Predicting Pain Response to Transcranial Direct Current Stimulation for Phantom Limb Pain in Limb Amputees
Conditions: Phantom Limb Pain
Sponsor: Spaulding Rehabilitation Hospital

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Title: Predicting Pain Response to Transcranial Direct Current Stimulation for Phantom Limb 
Pain in Limb Amputees.  
 
Protocol:  2015P002525 
 
Date: 06/06/2017  

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II.            SPECIFIC AIMS 
 
The specific aims of this experiment are as follows: 
 
Aim 1:  To assess the predictors of response to transcranial direct current stimulation 
(tDCS) in phantom limb pain of subjects with limb amputation. We will explore the aim 1 in 
an open-label pilot study in which patients will receive active tDCS during 5 daily sessions.  
 
The primary endpoint will evaluate the predictors of pain response to tDCS measured by changes 
in PLP as indexed by a Visual Analog Scale. The study will require a total of 4 weeks to be 
completed. The first week, each patient will give daily reports of their pain using a VAS, 

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accounting for their PLP experience in the past 24hs. This initial baseline week will be followed 
by five days of treatment and a final 2-week follow-up period without any treatment to examine 
the lasting effects of the therapy. We will examine whether the following predictors are 
associated with treatment response: lower or upper limb, bilateral or unilateral and traumatic or 
non-traumatic amputation, baseline pain, age and gender by building a multivariate model.  
IV. SUBJECT SELECTION 
In this pilot study, we will recruit 50 subjects with phantom limb pain (PLP) of any etiology 
(traumatic, vascular disease, diabetic amputees or others). Subjects will need to meet all of the 
following inclusion criteria and none of the following exclusion criteria: 
 
Inclusion Criteria: 
1. Able to provide informed consent to participate in the study. 
2. Subject is older than 18 years. 
3. 3 months of phantom limb pain (experienced regularly for at least once a week) after 
the amputated limb has completely healed.* 
4. Average pain of at least 4 on a numeric rating scale in the previous week (NRS; ranging 
from 0 to 10). 
5. If the subject is taking any medications, dosages must be stable for at least 2 weeks prior 
to the enrollment of the study. 
 
*The healing status of the limb will need to be confirmed by the subject’s physician or by the 
physician of the protocol Dr. David Crandell (Co-Investigator).  
 
Exclusion Criteria: 
1. Pregnancy or trying to become pregnant in the next 2 months. 
2. History of alcohol or drug abuse within the past 6 months as self-reported. 
3. Presence of the following contraindication to transcranial direct current stimulation 
✓ Ferromagnetic metal in the head (e.g., plates or pins, bullets, shrapnel) 
✓ Implanted head electronic medical devices (e.g., cochlear implants) 
 
4. Head injury resulting in loss of consciousness for at least 30 min or pos-traumatic 
amnesia for greater than 24 hours, as self-reported 

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5. Unstable medical conditions (e.g. uncontrolled diabetes, uncompensated cardiac issues, 
heart failure or chronic obstructive pulmonary disease). 
6. Uncontrolled epilepsy, as defined by previous clinical seizure in the past 3 months in 
patients with treatment for epilepsy. 
7. Suffering from severe depression (as defined by a score of >30 in the Beck Depression 
Inventory).* 
8. History of unexplained fainting spells or loss of consciousness as self-reported during the 
last 2 years. 
9. History of neurosurgery, as self-reported. 

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Description of interventions 
tDCS Stimulation Protocol: 
We will use Soterix Medical 1×1 tDCS stimulators device (© Soterix Medical Inc.), its sends a 
low-level current from the positive electrode, anode, to the negative electrode, cathode. During 
tDCS, low amplitude direct currents are applied via scalp electrodes and penetrate the skull to 
enter the brain. Direct current will be transferred by a saline-soaked pair of surface sponge 
electrodes (35 cm2) and delivered by a specially developed, battery-driven, constant current 

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stimulator with a maximum output of 10 mA. Subjects will receive daily stimulation sessions 
with active anodal tDCS for 5 days. Subjects are allowed to reschedule up to 1 stimulation visit. 
During each session, an anodal electrode will be placed over the primary motor cortex (M1), 
contralateral to the most painful amputation side and the cathode over the contralateral 
supraorbital area. Two milliamps of tDCS will be applied for 20 minutes [14]. 
 
DESCRIPTION OF ASSESSMENTS:  
The following tests will be administered: 
Visual Analogue Scale (VAS) for Pain: The VAS is a common assessment used which asks 
subjects to self-reportedly measure their pain on a visual scale (i.e., unbearable to none). We will 
use a VAS to determine subjects’ pain scores. Subjects will rate their pain from 0 – indicating no 
pain at all, to 10 – indicating the worst pain felt. This scale is also colored, from green (at 0) to 
red (at 10), as a visual indicator of pain. This assessment tool is frequently used in many research 
studies evaluating pain levels [15, 19, 20]. 
 
Visual Analogue Scale (VAS) for Stump Pain: any painful sensation in the stump. Subjects will 
rate their stump pain from 0 – indicating no pain at all, to 10 – indicating the worst pain felt. The 
scale will include colors to help in identifying the correct response [15]. 
 
Visual Analog Scale (VAS) for Phantom Limb Sensation: all non-painful sensations in the 
amputated part of the limb. Subjects will be presented with a scale starting at 0- No phantom 
limb sensation, to 10 – Full sensation of the amputated limb. The scale will include colors to help 
in identifying the correct response [15]. 
 
