Dose Dependent Effects of tDCS on Post-Operative Pain
Phase: PHASE1
Conditions: Total Knee Arthroplasty (Postoperative Pain), Total Hip Arthroplasty(Postoperative Pain)
Sponsor: VA Office of Research and Development

 
 
1 of  25 
Version 4, 05/08/2017 
 
 
 
 
 
 
PI Name: Jeffrey J. Borckardt, Ph.D. 
 
Study Title: Dose-dependent Effects of tDCS on Post Surgical Pain 
TABLE OF CONTENTS  
1. Specific Aims………………………………………………………………………………………………… 1 
2. Background and Significance……………………………………………………………………………… 2 
3. Preliminary Studies…………………………………………………………………………………………. 9 
4. Research Design and Methods……………………………………………………………………………14  
5. Protections of Human Subjects……………………………………………………………………………19 
6. References/Literature Citations……………………………………………………………………………22  
7. Facilities Available…………………………………………………………………………………………..29 
 
A. SPECIFIC AIMS___________________________________________________________________________ 
 
The proper control of acute and chronic pain is one of the most important areas in health care. Despite 
the profound advances in neuroscience over the past 20 years, we still largely use opiate narcotics, 
much as was done in the Civil War. Total knee arthroplasty (TKA) is one of the most common 
orthopedic procedures performed 1. Because the prevalence of arthritis is expected to grow 
substantially as the population ages 2 3, these procedures are likely to become even more common. 
Previous reports suggest that TKA improves functional status, and relieves pain in most patients, and 
the number and the rate of total knee arthroplasties is increasing steadily. While knee pain is often a 
complaint that precedes TKA, the procedure itself is associated with considerable post-operative pain 
lasting days to weeks. Adequate postoperative pain control is an important factor in determining 
recovery time and hospital length of stay 4 5 6. While the technology associated with the TKA procedures 
themselves has developed rapidly in the past several years, post-operative pain management 
techniques have not changed substantially in several decades. Primary methods used to manage post-
operative pain typically involve systemic opioid or other analgesic drug delivery, and regional blocks. 
Despite these pain-management strategies, patients still report considerable post-operative pain, and 
often struggle to complete post-operative physical therapy regimens. Additionally, systemic opioid 
analgesic use, has associated side-effects that can lead to post-operative complications including but 
not limited to mental-clouding, confusion, respiratory depression, interactions with other medications, 
addiction in some cases, fatigue, and gastric motility problems. Further, the TKA procedures along with 
the associated intraoperative anesthesia protocols have been associated with increased risk for post-
operative cognitive problems7 especially among the elderly8, and current post-operative pain 
management strategies can exacerbate these problems. For obese TKA patients, apnea is a real 
concern that systemic opioid use can complicate. These are relevant concerns as the population 
receiving TKA are more and more likely to be elderly and/or overweight8, 9. New analgesic strategies 
are needed that can be used adjunctively to existing strategies with the potential to reduce reliance on 
opioid analgesia. Several novel brain stimulation technologies including transcranial magnetic 
stimulation (TMS) and transcranial direct current stimulation (tDCS) are beginning to demonstrate 
promise as treatments for a variety of pain conditions 10 11 12 13 14, 15. Electricity has no metabolite or 
other residue, and can be delivered with minimal discomfort and without problems associated with 
drug-drug interactions. TMS and tDCS are minimally-invasive and appear effective in the management 
of chronic pain and experimentally-induced pain10, 11, 16-30. Recently, the PI on this proposal found that 
high frequency TMS for 20-minutes post gastric bypass surgery was associated with approximately 
Medical University of South Carolina 
Protocol 

 
 
2 of  25 
Version 4, 05/08/2017 
 
40% less patient-controlled opioid analgesia use than controls during the 48-hour post-operative period, 
with lower pain ratings26, 27, 30. This series of studies was the first to demonstrate the potential of brain 
stimulation technology to be part of a standard post-operative pain-management strategy, however 
TMS is more complicated to deliver than tDCS, has more adverse events, and is more cumbersome in 
the post-operative setting. In two independent preliminary pilot studies, the PI has shown that tDCS can 
reduce post-operative PCA use by as much as 46% while simultaneously reducing subjective pain 
ratings. Thus, a handful of preliminary studies have demonstrated the potential for brain stimulation 
techniques to adjunctively manage post-operative pain, but a more definitive trial is needed to evaluate 
the efficacy of tDCS using a more rigorous experimental design. Further more data is needed to 
determine optimal tDCS dosing parameters before tDCS will become a viable clinical intervention for 
post-operative pain across surgical specialties. 
Aim-1: Determine the effects of transcranial direct current stimulation (tDCS) on post-operative pain, 
patient-controlled analgesia (PCA) use, and post-surgical complications during the 48-hour post-
operative period following total knee arthroplasty (TKA)or total hip arthroplasty (THA). 
Hypothesis 1: Real tDCS (over sensory/motor and dorsolateral prefrontal cortices) will be 
associated with decreased PCA morphine-equivalent usage (primary outcome), decreased pain 
ratings (secondary outcome), and decreased post-operative complications compared to sham 
tDCS. 
Aim-2: Collect preliminary data regarding dose-dependent effects of tDCS on post-operative pain, PCA 
morphine-equivalent usage, and 6-month outcomes. 
Hypothesis 2a: The analgesic benefits of tDCS will be dose dependent such that one 20-minute 
post-operative tDCS session will be superior to sham, two sessions will be superior to one 
session, and four sessions will produce the largest analgesic effects in the present study. 
Hypothesis 2b: Patients receiving higher doses of real tDCS will evidence lower incidence (and 
dose) of 6-month opioid medication use, reduced pain, and better quality of life.  
 
B. BACKGROUND AND SIGNIFICANCE_________________________________________________________ 
 
Total knee arthroplasty (TKA) is one of the most common orthopedic procedures, and in 2001 
171,335 primary knee replacements and 16,895 revisions were performed1. Because the prevalence of 
arthritis is expected to grow substantially as the population ages2 3, TKA procedures are likely to 
become even more common. The rate of revision total knee arthroplasties is increasing by 
approximately 6 procedures per 100,000 persons per decade. TKA has been shown to improve 
functional status, and relieve pain in many patients. Between 1990 and 2002, the rate of primary total 
knee arthroplasties per 100,000 persons almost tripled. While knee pain is often a complaint that 
precedes TKA, the procedure itself is associated with considerable post-operative pain lasting days to 
weeks post-operatively, and adequate postoperative pain control is an important factor in determining 
recovery time, hospital length of stay, and long-term surgical outcomes 4 5 6  
Postoperative pain control: Opioid medications are the most powerful and effective drugs for pain 
relief, however there are risks and problems associated with opioid use 31. Among the risks are the 
numerous potential side-effects including: respiratory depression, nausea and vomiting, addiction, 
cough suppression, mental clouding, sedation, itching of the skin and nose, and constipation. Many of 
the side-effects of opioid medications are particularly problematic in elderly and obese patients. Thus, 
new interventions that have the potential to reduce reliance on postoperative opioids in this patient 

 
 
3 of  25 
Version 4, 05/08/2017 
 
population (such as TMS and tDCS; see Preliminary Studies) need to be explored. 
 
