Effects of Transcranial Direct Current Stimulation (tDCS) and Transcranial Ultrasound (TUS) on the Perception of Pain and Functional Limitations Due to Non-Specific Chronic Low Back Pain (NSCLBP).
Conditions: Chronic Pain, Chronic Low Back Pain
Sponsor: Spaulding Rehabilitation Hospital

 
 
 
 
 
 
 
 
 
Eﬀects of Transcranial Direct Current S4mula4on (tDCS) and Transcranial 
Ultrasound (TUS) on the Percep4on of Pain and Func4onal Limita4ons Due to 
Non-Speciﬁc Chronic Low Back Pain (NSCLBP) 
NCT02954432 
Document Date: December 1, 2021 

Detailed Protocol 2 
In phase II, we will recruit about 80 subjects in order to randomize 40 patients with NSCLBP for 
this study. Subjects will need to meet all of the following inclusion criteria and none of the 
following exclusion criteria: 
 
Inclusion Criteria: 
1. Providing informed consent to participate in the study 
2. 18 to 85 years old 
3. Having non-specific chronic low back pain as defined by [6, 7] (existing pain for at least 
3 months and having pain on at least half the days in the past 6 months) with an average 
of at least 3 on a 0-10 VAS scale 
4. Pain resistant (partial or no response) to common analgesics and medications for chronic 
pain such as Tylenol, Aspirin, Ibuprofen, Soma, Parafon Forte DCS, Zanaflex, and 
Codeine 
5. Must have the ability to feel sensation by Von-Frey fiber on the forearm 
 
Exclusion Criteria: 
1. Subject is pregnant 
2. Contraindications to tDCS in conjunction with TUS: 
a. Metallic implant in the brain 
b. Implanted brain medical devices  
3. History of alcohol or drug abuse within the past 6 months as self reported 
4. Use of carbamazepine within the past 6 months as self reported 
5. Suffering from severe depression (with a score of >30 in the Beck Depression Inventory) 
6. History of neurological disorders as self reported (including epilepsy (note patients will 
also be evaluated via EEG at baseline and any patient showing abnormal EEG activity 
will be removed)) 
7. History of unexplained fainting spells as self reported 
8. History of severe head injury resulting in more than a momentary loss of consciousness 
as self reported 
9. History of neurosurgery as self reported 
10. Unstable pain (defined as a difference in pain intensities larger than 4 points on a 0-10 
VAS scale between the average over the week prior to visit 2 and the average over the 
week prior to visit 4a [96])  
11. Large placebo responder: having a reduction of pain greater than 72.52% (VAS pain now 
post stimulation on V3 compared with VAS pain now pre stimulation on V2) or VAS 
now of 0 or 1 following any stimulation during Run-in period.  
12. Low Adherence during the Run-in stimulation visits (ie. not attending both Run-in 
stimulation visits within approximately one week) 
13. Low baseline pain: VAS pain weighted average < 3 prior to randomization during visit 4a  
 
 
III. 
STUDY PROCEDURES  
 
Because our protocol involves a run-in phase (Part I), we expect that up to 90 patients may enter 
the run-in phase so we will be able to randomize 40 eligible subjects to participate in this study 
(in phase II). When the target number of 40 subjects (for phase II) entering the randomized phase 

Detailed Protocol 4 
 
Part I – Run-in Period 
 
Visit 1  
Screening Visit – (Approx Time:  ¾ hour) 
 
Screening Procedures: 
At Screening, the PI and/or a co-investigator will once more conduct a review of 
inclusion/exclusion criteria to determine the subject’s eligibility for enrollment. Study 
procedures will be reviewed with the subject, and documentation of informed consent will be 
obtained.  
 
At Screening the following procedures will be completed: 
 
• 
Discuss study-specific procedures with the subject.  
• 
Review inclusion and exclusion criteria. 
• 
Obtain a signed and dated consent form. 
• 
Conduct a Demographics Survey and the Beck Depression Inventory. 
• 
Urine pregnancy exam (if applicable). 
 
This visit can be done remotely (There will be an electronically signed consent form, using Mass General 
Brigham REDCap eConsent and the visit will be done either by telephone or Zoom Healthcare) 
 
Visit 2 
Baseline Testing/1st Run-in SHAM stimulation visit (Approx Time: 1 ¼ hours) 
The first baseline testing might be completed on the same day as the screening visit if time allows 
and the subject agrees. 
  
