Combined Peripheral (BreEStim) and Central Electrical Stimulation (tDCS) for Neuropathic Pain Management
Phase: NA
Conditions: Pain Management
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-14-0564 
IRB APPROVAL DATE: 03/07/2016 
 
 
 
 
 
 
 
 
 
 
 
Combined peripheral (BreEStim) and central electrical stimulation (tDCS) for neuropathic 
pain management 
 
NCT03302793 
 
Version Date: 03/07/2016 
 
 

IRB NUMBER: HSC-MS-14-0564 
IRB APPROVAL DATE: 03/07/2016 
 
University of Texas – Houston Medical School Protocol (CPHS HSC-MS-xxxx) 
 
1.  Protocol Title: 
 
Combined peripheral (BreEStim) and central electrical stimulation (tDCS) for 
neuropathic pain management 
 
2.  Background: 
 
Neuropathic pain is a chronic condition caused by a primary lesion or dysfunction 
of the nervous system. It is characterized by spontaneous, ongoing pain, described 
as burning, shooting, prickling or electrical, and/or pain in response to innocuous 
stimuli (allodynia) and exaggerated pain in response to noxious stimuli 
(hyperalgesia)(Bennett 2010). Neuropathic pain has increasingly been recognized 
as an important contributor to suffering, poor rehabilitation outcomes and reduced 
quality of life of the persons with SCI. Currently, there is no effective 
pharmacological treatment. Surprisingly, only 7% of responders reported 
pharmacological treatment is effective for neuropathic pain following SCI in a postal 
survey (Finnerup et al. 2001a). On the other hand, pharmacological interventions are 
often associated with side effects, such as addiction, withdrawal, and constipation, 
and sedation which may affect participation in rehabilitation and/or life activities, etc. 
Mechanisms of neuropathic pain are not well understood. Pain is multi-dimensional, 
including sensational and affective (i.e., unpleasantness) components. These 
components are processed in parallel, and inseparable to each other (Price 2000; 
Frot et al. 2008). For example, when superficial tactile stimulation is applied to the 
hand area where acupuncture points are located, activation is seen only in 
somatosensory cortices. However, when the acupuncture points are stimulated, and 
pain is experienced by the subjects, activation of additional cortical areas, such as 
anterior cingulate cortex (ACC) and insula, is observed(Hui et al. 2000).  Therefore, 
it is important that sensational and affective components of neuropathic pain 
could theoretically be modulated separately for therapeutic purposes. 
Among various neurostimulation techniques (Kotze and Simpson 2008), including 
transcutaneous electrical nerve stimulation (TENS) (Norrbrink Budh and Lundeberg 
2004), electroacupuncture (Ulett et al. 1998), spinal cord stimulation (Finnerup et al. 
2001b), deep brain stimulation (Murphy and Reid 2001), transcranial direct current 
stimulation (tDCS) (Fregni et al. 2006; Boggio et al. 2008; Boggio et al. 
2009) has emerged as a promising non-invasive brain stimulation technique for pain 
management. tDCS uses a small weak current applied through two oppositely 
charge electrodes on the scalp to induce neuroplastic changes that can alter pain 
perception in patients with chronic pain patients, such as SCI patients. Both 
electrodes are connected to a battery-powered device that induces a constant 
electrical current (usually, at 2mA) for approximately 15 to 20 minutes (Moreno- 
Duarte et al. 2014). The analgesic effect of tDCS depends on electrode placement, 
however. In a recent study(Boggio et al. 2008),  anodal tDCS targeting primary 
motor cortex (M1) increases pain as well as sensory perception thresholds, 
while anodal tDCS of dorsal lateral prefrontal cortex (DLPFC) only increases pain 
threshold, without altering sensation thresholds. Anodal tDCS targeting M1 is 
believed to specifically modulate excitability of cortico-thalamic pathways, thus 
altering the sensational component of pain, while DLPFC stimulation arguably 