Recently, Alam et al32 evaluated the incidence of long- term analgesic use after low-risk surgery 
in adults not previously prescribed analgesics by conducting a retrospective cohort study using linked, 
population-based data in Ontario, Canada, from April 1, 1997, through December 31, 2008. Patients 
were identified that were dispensed an opioid within 7 days of a short-stay, minor surgery and the risk 
of long-term opioid use was assessed, defined as a prescription for an opioid within 60 days of the 1-
year anniversary of the surgery. Among 391,139 opioid-naive patients undergoing short-stay surgery, 
opioids were newly prescribed to 7.1%. At 1 year from surgery, an increase in the use of oxycodone 
was found (from 5.4% within 7 days of surgery to 15.9% at 1 year). Patients receiving any opioid 
prescription within 7 days of surgery were 44% more likely to become long-term opioid users within 1 
year compared with those who received no such prescription. Prescription of opioid analgesics 
immediately after surgery occurs frequently in adults and is associated with long-term use. Thus, post-
surgical opioid use appears to be a potential contributing factor to rising incidence and risk of long-term 
opioid use, dependence and abuse. Patient-controlled analgesia (PCA) pumps have been shown to be 
very effective in the management of postoperative pain. While the risk of PCA pump usage specifically 
and directly leading to future opioid abuse is relatively small (1% 33), opioid abuse appears to be on the 
rise in the United States 34. In many cases, both patients and physicians worry about the potential for 
dependence and abuse of opioid medications, and this sometimes results in under-treatment of acute 
and chronic pain 33.  
 
Several non-pharmacological approaches to modulating pain perception have been used 
successfully in postoperative populations. There is accumulating evidence that cognitive, relaxation, 
and hypnotic interventions can significantly reduce postoperative pain and recovery time 35 36 37 38 39 40 
41, 42. While the mechanisms of action of such approaches are unclear, there is some evidence 
suggesting that cognitive, relaxation and hypnotic interventions may increase activation of the prefrontal 
cortex and networks involved in inhibiting the affective dimension of pain experience 43 44. 
Unfortunately, these psychological approaches are resource dependent, requiring much time and highly 
skilled personnel. They are thus unlikely to be widely used in non-research settings. Since tDCS 
appears to be capable of focally exciting targeted cortical areas involved with central pain processing, 
and given our preliminary data suggesting significant postoperative pain reduction and decreased 
morphine use, further exploration of its potential applications in a balanced analgesic approach are 
warranted. A reasonable strategy for developing optimal balanced analgesia involves first studying 
optimal treatment combinations for individual procedures 35. Given the preliminary nature of our 
understanding of optimal management strategies for postoperative pain across the vast array of 
available surgical procedures, and given our preliminary findings of the potential effectiveness of tDCS 
in the management of post-operative pain (see preliminary studies section), it is prudent to ensure that 
the effect is real and to explore key basic parameters that may be related to optimizing it before 
expanding the procedure into managing pain from other surgical procedures. We have therefore 
chosen to use this study to extend and refine the technique using total knee arthroplasty (a group with 
which the investigative team has extensive experience), rather than to prematurely begin testing 
whether the effects generalize to other surgical populations. 
Pain and the Brain: Pain is a complex experience that has sensory-discriminatory, motivational-
affective and cognitive-evaluative dimensions 45. Experimental and clinical fMRI findings suggest that 
parietal areas, including the primary somatosensory cortex, are mainly involved in the sensory-
discriminative dimension of pain experience and frontolimbic networks are involved in the affective 
dimension 46 47. There is also evidence that the primary (SI) and secondary (SII) somatosensory 
cortices are involved in the temporal processing of pain experience. However, activation of SI tends to 
be limited to activation contralateral to the side of stimulation, whereas SII tends to demonstrate 
bilateral activation 47 48 49. When pain-relevant anxiety is manipulated experimentally, evidence emerges 
supporting the involvement of the anterior cingulate cortex (ACC) in the affective dimension of pain 

 
 
4 of  25 
Version 4, 05/08/2017 
 
experience 46 50. Innocuous thermal stimulation is associated with activation of the anterior ACC 
whereas noxious stimulation is associated with activation of both the anterior ACC and the ventral 
portion of the posterior ACC 51. Other brain structures that appear to be involved in the affective 
component of pain experience include the lateral and medial thalamus, insular cortex, and the 
supplementary motor area 52 53. There is some evidence supporting the notion that brain structures 
involved in processing the affective component of pain experience are activated bilaterally whereas 
structures involved in processing sensory-discriminative components demonstrate unilateral activation 
54 55. The role of the left prefrontal cortex in pain control is unclear. However, there is evidence to 
support the concept that left prefrontal activation is negatively correlated with pain unpleasantness 56 
suggesting a possible governing role of the prefrontal cortex on the affective dimension of pain 
experience. In fact, it has been shown that prefrontal activation is negatively correlated with pain 
catastrophizing 57. This is important as catastrophizing and pain-related anxiety have been identified as 
a reliable predictor of the development of chronic post-surgical pain. 58 Additionally, recent studies of 
expectancy and cognitively-mediated analgesia seem to suggest that cognitive effects on pain 
perception may involve genuine analgesia that is mediated by µ-opioid systems in the brain 59 and are 
associated with decreased activation of the thalamus, insula and anterior cingulate. These effects 
correlate with prefrontal cortex activation (where expectations, thoughts and belief-systems are 
believed to primarily operate in the brain 60). Thus, left prefrontal activation might result in similar 
analgesic effects, presumably by modulating limbic response to pain. Interestingly, there appears to be 
distinct laterality effects regarding dorsolateral prefrontal cortices. Activation of the left DLPFC but 
deactivation of the right DLPFC tends to be associated with pain inhibition (as well as improvements in 
mood). 56, 57, 60. 
Minimally-invasive brain stimulation technology: Transcranial direct current stimulation (tDCS), 
involves the application of low-amplitude electric current to the scalp. A battery-powered current 
generator (capable of delivering up to 2 mA of constant current flow) is attached to two sponge 
electrodes. The sponge electrodes are then soaked in saline, applied to the scalp, and held in place by 
a non-conducting rubber montage. During tDCS, low amplitude direct currents penetrate the skull to 
enter the brain. Although there is substantial shunting of current at the scalp, sufficient current 
penetrates the brain to modify the transmembrane neuronal potential 74, 75 76 and, thus, influence the 
level of excitability and modulate the firing rate of individual neurons. Unlike TMS, direct current does 
not directly induce action potentials, but rather, the current appears to modulate the spontaneous 
neuronal activity in a polarity-dependent fashion. Anodal tDCS applied over the cortex increases the 
excitability of the stimulated brain area, while cathodal tDCS applied over the same area decreases it 71 
77 78. Anodal tDCS applied over the occipital cortex produces short-lasting increases in visual cortex 
excitability 79 80. Hence, tDCS is believed to deliver its effects by polarizing brain tissue, and while 
anodal stimulation generally increases excitability and cathodal stimulation generally reduces 
excitability, the direction of polarization depends somewhat on the orientation of axons and dendrites in 
the induced electrical field.  
Minimally-invasive brain stimulation and pain perception: The first controlled laboratory study of 
motor tDCS was performed in only 8 healthy subjects who underwent quantitative sensory testing 
before and after cathodal, anodal, and sham tDCS sessions, performed in a random order 95. The 
active electrode was placed over the left M1 and the reference electrode above the right orbit. Cathodal 
tDCS lowered cold detection threshold, corresponding to a reduced sensitivity to A∂-fiber-mediated 
somatosensory inputs. No other change was observed. However, this result was not confirmed in a 
subsequent study with the same design but a larger series of subjects 96.  
 