There will be 2 SHAM stimulation visits to be completed approximately 48 hours apart over 
about one week (this visit will include the first SHAM stimulation session). The subject will 
receive 20 minutes of SHAM tDCS in conjunction with SHAM TUS.  
 
Before SHAM stimulation, the subject will complete the following assessments: 
• Urine pregnancy exam (if applicable) 
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Neurological and Physical Exam 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
• EEG recording 
• NIH CLBP RMD instrument 
• 29-PROMIS short form 
• Beck Depression Inventory (BDI) 
 
After SHAM stimulation subjects will complete the following assessments:  
• Adverse Events (AE) 

Detailed Protocol 5 
• Visual Analogue Scale (VAS) for Pain 
• Screening Form for Part II  
 
Visit 3 
2nd Run-In SHAM Stimulation Visit/ End of Run-In Week – (Approx Time:  ¾ hour) 
 
Before SHAM stimulation, the subject will complete the following assessments: 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
• 5 minute training session for motion tests to be performed during Part II 
 
After stimulation subjects will complete the following assessments:  
• Adverse Events (AE) 
• Visual Analogue Scale (VAS) for Pain 
• Screening Form for Part II  
 
Visit 4a   
Rescreening Visit – (Approx Time: 1 ¼ hours) 
This study will be scheduled ~1 week after the first baseline measurements were done.  
 
The subject will complete a series of assessments: 
• Urine pregnancy exam (if applicable) 
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Stroop test 
• Neurological and Physical Exam 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
• Quantitative Sensory Testing (QST) 
• Walking Test 
• Postural Stability/Standing Test 
• One Leg Stance Test 
• Trunk Mobility Test 
• Screening form for part II* 
 
* If the subject is eligible for part II, then they will complete visit 4b in the same day.  
 
Note, patients who exhibit large placebo effects (defined as exhibiting VAS=0 or 
VAS=1)following either of the two SHAM stimulation sessions[97]during Part I and score 
reduction higher than 72.52%; unstable pain intensities (defined as a difference in pain intensities 
larger than 4 (on a 0-10 VAS scale) between the average over the week prior to visit 2 and the 
average over the week prior to visit 4 [96]), low baseline pain (defined as weighted VAS avg < 
3) prior to randomization during visit 4) or who are not compliant with the Run-In protocol 
(defined as not completing both Run-in stimulation visits within approximately one week) will 
be excluded from the full trial [96-98], and thus will not receive MRIs and will not come for 

Detailed Protocol 6 
additional visits. By following this Run-in strategy, we will maximize trial resources by 
excluding patients who demonstrate poor compliance and are less likely to complete the trial. 
More importantly, we will increase the likelihood that the effects we are measuring in the full 
trial are biological in nature and directly caused by the stimulation intervention [97, 98].  Note, a 
patient can be screened out in any of the visits prior to Visit 4b. 
 
 
 
Part II –Interventional Period  
 
Visit 4b  
1st Stimulation Visit – (Approx Time: 1 hour) 
 
There will be 10 stimulation visits to be completed over the next 2 consecutive weeks (ideally 
Monday to Friday of each week). The subject will receive either 20 minutes of active tDCS in 
conjunction with active TUS, or sham tDCS in conjunction with sham TUS per day for the 
course of their stimulation visits.  
 
Randomization: 
Once eligibility and consent have been approved and completed, after all baseline evaluations 
and immediately before the first stimulation session of Part II, stratified blocked randomization 
will occur using the randomized list generated by an automatic web-based randomization 
program (www.randomization.com). Randomization will be based on placebo effect above or 
below -17.3% according to preliminary data. A staff member who is not involved in any of the 
study procedures will be responsible for creating the randomization list and monitoring it during 
the study. Subjects will be randomly assigned to treatment or placebo groups in a 1:1 allocation 
ratio. We will use permuted blocks of variable sizes (4) in a random manner to minimize the risk 
of study staff guessing at the next allocation. Randomization order will be kept in sealed 
envelopes.    
  
Blinding: 
 
All subjects and investigators will be blinded to the group assignment except for the co-
investigators providing stimulation and staff involved in the randomization process (the latter 
would otherwise not be involved in study procedures). Only the staff involved in the 
randomization will be authorized to break the blind if there is a clinical need as requested by the 
PI, clinical care providers, Medical Monitor, or IMC. The patients will remain blinded until they 
have completed all visits (whether they complete all 23 visits or drop out early), or in the case of 
an adverse event necessitating un-blinding.  
 