IRB NUMBER: HSC-MS-14-0564 
IRB APPROVAL DATE: 03/07/2016 
 
operates at medial pain pathways through cortical-striatal-thalamic-cortical loop, as 
such attenuating the affective component of the pain (Plow et al. 2012). In a recent 
review in 2014 (Moreno-Duarte et al. 2014), there are eight clinical trials using 
various neurostimulation techniques for chronic pain management in SCI in the last 
15 years. Among though studies, there were 3 tDCS, two TES (transcranial electrical 
stimulation), 2 rTMS (repetitive transcranial magnetic stimulation) and 1 TENS. 
Overall, the effect was heterogeneous. However, SCI patients were “responsive” to 
tDCS. Furthermore, the effect was better and longer-lasting when tDCS was 
combined with visual illusion in two studies (Soler et al. 2010; Kumru et al. 2013). 
We recently proposed an innovative treatment – Breathing-controlled electrical 
stimulation (BreEStim) for neuropathic pain management (Li et al. 2012a; Li 2013a). 
This technique was developed from our discovery of systemic effect of human 
voluntary breathing on motor function and pain perception (Li and Laskin 2006; Li 
and Yasuda 2007; Ikeda et al. 2009; Li and Rymer 2011; Li et al. 2012a; Li et al. 
2012b; Li 2013a), In the BreEStim treatment (see details in (Li 2013a)), human 
voluntary breathing signal is used to trigger an external electrical stimulator. A 
single-pulse electrical stimulation is then delivered to peripheral acupuncture points. 
After receiving the BreEStim treatment to the acupuncture points on the ipsilateral 
forearm daily for a week, a patient with constant shooting phantom pain secondary 
to an above-the-knee amputation reported no more shooting phantom pain, although 
he was still able to feel the shooting sensation occasionally in the phantom limb(Li et 
al. 2012a). 
In the recent study (Li 2013b), an SCI patient (male, 40 years of age, T8 ASIA A 
SCI resulted from traumatic injury 4.5 years ago) received a 5-day electrical 
stimulation (EStim) treatment first, waited for 1 week for washout, and then received 
a 5-day BreEStim treatment. The duration of a single electrical stimulus was 0.1 ms. 
Surface electrodes were placed on the right forearm for acupoints (Neiguan and 
Weiguan). BreEStim had a greater pain reduction effect than EStim. Similar to the 
observation in the patient with traumatic above-the-knee amputation (Li et al. 
2012a), BreEStim to acupoints on the forearm was not likely to modify the sources of 
noxious stimuli at the level of SCI (thoracic area) or at the residual limb (i.e., lower 
extremity). Rather, BreEStim modified how patients react to the noxious stimuli 
at the central level, i.e., the affective response to the same stimuli. Our case 
reports suggest that patients could tolerate the same noxious stimuli better after 
BreEStim. This is possibly realized by increasing pain threshold. In other words, 
BreEStim is likely to influence the affective component of pain. 
Therefore, we hypothesize that combined tDCS and BreEStim treatment 
improves pain control by targeting different components of pain simultaneously as 
discussed above. 
 
3. 
Purpose of the Study: 
In summary, anodal tDCS targeting M1 will be selected since this approach 
influences sensational components of pain perception. BreEStim is shown to 
modulate the affective component of pain perception. Therefore, we expect that that 
combined BreEStim and tDCS treatment has addictive analgesic effects as 
compared to BreEStim or tDCS alone. We will test this treatment in healthy subjects 
and for neuropathic pain management in common patient populations, such as brain 
injury (BI), spinal cord injury (SCI), and amputation. 

IRB NUMBER: HSC-MS-14-0564 
IRB APPROVAL DATE: 03/07/2016 
 
Weiguan 
4.  Description of Study: 
 
This study has 4 experiments. The main idea is to test the effectiveness of the new 
intervention for neuropathic pain management for healthy subjects and one patient 
population (SCI, BI, or amputation) in each experiment. We request to recruit 20 
subjects (5 subjects each group for healthy, SCI, BI and amputation). Overall, We 
plan to adopt recently published BreEStim (Li et al. 2013) and tDCS(Boggio et al. 
2008) research protocols in this experiment. Briefly, this will be a single-center, 
randomized, cross-over trial to determine whether there is additive analgesic effect 
of a single session of combined and BreEStim and tDCS stimulation in healthy, and 
other patient subjects. 
 
Subject recruitment 
A total of 20 patients is planned to be enrolled as a pilot study for the 
following patient populations: healthy, BI, SCI and amputation. The estimated 
number of total patients will be calculated based on our pilot study with 5 subjects for 
each group. Patient subjects will be screened at the outpatient clinic of TIRR 
Memorial Hermann Hospital. Subjects will be recruited and enrolled in the project if 
they meet the inclusion and exclusion criteria (see subject population). 
 