A third tDCS study was characterized by the use of a unqiue tDCS design, called high-definition 
tDCS (HD-tDCS; see preliminary studies section) 97. With this method, 4 cathodes are placed 
equidistant (7 cm) from each other and from the anode, which serves as the active electrode. This 
montage increases the spatial selectivity of the stimulation. Anodal HD-tDCS delivered to the left M1 

 
 
5 of  25 
Version 4, 05/08/2017 
 
decreased cold detection and pain thresholds, and increased warm sensory thresholds, but did not alter 
heat pain thresholds. This antinociceptive effect of anodal HD-tDCS runs counter the absence of effect 
of anodal tDCS in the other studies performed in healthy subjects95, 96, but fits well with the proved 
analgesic effect of anodal (but not of cathodal) tDCS in chronic pain, of either neuropathic or non-
neuropathic origin 21, 79, 91. This observation could illustrate the respective influence of disease-related 
homeoplastic cortical plasticity and stimulation polarity on tDCS efficacy. In general, anodal tDCS tends 
to reproduce the main effect of high-frequency rTMS that is a decreased sensitivity to cold stimuli and a 
reduced susceptibility to cold pain. It is generally accepted that cortical excitability is reduced by 
cathodal tDCS and increased by anodal tDCS because of induced processes of axonal 
hyperpolarization and depolarization, respectively 78. Because high-frequency rTMS is thought to 
increase cortical excitability, the similarity between the effects of high-frequency rTMS and those of 
anodal tDCS on thermal sensation seems logical. Both methods likely activate some cortical neural 
circuits running through the precentral gyrus and involved in cold sensation processing. However, this 
simple approximation should be viewed with caution because, as mentioned above, it is difficult to take 
the effect on motor corticospinal output as a general rule of action of a type of cortical stimulation. In 
addition, even if anodal stimulation is exciting and cathodal stimulation is inhibiting, the efficacy of the 
stimulation may depend partly on the orientation of the axons in the induced electrical field. Moreover, 
the site of induced biological effects is thought to locate under the active electrode because it is 
assumed that the other electrode is a reference. This assumption is probably wrong if we consider that 
in most of tDCS studies, the reference electrode is placed at the forehead or over the orbit, and thus 
quite close to the orbitofrontal cortex. In these cases, what is interpreted as the effect of anodal 
stimulation of M1 may be the effect of cathodal stimulation of orbitofrontal cortex.  
Stimulation of the primary motor cortex (M1) and dorsolateral prefrontal cortex (DLFPC) may 
both reduce the perception of pain, but they likely do so via different mechanisms. In a recent study, 
pain thresholds to electrical stimulation were assessed in 20 healthy volunteers before and during 
anodal tDCS. Four conditions of stimulation were compared: M1, DLPFC, occipital cortex, and sham. 
Anodal tDCS of M1 increased both detection and pain thresholds, while stimulation of DLPFC 
increased pain thresholds only. The results suggested that 1) anodal stimulation of M1 but not DLPFC 
could induce analgesia by modulating sensory discrimination and 2) stimulation of DLPFC could 
modulate the perception of pain via mechanisms independent of sensory perception 19. An adjunctive 
study with 22 healthy volunteers showed that anodal tDCS of the DLPFC (but not M1, occipital, or 
sham) could decrease the perception of unpleasantness and reduces emotional discomfort/pain while 
subjects viewed emotionally aversive images 20. 
Overall, we have accumulated considerable knowledge over the past few decades about the 
relationships between acute/post-surgical pain, pain management strategies, opiate addiction risks, and 
brain responses to painful stimuli. Additionally, several new brain stimulation technologies have been 
introduced and tested, and when combined in a thoughtful way with our growing knowledge of pain 
processing in the brain, there is considerable evidence supporting their potential role in current pain 
management strategies. Much less attention has been paid to integrating brain stimulation technology 
into the post-operative setting which is unfortunate given the limits of currently available post-operative 
pain-management resources, the risks associated with current pain management strategies, and the 
sky-rocketing increase in opiate addiction in the US. The present study builds on accumulating 
knowledge about pain processing in the brain and clinical efficacy data supporting brain stimulation for 
pain. This study will be the first randomized, double-blind, controlled dosing study of tDCS technology 
as an adjunctive pain management strategy for post-operative pain. Data from this trial will likely yield 
information regarding the feasibility and efficacy of tDCS as a post-operative pain-management 
approach. If the proposed pilot trial suggests significant and meaningful effects of tDCS as an 
adjunctive post-operative pain management strategy, this might change the way post-operative pain 
management is approached in the future. Findings from this study will be used to evaluate the 

 
 
6 of  25 
Version 4, 05/08/2017 
 
necessity for an even larger-scale, multi-site clinical trial of the technique, and to determine whether 
future investigations of tDCS across different surgical specialties might be warranted. 
 
C. PRELIMINARY STUDIES___________________________________________________________________ 
 
Motor Cortex tDCS Laboratory Pain Pilot: Twenty-four healthy, medication-free, adult volunteers (18 
female; 6 male; 3 African American; 1 Asian; 20 Caucasian) with a mean age of 26.58 (SD=6.11; range 
19 to 43) provided written informed consent to participate in this pilot. Participants did not have 
depression, chronic pain, epilepsy, seizure-history, or implanted medical devices. Two participants 
were nicotine dependent smokers. Quantitative Sensory Testing (QST) was conducted using the ATS 
thermode of the Medoc Pathway system (Medoc Advanced Medical Systems Ltd, NC, USA) attached 
to the left volar forearm of each subject’s left arm ~5 cm from the wrist. The thermode heated or cooled 
(randomly-ordered) from 32ºC at the rate of 0.25ºC per second. Participants pressed a button to stop 
the thermode as soon as they detected any change in temperature (sensory threshold), when it 
reached the level considered to be painful (pain threshold), and when they could no longer tolerate the 
stimulus (pain tolerance). After 10 trials, the CHEPS thermode from the Medoc Pathway System was 
used to deliver 20 brief (0.75s) suprathreshold thermal stimuli (individual heat pain threshold plus 
1.5ºC) to the left volar forearm of subjects at the rate of 1 stimulus every 1.5 seconds. During the 30-
seconds of repeated stimulation, subjects continuously indicated their level of pain intensity using a 
dynamic computerized visual analogue scale (CVAS) controlled by the mouse. The CVAS recorded the 
position of the digital marker on the VAS each second. The mean of the pain ratings during the first 3-
seconds and the last 3-seconds of the 30-second wind-up trial were examined to determine the amount 
of wind-up pain experienced by each participant.  
 