Visual Analog Scale (VAS) for Phantom Limb telescoping: refers to the shrinking and retraction 
of the phantom towards the residual limb. Subjects will be presented with a scale starting at 0 - 
indicated that the phantom was enlarged, and 10 meant that the phantom was completely 
retracted into the stump the scale will include colors to help in identifying the correct response 
[15]. 
 
Adapted Groningen Questionnaire after Arm Amputation: This questionnaire will be applied to 
obtain information’s concerning complaints that may be developed after arm amputation and has 
been used in several clinical trials assessing PLP [21]. 
 
Adapted Groningen Questionnaire after Leg Amputation: This questionnaire is originally meant 
to obtain information’s concerning complaints that may be developed after arm amputation.  We 
adapted the current arm version for lower limb amputation. This questionnaire [21] has been 
used in several clinical trials assessing PLP. 
 
Pain and medication diary: To help monitor pain levels and medication use information, as well 
as safety. Subjects will be asked to record the number of phantom limb episodes on a daily basis, 
using a pain diary. They will record the intensity of the strongest episode as well as phantom 
limb sensation and stump pain on a colored visual analog scale included in the diary, where 0 
represents no pain at all and 10 represents the highest pain the patient has ever felt. Moreover 
subjects will record their current medications and dosages daily in a pain medication diary, until 
completion of the study. 

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Beck depression Inventory: This self-report inventory consists of 21 multiple-choice questions 
and is widely used method to classify depression severity. It assesses for the presence of several 
symptoms related to depression, such as irritability, hopelessness and decreased cognitive 
performance. Physical symptoms such as weight loss and fatigue are also included. This 
instrument has been used previously to evaluate depression severity in patients with phantom 
limb pain [22], as well as in other chronic pain conditions [23, 24]. 
 
Beck anxiety Inventory:  This self-report inventory consists of 21 multiple-choice questions about 
how the subject has been feeling in the last week, expressed as common symptoms of anxiety 
(such as numbness and tingling, sweating not due to heat, and fear of the worst happening). It is 
designed for an age range of 17–80 years old. Each question has the same set of four possible 
answer choices, which are arranged in columns and are answered by marking the appropriate one 
with a cross [25]. 
 
Mini Mental State examination (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. It will be 
used as a baseline evaluation [26]. 
 
Quality of Life Assessment (Short version of SF-36): The short version of the SF-36 health 
survey is used as a measurement of quality of life. It provides a profile of functional health and 
well-being scores. It is also used as a psychometrical index of physical and mental health. This 
instrument is widely used as a quality of life assessment in patients after an amputation and those 
suffering from phantom limb pain [27-30]. 
 
Stroop test: In this task the subject is presented with names of colors written in the same color or 
in a different color, thus on the one hand the word names a color (red) and is written in another 
color (blue). In this task, the automatized behavior (reading) is in conflict with the desired 
response (naming the color). The Subject has to inhibit/suppress the automatic response of 
reading and naming the color the word is written in. The Stroop is one of the most commonly 
used tools for determining attentional problems, also used to assess executive function and 
working memory [31, 32]. Stroop test will be applied as a preliminary safety assessment of 
cognitive changes from baseline to post and follow-up visits. 
 
Side Effects Questionnaire for tDCS: At each stimulation session, subjects will complete a 
questionnaire to evaluate potential adverse effects of tDCS (tingling, burning sensation, 
headache, neck pain, mood alterations) on a 4-point scale (None, mild, moderate and severe). 
The subjects will be asked whether they have experienced any side effects in an open-ended 
manner and they will then be specifically asked about headache, neck pain, scalp pain, scalp 
burns, tingling, skin redness, sleepiness, trouble concentrating, and acute mood change. If any 
side effects are reported, the degree of relatedness to the intervention will be assessed on a 5-
point scale. This type of adverse events questionnaire has been used frequently in our previous 
tDCS studies [23], including in patients with phantom limb pain [33]. 
 
 

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VI.            BIOSTATISTICAL ANALYSIS 
Data forms and questionnaires will be coded in a standardized manner, and double-entered into 
our database. Digital measures/recordings will be similarly tracked in our database and regularly 
backed up. Analyses will be conducted using standard statistical software such as SAS and 
Matlab. 
 
Sample size calculation: 
This is an open label pilot study, we aim to recruit 50 participants with upper or lower, bilateral 
or unilateral amputation of any etiology that present chronic phantom limb pain at least in one of 
the amputated limbs. Given  we are planning to build a multivariate regression analysis with up 
to 5 variables and considering 10 subjects per variable, a sample of 50 subjects would be 
appropriate for this exploratory analysis. The goal of this study is to provide data to generate 
further hypothesis regarding whether demographic and clinical factors influence treatment 
response as to be used for designing a randomized clinical trial (RCT). Therefore the goal of this 
study is not confirm a priori hypothesis but to provide critical data to design a RCT testing the 
effects of tDCS in this population of PLP. 
 
Statistical Analysis 
 
For aim 1:The primary outcome is PLP indexed by VAS. PLP will be analyzed using changes in 
pain. To analyze these data, we will build a multivariate linear regression model in which the 
dependent variable will be the Visual Analogue Scale (VAS) for PLP using the following 
covariates: baseline pain (VAS), amputated limb (upper/lower), etiology of amputation 
(traumatic/ non traumatic), laterality of amputation (unilateral/bilateral), age, and gender. The 
first step will be perform a univariate analysis for each one of our predictors using univariate 
linear regression and obtain the values for the unadjusted b coefficients and 95% confidence 
intervals (CIs). After that, predictors associated with the outcome at a p level <0.01 will be used 
to build a multivariate linear regression using a forward stepwise model.   
Additional statistical models for secondary outcomes will be developed in an exploratory 
manner. Therefore, we will not correct P values for multiple comparisons. 

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