The interventions/Experimental procedures 
 
The experiment consists of 3 sessions, including 1) BreEStim + Sham tDCS (i.e., 
BreEStim only), 2) BreEStim +active tDCS, and 3) tDCS only. Three sessions will be 
conducted on three different days with an interval of at least 24 hours. In each 
session, a conditioning tDCS (active or sham) will be performed first, then followed 
by BreEStim. 
Anodal tDCS targeting M1 (Boggio et al. 2008) will be used. During each 
session, subjects will receive either active or sham stimulation to M1. A pair of 
surface sponge electrodes (35cm2) will be soaked in saline and applied to the scalp. 
The anode electrode will be placed over C3 according to the 10-20 system for EEG 
electrode placement. The reference cathode electrode will be placed over the 
supraorbital area on the opposite side. For all active tDCS conditions, DC will be 
delivered by a specially developed, battery-driven, constant current stimulator 
(Soterix Medical, NY) with a maximum output 
of 10mA. A constant current of 2 mA will be 
applied for 15 min (the effect is usually 
expected to last 1-2 hours after tDCS) 
(Boggio et al. 2008). After the 15-min tDCS 
(active or sham), BreEStim will follow 
immediately. 
 
Figure 1 The experimental setup with 
 
Weiguan 
BreEStim 
 
The same BreEStim protocol (Li et al. 
2013) will be used. Briefly, subjects will wear 
facemask that will be connected to a Pneumotach system to record breathing 
signals. Surface electrodes will be trimmed to be applied to acupuncture points 
(Neiguan and Weiguan) (see Figure for experimental settings). In the BreEStim 
treatment, a single-pulse (0.1 ms square wave) electrical stimulation is delivered to 

IRB NUMBER: HSC-MS-14-0564 
IRB APPROVAL DATE: 03/07/2016 
 
acupuncture points when subjects are taking a fast, strong, and deep inhalation, 
similar to a deep breath but faster and stronger. It is important to mention that 
subjects control the intensity of electrical stimulation, to increase the intensity as 
tolerated gradually. Subjects will be explicitly instructed that aversiveness of painful 
stimulation is part of treatment protocol. To standardize, the total number of 
electrical stimuli is 200. Sufficient rest time will be allowed during the treatment. The 
BreEStim treatment takes about 30 minutes. 
The above intervention will be applied to the following subject populations: 
Experiment 1: the effect of combined BreEStim and tDCS treatment in healthy 
subjects 
 
Experiment 2: the effect of combined BreEStim and tDCS treatment on neuropathic 
phantom pain in amputation subjects 
 
Experiment 3: the effect of combined BreEStim and tDCS treatment on neuropathic 
pain in SCI subjects 
 
Experiment 4: the effect of combined BreEStim and tDCS treatment on neuropathic 
pain in BI subjects 
 
Specimens: 
No specimens will be collected 
 
5.  Subject Population 
 
In experiments 1-4, 5 subjects for each population (healthy, SCI, BI, and amputation) 
will be recruited and tested. An estimated number of patients will be obtained after 
the pilot study. 
In experiment 1, healthy subjects will be recruited from residents, staff, therapists 
at TIRR Memorial Hermann in response to the flyer. The following 
inclusion/exclusion criteria will be followed (1) age between 18 and 60 years, (2) no 
clinically significant or unstable medical, neuropsychiatric, or chronic pain disorder, 
(3) no history of substance abuse or dependence, (4) no use of central nervous 
system-effective medication, (5) no history of brain surgery, tumor, pacemaker, or 
intracranial metal implantation or atrial fibrillation. 
 
Patient subjects will be recruited from the TIRR outpatient clinic for experiments 
2-4 for a total of 15 subjects. 
 
Inclusion criteria: A patient who 1) has neuropathic pain after traumatic 
spinal cord injury or amputation or brain injury; 2) has chronic pain, >3 
months; 3) is between 18 to 75 years of age; 4) is stable on oral pain 
medications at least two weeks. Patients are allowed to continue their pain 
medications, i.e., no change in pain medications. 
 
Exclusion criteria: Patients will be excluded if they 1) are currently adjusting 
oral pain medications for their neuropathic pain; 2) have pain, but not 
neuropathic, e.g., from inflammation at the incision wound of the residual limb 

IRB NUMBER: HSC-MS-14-0564 
IRB APPROVAL DATE: 03/07/2016 
 
or neuroma; 3) have a pacemaker in order to avoid possible side effects of 
electrical stimulation; 4) have amputation in their arm(s); 5) have SCI 
involving impairment of arms; 6) are not able to follow commands, or to give 
consent; 7) have asthma or other pulmonary disease; 8) are not medically 
stable; 9) have preexisting psychiatric disorders; 10) alcohol or drug abuse. 
 