The tDCS device was a Phoresor-II Auto (Model PM850, Iomed, Salt Lake City Utah, USA). 
Participants were randomized to receive real or sham tDCS. For real tDCS, the device was ramped to 2 
mA and maintained this current for 20 minutes. For sham tDCS, the device was ramped to 2 mA, but 
after 30 seconds, was ramped back down to 0 mA and stayed off for the remainder of the 20 minutes. 
During stimulation, participants rated the painfulness and unpleasantness of any scalp sensations using 
numeric rating scales (e.g., 0=no pain to 10=worst pain imaginable). Ratings were collected at 
stimulation onset, 5-minutes, 10-minutes, 15-minutes, and during the last 30-seconds of stimulation). 
Further, verbal descriptors of all scalp sensations, pain-related or otherwise, were recorded as well as 
all adverse events associated with the study. At the end of the study, participants were asked to guess 
whether they received real or sham tDCS. Further, they were asked to rate their confidence in their 
guess (0=completely guessing to 10=absolutely sure). 
 
Participants rated the scalp pain associated with real tDCS as 1.98 (SD=2.02) out of 10 on 
average while those receiving sham tDCS rated their scalp pain as 0.18 (SD=0.27). These means are 
both low considering the 11-point range of the NRS, but they were significantly different (t(22)=2.94, 
p=.008). Participants receiving real tDCS rated the unpleasantness of the scalp sensations as 3.34 
(SD=2.44) out of 10 on average whereas those receiving sham rated the unpleasantness as 0.43 
(SD=0.49) on average (t(22)=3.88, p=.001). The scalp painfulness and unpleasantness ratings 
associated with real tDCS decreased over time during stimulation. Despite the between group 
differences in stimulation painfulness and unpleasantness, participants were not able to correctly guess 
whether they received real or sham stimulation at a rate better than chance (X2(1)=2.10, p=.21, ns). In 
the real stimulation group, 46% of participants guessed correctly (X2=.004, p=.94, ns) and in the sham 
group 18% guessed correctly (X2(1)=2.23, p=.14, ns). The average guess-confidence rating was 5.50 
(SD=3.10) in the real tDCS group and 4.55 (SD=2.16) in the sham group (t(22)=0.86, p=.399, ns). 

 
 
7 of  25 
Version 4, 05/08/2017 
 
 
Qualitative descriptors of the scalp sensations during tDCS included "itchiness" (21% of total 
sample), "tingling" (21%), "prickling" (13%), "pressure", "stinging", "uncomfortable", and "warm" (8% 
each). A total of 37 qualitative descriptors were offered by participants in the real tDCS group and 17 
from those in the sham group. Those offered by participants in the sham group were primarily during 
the 30 seconds of stimulation delivered before ramping the device back down to 0mA for the remainder 
of the 20-minute session. There were no adverse events, and no report of any post-stimulation side-
effects.  
 
Sensory Thresholds: There was a significant main effect for time (pre- to post- stimulation; 
F(1,166)=148.77, p<.0001) but no main effect for condition (real vs sham stimulation; F(1,26.4)=0.04, 
p=.85, ns) on heat sensory thresholds. The procedural pain covariate was not significant (F(1,21=4.16, 
ns). However the time X condition interaction was significant (F(1,166)=5.34, p=.02). Participants in the 
real stimulation group evidenced a 0.54ºC increase (estimated marginal mean after controlling for 
procedural painfulness) in heat sensory threshold pre- to post- stimulation, relative to the sham group. 
For cold sensory thresholds, there was also a significant main effect for time (F(1,165)=50.82, p<.0001) 
but not for condition (F(1,29)=1.64, p=.21, ns), but the time X condition interaction term was significant 
(F(1,165)=7.74, p=.006). The procedural pain covariate was not significant (F(1,21)=3.17, ns). 
Participants in the real stimulation group evidenced a 0.76ºC decrease (estimated marginal mean after 
controlling for procedural painfulness) in cold sensory threshold pre- to post- stimulation relative to 
sham. 
 
Thermal Pain Thresholds: A main effect for time was observed on heat pain thresholds 
(F(1,260)=64.94, p<.0001), but no main effect was found for condition or for the time X condition 
interaction term (F(1,22.8)=0.48, p=.49, ns; F(1,260)=0.19, p=.66, ns). The procedural pain covariate 
was not significant (F(1,21)=0.21, ns). For cold pain thresholds, a significant main effect was found for 
time (F(259)=4.55, p=.03) but not condition (F(1,22.1)=2.82, p=.11, ns). Only a marginal effect was 
observed for the time X condition interaction term (F(1,259)=3.18, p=.07). The procedural pain 
covariate was not significant (F(1,21)=0.85, ns). Participants that received real stimulation evidenced a 
0.82ºC decrease (estimated marginal mean after controlling for procedural painfulness) in cold pain 
threshold relative to sham. 
 
Thermal Wind-up Pain: A significant time (pre- to post- stimulation) X condition (real versus 
sham stimulation) X wind-up pain slope interaction was observed (F(4,44)=5.43, p=.001). For those 
receiving real stimulation, the wind-up pain slope decreased by 0.25 CVAS pain-rating points-per-
second (during the 30-second wind-up trial) following stimulation relative to baseline (t(21.8)=2.21, 
p=.036). However, in the sham stimulation group, there was no change in wind-up pain slope pre- to 
post- stimulation (t(30)=0.52, p=.61, ns). 
In our recent laboratory pilot, real tDCS was associated with significantly decreased heat and 
cold sensory thresholds, decreased thermal wind-up pain, and a marginal analgesic effect for cold pain 
thresholds, all after controlling for procedural painfulness ratings. No significant effects were observed 
for heat pain thresholds. Similar studies using TMS suggest that stimulation of the motor cortex is 
associated with changes in heat and cold sensory thresholds as well as heat and cold pain thresholds 
89, 98, 99. Using tDCS, Bachmann et al 95 found that cathodal stimulation over the motor cortex 
significantly impacted cold sensory, mechanical sensory and mechanical pain thresholds in the 
contralateral hand. Bachmann et al found no significant effects for cold pain thresholds, pressure pain 
thresholds or wind-up pain.  The simplest explanation for the divergence between these findings and 
those from the present study, is the significant difference in the spatial profile of induced brain current 
flow. Craig et al found that the application of innocuous cold stimuli activates the human thermosensory 
cortex located in the contralateral insula 100. Painful heat and cold stimuli activated the contralateral 
anterior cingulate cortex (ACC), contralateral primary motor and sensory cortex (MI: primary motor 
cortex/SI: primary sensory cortex), bilateral secondary sensory cortex (SII: secondary sensory cortex) 

 
 