If the subject receives sham stimulation during Part II, he/she may re-enroll into an open label 
portion of the study, where he/she will receive 10 days of active tDCS/TUS.  Un-blinded co-
investigators (e.g., who provided stimulation) will coordinate with subjects electing to enter into 
the open label phase, which will be conducted by the un-blinded study staff. In the open label 
phase, we will complete the VAS assessments on Day 5 and Day 10 of stimulation. This 

Detailed Protocol 7 
collected data will not be analyzed with the main data collected in the study. This data will be 
used for exploratory analyses only. 
 
After stimulation subjects will complete the following assessments:  
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Stroop test 
• Neurological and Physical Exam 
• EEG recording * 
• Adverse Events (AE) 
• Visual Analogue Scale (VAS) for Pain 
* The EEG can be performed at anytime during the first week of stim (V4b-V8).  
 
Visits 5-7  
2-4th Stimulation visits – (Approx Time: ¾ hour) 
 
During the next 3 stimulation sessions – the subject will receive either 20 minutes of active tDCS 
in conjunction with active TUS, or sham tDCS in conjunction with sham TUS.  
 
Before stimulation, the subject will complete a series of assessments: 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
 
After stimulation subjects will complete the following assessments:  
• Visual Analog Scale (VAS) for Pain 
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Stroop Test 
• Adverse Events Questionnaire (AEs) 
• MRI at Martinos Center***  
*** The MRI will be taken at most one time for each subject that is eligible for Part II at any 
time during the remaining of the study, even after the last follow up visit. 
 
Visit 8 
5th Day of stimulation – (Approx Time: 1 ¾ hours) 
 
Before stimulation, the subject will complete a series of assessments: 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
 
After stimulation subjects will complete the following assessments: 
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Stroop test 
• Neurological and Physical Exam 

Detailed Protocol 8 
• EEG recording** 
• Adverse Events (AE) 
• Visual Analogue Scale (VAS) for Pain 
• Quantitative Sensory Testing (QST) 
• NIH CLBP RMD instrument 
• 29-PROMIS short form 
• Beck Depression Inventory (BDI) 
 
Visit 9  
6th Day of Stimulation – (Approx Time: ¾ hour) 
 
Before stimulation, the subject will complete a series of assessments: 
• Urine pregnancy exam (if applicable) 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
 
After stimulation subjects will complete the following assessments: 
• Visual Analog Scale (VAS) for Pain 
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Stroop test 
• Adverse Events Questionnaire (AEs) 
 
Visits 10-12  
7-9th Day of Stimulation visits – (Approx Time: ¾ hour) 
 
Before stimulation, the subject will complete a series of assessments: 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
 
After stimulation subjects will complete the following assessments: 
• Visual Analog Scale (VAS) for Pain 
• Visual Analog Mood Scale (VAMS)  
• Mini Mental State Examination (MMSE) 
• Stroop test 
• Adverse Events Questionnaire (AEs) 
 
 
Visit 13 
10th Day of stimulation – (Approx Time: 2 hours) 
 
Before stimulation, the subject will complete a series of assessments: 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
 

Detailed Protocol 9 
After stimulation subjects will complete the following assessments: 
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Stroop test 
• Neurological and Physical Exam 
• Adverse Events (AE) 
• Visual Analogue Scale (VAS) for Pain 
• Quantitative Sensory Testing (QST) 
• NIH CLBP RMD instrument 
• 29-PROMIS short form 
• Beck Depression Inventory (BDI) 
• Walking Test 
• Postural Stability/Standing Test 
• One Leg Stance Test 
• Trunk Mobility Test 
 
Visit 14, 15, 16, 17 and 18 
Bi-weekly stimulation visits– (Approx Time: ¾ hour) 
 
Before stimulation, the subject will complete a series of assessments: 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
 
After stimulation subjects will complete the following assessments: 
• Visual Analog Scale (VAS) for Pain 
• Adverse Events Questionnaire (AEs) 
 
 
Visit 19 
Last bi-weekly stimulation visit– (Approx Time: 2 hours) 
 
Before stimulation, the subject will complete a series of assessments: 
• Visual Analogue Scale (VAS) for Pain 
• Pain/Medication Diary 
 