 
6.  Data Analysis 
Pre-intervention and post-intervention measurements include electrical sensation 
and pain thresholds and warm sensation and heat pain thresholds as used in our 
recent study (Li et al. 2013). In addition, visual analogue scores (VAS), modified 
visual analogue scores (mVAS) will be recorded in patient subjects. These 
measurements will be taken pre- and post-intervention for both sessions. VAS has 
been extensively used and validated (McCarthy et al. 2005). mVAS further quantifies 
the effect of pain reduction by measuring duration and amount of change in VAS, 
i.e., how much pain was reduced and how long it lasted (reduction × hours). It is 
necessary to note that pain rating is very subjective. This cross-over design uses 
subjects as their own control. 
Heart rate variability as objective outcome measurements 
We have been searching for non-invasive objective pain outcome assessment. Heart 
rate variability has recently recognized a physiological marker for pain assessment 
(Cowen et al. 2015), see also Appelhans & Leucken 2008 (both articles are uploaded to 
the iRIS). 
We propose to add 5 minutes of Heart Rate recordings before and after the 
interventions. Experimental procedures and data analysis will be adopted from the 
above articles. 
Two-way repeated measures ANOVA with factors INTERVENTIONS (3 levels, 
BreEStim only, tDCS only and tDCS+BreEStim) and TIME (pre- and post- 
intervention) will be used determined statistical significance for each threshold 
(electrical sensation and pain thresholds, and thermal sensation and pain threshold, 
mVAS). It is expected that BreEStim + tDCS will have better analgesic effect that 
BreEStim or tDCS alone. 
 
7.  Potential Risks/Discomforts: 
 
The risks associated with this study are minimal. Electrical stimulation has been 
used extensively in clinical settings. Patients may feel uncomfortable, or even painful 
during electrical stimulation. The patients will be specifically instructed that they are 
encouraged to increase the intensity of electrical stimulation to the level they may 
feel uncomfortable, but they need to be able to tolerate at that level if given 
repetitively. They are also explicitly instructed to decrease the intensity of electrical 
stimulation if they cannot tolerate it. Surface electrodes can cause skin irritation from 
the tape adhesive or the electrode paste. Breathing through a face mask may be 
make patients feel uncomfortable. All tested subjects in the previous studies 
(approximately 70 subjects, including patients) tolerated the mask well. 
 
All the tDCS safety papers (poreisz 2007- 
http://www.ncbi.nlm.nih.gov/pubmed/17452283, kessler 2011- 
http://www.ncbi.nlm.nih.gov/pubmed/22037128 , nitsche 2003- 
http://www.ncbi.nlm.nih.gov/pubmed/14580622) point to adverse effects as 

IRB NUMBER: HSC-MS-14-0564 
IRB APPROVAL DATE: 03/07/2016 
 
itching/tingling. Over 600 studies have published using tDCS and Soterix units 
operate within the established current intensities/durations (0-2 mA, 10-40 min). 
 
8.  Benefits: 
 
There are several potential benefits in this study: 1) direct benefit to subjects as their 
neuropathic pain may be relieved by the intervention; 2) benefit to the class of 
subjects: other patients in the same patient population may be benefit if the 
intervention is applied to them; 3) adding to the knowledge base: the findings will be 
definitely added to the knowledge base. Specifically, the study will provide evidence 
of an alternative and innovative intervention for neuropathic pain management. 
 
9. Risk-benefit Ratio: 
 
In view of the minimal risk, benefits and the knowledge to be gained far outweigh the 
risks. 
 
10. Consent Procedures: 
 
Informed consent will be obtained from the subject at the Motor Recovery Laboratory 
(B-107) at TIRR Memorial Hermann. After a subject is identified and interested in 
participating, informed, written consent will be obtained by the study coordinator. 
 
11. Confidentiality Procedures: 
 
In order to minimize risk to confidentiality, all data will be de-identified, coded with a 
study specific identification number, maintained on a password-protected server, 
and/or kept in a locked office. No findings will be released without written 
authorization by the subject. 
 
12. Costs: 
 
The subject will not be expected to pay any costs. 
 
13. Payments: 
 
Subjects will receive a Wal-mart gift card of $20 for each experimental session. The 
purpose of this payment is to improve subject recruitment and retention. Subject 
payment will be charged to PI’s startup funds. 
 
 
 
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