8 of  25 
Version 4, 05/08/2017 
 
and mid-insular cortex, thalamus, and the vermis and paravermis of the cerebellum 101 64. Thus, the 
differing effects of tDCS and TMS seen on laboratory pain measures and non-painful thermal and 
nociceptive thermal signals may be due, in part, to the transmission of signals related to perception via 
these different stimulus types may occur through unique pathways.95 In addition, tDCS modulation of 
innocuous thermal thresholds may be more easily achieved than modulation of thermal pain thresholds, 
as thermal perception and distinction thresholds are lower than thermal pain thresholds. 95  
tDCS Effects on Post-Procedural Pain Pilot: 102 Recently, the PI conducted the first-ever pilot study 
on the effects of tDCS on post- Endoscopic Retrograde Cholangiopancreatography (ERCP) pain. 
Nineteen Caucasian females (mean age=37.2 StdErr=2.4) were enrolled. After ERCP, participants 
were randomly assigned to receive 20-minutes of tDCS with anode over the left-prefrontal cortex and 
cathode over the gut representation of the sensory cortex. No serious adverse events were associated 
with tDCS. Side-effects of tDCS were limited to tingling (42%), itching (47%) and mild stinging (11%) 
under the electrodes. Patients that received a single 20-minute dose of real tDCS used 22% less total 
hydromorphone than those that received sham at the end of the 24-hour inpatient post-procedural 
period (Cohen's d=.38). The slope of the cumulative PCA usage curve was significantly steeper in the 
sham tDCS group compared to real (t(355)=10.80, p<.0001). VAS pain scores suggested an arithmetic 
advantage for real tDCS compared to sham (not statistically significant likely due to limited power). 
Results from this pilot feasibility study suggest that tDCS is safe, well-tolerated, and may be able to 
reduce post-ERCP opioid requirements without increasing subjective pain ratings.  
tDCS Effects on Post-Total-Knee-Arthroplasty (TKA) Pain Pilot: In a very recent preliminary pilot 
study, the PI randomly assigned 40 patients undergoing unilateral TKA to receive a total of 80 minutes 
of real (n=20) or sham tDCS (n=20) with the anode over the knee representation of the motor strip and 
cathode over the right dorsolateral prefrontal cortex. 20-minute tDCS treatments were delivered: 1) in 
the PACU, 2) 4 hours later, 3) the morning of post-operative day-1, and 4) the afternoon of post-
operative day-1. VAS pain and mood ratings were collected every 4 hours following surgery provided 
that patients were awake. The slopes of the cumulative PCA usage curves were significantly different 
between groups, and those TKA in the real tDCS group used 44% less PCA dilaudid at 48-hours post-
op (p=.007; Cohen’s d=1.0). Despite significantly lower PCA dilaudid levels, VAS ratings of pain-on-
average were also significantly lower in the real tDCS group (t(37)=2.28, p=.029). No adverse events or 
serious adverse events were encountered. There were no cases in which tDCS needed to be 
discontinued due to patient discomfort or tDCS-related complications. 
 
Overall, we have found that stimulating pain-modulating areas of the human cortex can 
significantly reduce post-operative opioid requirements without negatively impacting subjective pain 
ratings, and in some cases, it can significantly decrease pain ratings even though patients use less 
opioids. Further, we observe large effect-sizes for 20-minutes of TMS and for 80-minutes of tDCS. The 
investigators have demonstrated the feasibility of, and expertise for conducting brain stimulation in the 
post-operative setting and these promising, preliminary findings of novel brain stimulation technologies 
suggest that future studies are warranted. The field of minimally-invasive brain stimulation for pain is 
expanding rapidly, but it is still in its infancy. tDCS appears to have the potential to serve as an adjunct 
to post-operative pain management strategies, but more studies are needed in this area employing 
larger-scale, well-controlled clinical trial designs to evaluate the specificity of tDCS dosing strategies 
and to begin to elucidate possible mechanisms of action. 

 
 
9 of  25 
Version 4, 05/08/2017 
 
 
D. RESEARCH DESIGN AND METHODS (including data analysis) 
Figure 1. Study overview and patient flow 
Overview: The proposed study employs a 
randomized, double-blind, sham-controlled 
design to evaluate the effects of tDCS on 
pain among veterans receiving unilateral 
TKA or unilateral THA. Further, this study 
will examine dose-dependency of the 
tDCS analgesic effects. 120 patients 
undergoing TKA will be randomly 
assigned to one of four groups: Group1-  
4-sessions of real tDCS, Group2-  2-
sessions of real tDCS (+ 2 sham-
sessions), Group3-  1-session of real 
tDCS (+ 3 sham-sessions), or Group4-  4-
sessions of sham tDCS. Participants' PCA 
opioid pump usage will be tracked and 
pain and mood ratings will be collected 
(see figure 1). Follow-up ratings and 
opioid use data will be collected at 1, 3 
and 6-months post-op. 
 
Participants: Participants will be 120 patients undergoing TKA or THA surgery at the Ralph H. Johnson 
VAMC in Charleston SC. Inclusion/Exclusion criteria are as follows: 
1) Between the ages of 25 and 90 
2) No implanted medical devices above the waist 
3) Mentally capable of reading, writing, giving consent, and following instructions 
4) Not pregnant 
5) Cleared for and scheduled for unilateral TKA or THAsurgery 
6) No history of seizures 
7) Not allergic to latex rubber 
8) No psychiatric conditions except for depression and/or anxiety disorders as these are commonly 
seen in patients with chronic pain 
 
Participants will be recruited by members of the research team from the Orthpaedic Surgery 
pre-operative clinic. Eligible and interested participants will be enrolled in the study during their hospital 
stay for TKA or THA and for the following 6-month follow-up period. Data will be psychosocial, pain and 
behavioral ratings, medical surgical outcomes and PCA opioid use. All data will be collected by the 
study investigators, clinicians and the research team. 
Dependent Measures: See table-1 for the schedule of measurement.  

 
 