After stimulation subjects will complete the following assessments: 
• Visual Analog Mood Scale (VAMS) 
• Mini Mental State Examination (MMSE) 
• Stroop test 
• Neurological and Physical Exam 
• EEG recording 
• Adverse Events (AE) 
• Visual Analogue Scale (VAS) for Pain 
• Quantitative Sensory Testing (QST) 
• NIH CLBP RMD instrument 

Detailed Protocol 13 
calculated as the difference between the rating of the series of 10 stimuli and the 
rating of the single stimulus.”[103] A 6.65, 300 g Von Frey filament will be used 
as the stimulus unless the subject does not feel comfortable performing the test 
with the heaviest fiber. If so, we will reduce the weight of the fiber until it is 
tolerable by the subject or we will perform the test with the fiber the subject rated 
as painful, as long as it is tolerable, during the Von Frey Assessment.  
• Pain-Pressure Tests (PPT): PPT will be determined using an FDA approved 
algometer as described in the research strategy. This assessment is often used as a 
measurement for pain-pressure thresholds in pain patients. Thus, it poses no 
significant risk to subject safety. The FDA approved algometer will be alternately 
applied three times, in counter-balanced fashion, ipsilateral to the most painful 
low back area (if bilateral pain, performed contralateral  to the dominant side) to 
determine participants’ baseline pressure pain thresholds (PPTs). Participants will 
indicate when the increasing pressure stimulation first became painful (via PPT). 
• Conditional Pain Modulation (CPM): Following the baseline PPT determination, 
participants will undergo a series of cold water immersions that will consist of 
placing the contralateral hand, up to the wrist, into cold water for about 1 minute. 
The cold water will be maintained at a temperature that produced a moderately 
painful sensation as during initial health assessment. Participants will be told they 
can remove their hand from the water at any time. Approximately 30 seconds 
after initiation of each cold water immersion, while the hand is still immersed, the 
algometer will be used to deliver noxious mechanical stimulation to either the 
palm or the back.  Participants will indicate when the increasing pressure 
stimulation first becomes painful, which represented their conditioned PPTs. 
There will be a 2-minute rest period between each CPM trial [60].  
 
EEG recording: EEG recordings will be taken at the first baseline visit before the first sham 
stimulation session, one time at any point during the first week of stimulation of Part II and one 
in the last stimulation visit, to monitor brain activity and saved for post recording evaluation.  
 
MRI: Patient MRIs will be assessed to correlate brain anatomy with patient pain characteristics 
and response to treatment.   
 
Neurological and Physical Exam: Trained study staff will conduct baseline and follow-up 
neurological examinations focused to ensure subject safety one week prior to stimulation, on the 
first day of stimulation, at the end of each stimulation week, and during each follow up visit 
[104]. 
 
Visual Analog Mood Scale (VAMS): This is a self-assessment scale in which subjects rate their 
own emotions, including anxiety, depression, stress, and sleepiness along a 100 mm line.  
 
Mini Mental Status Exam (MMSE): This is a sensitive, valid and reliable 30-point questionnaire 
that is used extensively in clinical and research settings to measure cognitive impairment. This 
instrument will be used as a brief screening of cognitive abilities. The MMSE will be 
administered at the baseline evaluation and every subsequent visit. 
 

Detailed Protocol 16 
which we will use the method of last observation carried forward. The primary outcome will be 
TS and CPM [118] (in phase 1) and VAS (in phase 2) changes as indexed by VAS scores, 
biomechanical function changes as indexed with the motion analysis suite, and global self-
assessment changes. Differences between the two groups (active tDCS in conjunction with active 
TUS and SHAM tDCS in conjunction with SHAM TUS) will be tested using Student's t-test and, 
in addition, we will adjust for important baseline variables and also test the time effect in general 
mixed longitudinal models. This model will be used for the primary and secondary outcomes. 
Secondary analyses will be conducted in an exploratory manner (no correction for multiple 
comparisons). Similar analysis will be conducted for the adverse effects measuring continuous 
outcome and for the categorical outcomes we will use Fisher’s exact test. In both cases, for 
safety analysis we will use uncorrected p-value to increase the likelihood of detecting 
detrimental adverse effects. 
 

Detailed Protocol 17 
 

Detailed Protocol 18 

Detailed Protocol 19 
332-6. 

Detailed Protocol 20 

Detailed Protocol 21 

Detailed Protocol 22 

Detailed Protocol 23 

Detailed Protocol 24