 scale used to measure the expectation 
of post-acupuncture pain relief. During every fMRI scan session, after each verum or placebo 
acupuncture treatment, subjects will be asked to use the scale to rate how much pain relief they 
expect from this particular treatment, with 0 indicating a very negative expectation of “does not 
work at all” and 10 indicating a very positive expectation of “complete pain relief.” Studies have 
shown that expectation can significantly influence an individual’s perception of pain relief [44- 
50]. 
State-Trait Anxiety Inventory (STAI): The STAI consists of two 20-item self-report inventories. It 
is a rapid but detailed assessment that distinguishes between basal (part one inventory) and 
reactive (part two inventory) anxiety [51]. Scores range from 20 to 80 with higher scores 
indicating a greater level of anxiety. Some studies suggest that subjects with high initial anxiety 
scores tend to experience more pain relief after acupuncture treatment than those with low 
anxiety scores [52, 53]. 
Sessions 2-7 are acupuncture treatment visits. Session 2 (treatment 1) will be applied in the 
fMRI scanner. Based on previous studies from other groups [2, 54, 55] and our group [31, 32, 
56, 57], we decided to administer treatment six times in about one month (approximately two 
times per week for the first two weeks and one time per week for the last two weeks). While we 
prefer study sessions to occur at these intervals, scheduling adjustments can be made without 
affecting the integrity of the research. The rationale for this is that the effects of acupuncture 
have been shown to last up to six months following the intervention, so slight adjustments to the 
preferred treatment plan are not consequential to treatment effects. 
All brain imaging will be performed with a 3-axis gradient head coil in a 3 Tesla Siemens MRI 
System equipped for echo planar imaging. A high-resolution 3D MPRAGE sequence will be 
collected for anatomic localization of significant signal changes. Functional MRI images will be 
acquired using a gradient echo T2*- weighted pulse sequence (TR/TE = 2000/30ms, flip angle = 

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90˚, FOV = 192x192 mm, 48 AC-PC aligned slices, slice thickness = 3.0 mm with 0.6 mm inter- 
slice gap, 90 image volumes per slice, matrix = 96x96). fMRI scans will include one resting state 
scan (8 minutes) during which subjects will be told to open their eyes and two ten-minute scans 
of different treatments, which is identical to our previous study. 
All participants will be asked to fill out the MGH Acupuncture Sensation Scale (MASS) following 
each treatment. Additionally, participants randomized to the video conditions will fill out the 
Vividness Scale. The Vividness scale will use a 0-10 vividness scale to measure imagery 
vividness during the fMRI scans. The scale ranges from Not Vivid/Unclear (0) to Vivid/Clear 
(10). 
Session 8 will involve a resting state MRI scan. In addition, subjects will complete the clinical 
and psychometric measurements used during session 1 and undergo QST testing. Subjects will 
complete the Final Questionnaire during this session and EEG data will be collected. 
Procedures for video guided acupuncture imagery treatment and control condition 
VGAIT and control conditions will last about 25 minutes; the time is the same as real 
acupuncture (see the following for details). The same licensed acupuncturist will carry out the 
VGAIT and control conditions. 
Procedures for acupuncture administration Similar to our previous studies [31, 32, 56, 57], 
acupuncture procedures will last approximately 30 minutes in total and will be carried out by a 
licensed acupuncturist on the side with the most severe symptoms or the side as chosen by 
subjects to need more treatment. 
Verum acupuncture procedures Verum acupuncture will be applied on ST35, Xi Yian (extra 
point), GB34, SP9, GB39, and SP6 based on literature [2, 32, 54, 56-60]. After insertion and 
obtainment of deqi sensation, needles will be manipulated in the order of GB34, SP9, ST35, Xi 
yuan (extra point), GB39, and SP6. 
Placebo (sham) acupuncture procedures Placebo acupuncture will be applied at six sham 
points using sham acupuncture needles [24, 49, 61-63]. Sham point 1 is located 1 cun posterior 
to the superior 1/3 of K9 and K10, sham 2 is located 1 cun posterior to K8, sham 3 is located at 
midpoint of sham 1 and 2, sham point 4 is located 1.5 cun anterior and inferior to GB34, and 
sham points 5-6 are located 1.5 cun and 3 cun inferior to sham point 2, sham points 7-8 are 
located 1.5 cun and 3 cun inferior to sham point 4, respectively. All sham points are located on 
the lower leg where there is no meridian passing through. 
 
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