10 of  25 
Version 4, 05/08/2017 
 
THE BECK DEPRESSION INVENTORY (BDI) is a well-researched, brief, self-report depression 
screening instrument. It consists of 21-items that assess different aspects of depression (e.g., 
anhedonia, excessive guilt, suicidal ideation, vegetative symptoms, tearfulness). 103-108 IF ITEM #9 
(SUICIDAL IDEATION) IS ENDORSED, PARTICIPANTS WILL UNDERGO A FACE-TO-FACE SELF-
SAFETY SCREEN (I.E., INTERVIEW ASSESSING IDEATION, INTENT, PLAN, MEANS) AND A 
REFERRAL WILL BE MADE TO MENTAL HEALTH SERVICES IF NECESSARY FOR FORMAL 
EVALUATION AND TREATMENT AS INDICATED. 
THE BECK ANXIETY INVENTORY (BAI) is a well-researched, brief self-report anxiety screening 
instrument. It consists of 21-items that assess different aspects of anxiety experience (e.g., 
physiological, cognitive, behavioral). 109  
THE BRIEF PAIN INVENTORY (BPI) is a 17-item self-report questionnaire designed to assess chronic 
pain intensity and the impact of pain on general functioning, relationships and mood. 110, 111  
THE MCGILL PAIN QUESTIONNAIRE (MPQ) is a 21-item self-report scale designed to capture the 
quality and intensity of the pain experience. 112, 113 Subjects are asked to place a mark next to 
appropriate descriptors of their pain. The descriptors are assigned scores and the values load onto 4 
factors: 1) Sensory, 2) Affective, 3) Evaluative, and 4) Miscellaneous.  
VISUAL ANALOGUE SCALE (VAS) RATING SCALES anchored with "no pain" and "worst pain 
imaginable" will be collected twice daily during the inpatient stay to assess pain at its worst, pain at its 
least, pain on average, and pain 'right now'. Additionally, participants will rate pain "Unpleasantness" 
using VAS in order to assess the affective component of the pain experience. The same system will be 
used to assess changes in mood at its worst, mood at its best, mood on average and mood 'right now' 
but the anchors will be "extremely depressed, sad or agitated" and "extremely good mood." This VAS 
method of pain assessment was chosen because it can be administered numerous times each day and 
it is highly sensitive to changes in pain perception and mood. VAS ratings will be collected immediately 
prior to, during, and immediately following all physical therapy sessions (inpatient and outpatient) during 
the 3-month follow-up period.  
DAILY PAIN DIARY: The diary will require participants to record their average pain rating, pain at its 
worst, pain at its least, Activity level, Mood, sleep from previous night, and the number of times 
prescription pain medications were taken that day. Participants will be asked to fill out this form each 
day at night for the first 8 weeks post-surgery. 
KNEE FLEXION MEASURE: A Gollehon Extendable Goniometer will be used to measure degrees of 
knee flexion at each post-operative physical rehabilitation visit.  
POSTOPERATIVE COMPLICATIONS will be defined as any event, illness or postoperative occurrence 
that negatively impacts the health, well-being or functioning of the patients enrolled in the trial (including 
but not limited to headaches, confusion, delirium, nausea, vomiting, infections, and cardio-vascular 
complications). These events are tracked by medical staff as part of routine care, and the information 
will be gathered and recorded in the research database as well as length-of-stay at the time of 
discharge.  
PATIENT CONTROLLED ANALGESIA (PCA) PUMP USAGE: After tDCS administration, patients will 
be started on a patient controlled analgesia (PCA) pump. For statistical analyses of PCA pump usage, 
morphine-equivalent analgesic dose will be calculated (e.g., 0.2 mg of hydromorphone = 1.0 mg of 
morphine). Initial PCA settings will consist of hydromorphone 0.2mg/dose with a lockout interval of 10 
minutes. The 4-hour maximum dose will be 4.8mgs with no continuous infusion. If a patient does not 
tolerate hydromorphone, the PCA medication can be changed to a different opioid and morphine-
equivalent dosing will be used. If pain is not adequately controlled, the patient will be reassessed by 

 
 
11 of  25 
Version 4, 05/08/2017 
 
study personnel prior to increasing the PCA dosing regimen. PCA pump usage will be downloaded from 
the PCA pump after discharge from the hospital. 
MEDICAL OUTCOMES STUDY SHORT-FORM 36 HEALTH SURVEY (SF-36) is a 36-item measure of 
general health intended to capture quality of life, functional ability and well-being (mental and physical). 
The SF-36 will be administered pre-surgery, at discharge, 3-month and 6-month follow-up.  
BEST GUESS QUESTIONNAIRE will be used to determine how accurately patients, raters and tDCS 
operators were able to assess which treatment the patient received. This will assess our success in 
masking the sham treatments. Any time a guess-confidence rating is greater than 8 (on a 0 to 10 
numeric rating scale), the PI will follow-up with the participant and/or administrator in order to determine 
what factors contributed to this level confidence. If the guess is verified correct by the statistical support 
personnel and any valid systematic administrative factors are identified (e.g., the participant or tDCS 
administrator reports that the he/she overheard the device-masking assistant discussing the device 
configuration, accidentally viewed the randomization codes, or felt/heard some unique tDCS-induced 
sensations that led them to correctly guess the condition), the participant will remain enrolled in the 
study (and no feedback will be provided to the administrator or participant regarding whether the guess 
was correct in order to avoid providing information that may further jeopardize the blind in later 
subjects). The participant's data will be dropped from analyses and steps will be taken to correct the 
mask procedure. 
Table 1. Overview of the measurement schedule for the proposed study (POD=post-operative day) 
Measure 
Admission 
PACU 
POD-0 
POD-
1 
POD-2 
Discharge 
2-weeks 
4-weeks 
8-weeks 
3 months 
6-months 
BDI 
X 
 
 
 
 
X 
 
 
 
X 
X 
BAI 
X 
 
 
 
 
X 
 
 
 
X 
X 
BPI 
X 
 
 
 
 
X 
 
 
 
X 
X 
SF36 
X 
 
 
 
 
X 
 
 
 
X 
X 
PCA 
 
X 
X 
X 
X 
 
 
 
 
 
 
VAS 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
MPQ 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Pain Diary 
 
 
 
 
 
 
X 
X 
X 
 
 
Complications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ROM 
 
 
 
 
 
 
X 
X 
X 
 
 
LOS 
 
 
 
 
 
X 
 
 
 
 
 
 
Anesthesia/Surgical Measures and Procedures: Patients must be scheduled to receive unilateral total 
knee arthroplasty (total knee replacement) or unilateral total hip arthroplasty (total hip replacement) at 
the Ralph H. Johnson VAMC, to be done either cemented or cementless, either computer-assisted or 
conventional. The anatomical approach will be decided-upon by the surgeon based on clinical 
presentation, but procedure type and device manufacturer information will be recorded to permit 
statistical control for different procedural and device implications on post-operative pain. Preoperatively, 
patients will receive sedation of up to 2 mg of midazolam and 100 micrograms of fentanyl for their 
comfort during regional anesthesia block placement. A peripheral femoral nerve block catheter will be 
placed utilizing sterile technique (chloroprep, sterile glove and drape) and femoral nerve stimulation (< 
0.5mA) with or without under ultrasound guidance. A 20 ml bolus of  0.5% ropivacaine will be given 
through the block needle prior to nerve block catheter placement. The catheter will then be placed at a 
depth less than 5 cm passed the needle tip and secured to the skin using sterile occlussive dressings. 
The patient will also receive a single injection sciatic nerve block with a 20 ml bolus of 0.5% ropivacaine 
utilizing nerve stimulation (< 0.5 mA) with or without ultrasound guidance. Intraoperative management 

 
 
12 of  25 
Version 4, 05/08/2017 
 
will be standardized to a general anesthetic with laryngeal mask airway or endotracheal intubation 
(isoflurane, fentanyl (up to 250 mcg) and succinylcholine or vecuronium).  Reversal of neuromuscular 
blockade will be performed with neostigmine and glycopyrolate as required.  Intra-articular injection of 
local anesthetics or opioids will not be performed in any patient. The patients will be started on the 
patient controlled analgesia (PCA) pump for pain. The PCA will be discontinued on post-operative day-
2 at which time the patient will be transitioned to po pain medications (oxycodone). Surgery and 
anesthesia duration will be recorded and post-operative care will be standardized among all subjects as 
per standard VAMC clinical protocols. 
tDCS Electrode 
Placement: All 
participants will have 
an EEG 10-20 cap 
placed F3 will be 
marked with a non-
toxic felt-tipped pen. 
The tDCS anode will 
be placed over the 
mark (see figure 8) 
and the cathode will 
be placed over the 
right dorsolateral 
prefrontal cortex (F4). 
Electrodes will be held 
in place with Velcro 
straps. 
tDCS Methods: tDCS 
will be delivered in four 
20-minute-sessions 
(100 minutes total) 
and will be conducted with the Phoresor-II Auto (Model PM850, Iomed, Salt Lake City Utah, USA) using 
2mA current. This constant current device ramps up to the desired amplitude to minimize discomfort for 
participants and ramps the amplitude back to 0mA at the end of the programmed treatment duration. 
Electrodes will be standard small (4cm X 4cm) sponge electrodes soaked in a sterile solution of 0.9% 
sodium chloride insulated by a latex casing. The current density and total charge delivered by the 
above parameters is consistent with those used safely in the current research literature on tDCS. A 
very low dose (0.125mL) of topical benzocaine (6%) cream may be applied to the skin beneath the 
sponge electrodes for ~10 minutes and then removed if the participant experiences strong cutaneous 
sensations (patient report) during stimulation. After stimulation, a vitamin-E/Aloe cream will be applied 
to the skin under the electrodes following each treatment to reduce risks associated with skin drying.  
tDCS Dosing: Custom-developed software will be used to generate random number sequences and 
save them in a file-format readable by the tDCS blinding software. Participants will be randomized to 
one of four groups in order to assess the effects of total tDCS charge on post-operative pain. 
 
Group1 will receive a total of four 20-minute sessions of active 2mA tDCS (2 sessions on post- 
 
op day 0; and 2 sessions on post-op day 1) 
 
Group2: will receive a total of two 20-minute sessions of active 2mA tDCS (2 sessions on 
 
 post-op day 0; and 0 sessions on post-op day1) followed by 2 sessions of sham tDCS (both on 
 
post-op day 1). 
Figure 8. Trajectory of anodal stimulation associated with the proposed tDCS electrode placement strategy 

 
 
13 of  25 
Version 4, 05/08/2017 
 
 
Group3: will receive a only one 20-minute session of active tDCS on post-op day 0, followed by 
 
 three sessions of sham tDCS (1 on post-op day 0 and 3 on post-op day 1). 
 
Group4: will receive a total of four 20-minute sessions of sham tDCS (2 sessions on post-op day 
 
 0; and 2 sessions on post-op day 1) 
 
This dosing scheme will permit investigators to determine whether more stimulation over time is 
superior to less stimulation, as well as to determine the efficacy of motor tDCS in the management of 
perioperative pain. 
Blind Maintenance: To ensure blinding, specially-developed software will be utilized to switch the tDCS 
on and off without any intervention from the patient or experimenters. This will be controlled via a silent 
solid-state relay driven by an Ontrak ADU218 (Ontario, Canada). For Sham tDCS sessions the 
stimulator will be turned off following 45s. The initial sham stimulation mimics the transient scalp 
sensation that is perceived when the stimulator is initially switched on. The order of treatment 
administration will be encoded in the software so that the administrator only enters a patient number 
and a session-number to start stimulation without knowing whether those specific numbers area 
associated with active or sham tDCS. The double-blind may only be broken if the clinical presentation 
of the patient suggests potential cognitive dysfunction, seizure activity, severe headache or extreme 
skin irritation under the electrodes. 
Procedures and Flow: After determining eligibility and interest, written informed consent will be obtained 
from participants in the Orthpaedic Surgery Pre-operative clinic. Participants will complete the 
screening questionnaires and all questions about the study procedures, risks, and benefits will be 
answered. On the day of surgery, the corresponding Admission questionnaires will be completed. After 
surgery, participants will be transferred to the post-anesthesia care unit (PACU), awakened, and be 
hooked-up to standard clinical physiological monitors. Patients will be started on a PCA pump. 
Pain/mood ratings will be collected and the EEG 10-20 caps will be placed. The anode and cathode 
placement positions will be marked and the caps will be removed. Sponge electrodes will be soaked in 
saline, affixed in their rubber electrode casings, attached to the tDCS machine, placed on the scalp, 
and held in place with Velcro straps. The participant's study ID number and tDCS session number will 
be entered into the tDCS controller software, linked to the randomization file, and the stimulation 
session will begin (double-blind). After 20-minutes, the electrodes will be removed and pain/mood 
ratings will be collected again. Four hours later, the tDCS procedures will be repeated in the 
participants' hospital room. On post-op day-1, two tDCS sessions will be conducted separated by at 
least 3 hours. Pain and mood ratings will be collected before and after each tDCS session. Range of 
motion measurements will be collected before and after each physical therapy session. On the day of 
discharge, participants will complete the Discharge questionnaire packet. Total length of stay, and post-
surgical complications will be recorded. At all follow-up time-points, participants will complete the 
corresponding measures and opioid use status will be tracked via patient report and verified via chart 
review. 
Statistical Analysis and Power: The orthopaedic surgeons at the Ralph H. Johnson VAMC conduct 
~100 unilateral total knee arthroplasties and ~50 unilateral total hip arthroplasties each year . Thus, in 
order to meet the proposed n-size of the current study, 24 (out of 100) participants will need to be 
eligible and interested in participating in the trial each year. We will over recruit to permit for drop-outs 
and participants lost to follow-up. For analysis of primary outcomes associated with Aim-1, participants 
receiving any active tDCS (groups 1,2 & 3) will be collapsed and compared to the sham-only group. 
Multivariate multiple regression will be used with group-assignment entered into the model as a binary 
predictor. Surgery and anesthesia duration, depression & anxiety scores, sex, age, pre-tDCS pain, 
(ROM) Means and pre-op chronic opioid status will be entered into the model as covariates to permit 
for statistical control of these potentially confounding variables. Overall differences between real and 

 
 
14 of  25 
Version 4, 05/08/2017 
 
sham tDCS groups will then be examined for our primary outcomes: total post-op PCA morphine-
equivalent dose, VAS pain-on-average ratings, and mean number of post-operative complications. 
Using the most conservative effect-size estimate from our series of pilot studies (d=.70), with 90 
patients in the active tDCS group and 30 in the active-sham group, power is good to detect significant 
effects if they exist (alpha=.016 (corrected for multiple DV's); 1-ß >.80; see figure 9). For Aim-2, 
MANCOVA will be conducted using all 4 groups and all primary dependent measures in the same 
model (controlling for surgery and anesthesia duration, depression & anxiety scores, pre-tDCS pain, 
physical rehab measures and chronic opioid status). With four groups of 30 patients each, assuming a 
moderate effect size f2(V)=.2, and alpha of .05, power is good detect significant main effects in the 
model (1-ß >.80). Secondary analyses will be conducted to evaluate long-term effects of tDCS on pain, 
functioning and quality of life (i.e., 2-wk, 4-wk, 8-wk, 3-month and 6 month-follow-up). 
Problems/Challenges/Potential Pitfalls: The proposed tDCS device is an FDA-approved iontopohoresis 
device, and its use for tDCS applications is off-label. The tDCS procedure is minimal-risk and FDA-
approval for tDCS 
applications using this 
device is not necessary. 
The PI has received MUSC 
IRB-approval for conducting 
tDCS in the perioperative 
setting and thus there are 
limited concerns about 
receiving approval to 
conduct the proposed 
research at the Ralph H. 
Johnson VAMC. 
Competing Trials Locally or 
Nationally and Distinction: 
The PI has an ongoing NIH-
funded clinical trial of tDCS 
for post-operative pain at 
MUSC. However, that trial is 
focused on optimal cortical targets for stimulation (not dosing) and does not involve the veteran 
population. The proposed study will be on veterans and will focus on dose-dependent effects of tDCS 
on post-operative pain and post-surgical recovery. 
Impact on Clinical Practice and Future Studies: If positive, this high-quality clinical trial could shift the 
paradigm of post-operative pain management to take advantage of recent neuroscience developments. 
Findings from this study will be used to evaluate the necessity for a multi-site clinical trial, and to 
develop future cross-surgical-specialty studies. 
This study will be the first randomized, double-blind, controlled study of tDCS technology as an 
adjunctive pain management strategy for post-operative pain. Data from this trial will likely yield 
information regarding the feasibility and efficacy of tDCS as a post-operative pain-management 
approach. If the proposed pilot trial suggests significant and meaningful effects of tDCS as an 
adjunctive post-operative pain management strategy, this might change the way post-operative pain 
management is approached in the future. Findings from this study will be used to evaluate the 
necessity for an even larger-scale, multi-site clinical trial of the technique, and to determine whether 
future investigations of tDCS across different surgical specialties might be warranted. 
Figure 9. Power by sample-size for primary aim of the proposed study (Aim-1 target n-size = 90 patients) 

 
 
15 of  25 
Version 4, 05/08/2017 
 
 
E. PROTECTION OF HUMAN SUBJECTS________________________________________________________ 
 
E.1. Risks to subjects 
Human Subjects Involvement and Characteristics 
 
Subjects will be 120 patients undergoing TKA and THA surgery at the Ralph H. Johnson VAMC.  
Inclusion/Exclusion Criteria 
 
1) Between the ages of 25 and 90 
2) No implanted medical devices above the waist 
3) Mentally capable of reading, writing, giving consent, and following instructions 
4) Not pregnant 
5) Cleared for and scheduled for TKA or THA surgery 
6) No history of seizures 
7) Not allergic to latex rubber 
 
Sources of Material 
 
Participants will be enrolled in the study during their hospital stay for TKA or THA and for the following 6 
month follow-up period. Data will be psychosocial, pain and behavioral ratings, medical surgical outcomes and 
PCA opioid use. All data will be collected by the study investigators, clinicians and the research team.  
 
Potential Risks 
 
The risks associated with tDCS are minimal. There is no documented risk of seizure associated with 
tDCS, but participants with a history of seizure disorder will be excluded to ensure optimum safety. Side effects 
associated with tDCS include mild headache, tingling, itching, or stinging under the electrodes, and skin irritation. 
The effect-size of tDCS for post-operative pain appears to be moderate and therefore does not eliminate pain 
entirely. Nonetheless, if a participant experiences total analgesia via tDCS (which is believed to be an extremely 
unlikely occurrence as it has never been reported in any of the 1000+ participants who have received tDCS for 
pain control around the world), it is possible that they might not receive signals indicating over-extension or over-
use of their knee(s) after surgery and might incur damage in the joint(s). 
 
Safety in case of pregnancy:  
 
Pregnant women will be excluded from the proposed research. 
 
Risks regarding Confidentiality 

 
 
16 of  25 
Version 4, 05/08/2017 
 
 
Despite efforts to maintain subjects’ anonymity and confidentiality, there is always some minimal 
risk of people other than the study investigators gaining access to subjects’ information. Every effort will 
be made to ensure that subject information will be collected and stored in a manner that ensures the 
highest level of protection of confidentiality.  
 
E.2. Adequacy of Procedures for Protecting and Minimizing Risk: 
 
Recruitment and Informed Consent 
Patients scheduled to undergo TKA or THA surgery at the Ralph H. Johnson VAMC will be 
recruited during their pre-operative visit in the Orthopedic Surgery Clinic. A letter of invitation will be 
mailed to perspective participants whom medical staff on the study feel may be eligible to participate in 
the approved research. These prospective subjects that will receive letters will be identified through 
clinic referrals from the Ralph H. Johnson VA in Charleston, Sc. A HIPAA waiver of authorization will be 
on file with the IRB giving the research team permission send IRB approved generic letters of invitation 
to perspective participants. Written-informed consent will be obtained during this pre-op visit. 
 
Protection against Risks 
There are 3 areas in which safeguards to protect subjects from undue risk require discussion.  These include 
the procedures used to obtain informed consent, the procedures used to ensure confidentiality of the subjects’ data, 
and the procedures used to minimize possible risks associated with the laboratory procedures. 
Informed Consent. In the consent forms and discussions with an investigator, subjects are advised fully of 
the procedures to be used, the amount of time required of them, the research procedures that will be conducted, 
the possible risks and benefits of the procedures, their right to refuse participation in the study without prejudice, 
their right to terminate participation at any moment without prejudice, and the name and telephone number of the 
Principal Investigator. All subjects will be required to have capacity to consent. 
Confidentiality of Subjects’ Responses. In the informed consent form, subjects are told that the information 
they provide and all findings will be kept strictly confidential, with access limited to the research staff and the 
possible exception of state or federal regulatory personnel. No one but the project staff has access to the master list 
linking subjects’ names to code numbers, and all information obtained is coded.  The respective master lists are 
kept under strict lock and key.   
Research Procedures. We have described above the potential risks of the research procedures. If the 
subject shows deterioration in their clinical status, we will stop him/her from proceeding in the study, and 
coordinate appropriate care with a physician at the Ralph H. Johnson VAMC.  
Participation in the study will be treated as confidential, as will all records. We will protect the identity of 
our subjects by keeping the data in file cabinets in the PI’s locked office, to which only they have a key and by 
storing electronic data on secure servers designed for use and access by Brain Stimulation Lab members only.  
Data and Safety Monitoring Board. Dr. Borckardt will choose a group of faculty at the VAMC to monitor 
the data on a bi-annual basis with respect to subject safety issues throughout the award period. 
 
 
E.3. Potential benefits of the proposed research to the subjects and others 
 
Participants will receive little clinical benefit from participating in the study although if they are 
randomized to a real tDCS group, there is a chance that they will experience less pain than if they had 
been randomized to a sham group. 
 

 
 
17 of  25 
Version 4, 05/08/2017 
 
E.4. Importance of the knowledge to be gained 
 
The proper control of acute and chronic pain is one of the most important areas of health care. Despite 
the profound advances in neuroscience over the past 20 years, we still largely use opiate narcotics for pain 
control. Total joint replacement procedures involving the knees and hips are some of the most common 
orthopedic procedures performed. Because the prevalence of arthritis is expected to grow substantially as the 
population ages, these procedures are likely to become even more common. Adequate postoperative pain control 
is an important factor in determining recovery time and hospital length of stay. Primary methods used to manage 
post-operative pain in general involve systemic opioid or other analgesic drug delivery and regional blocks. 
Despite these pain-management strategies, patients still report considerable post-operative pain, and often 
struggle to complete post-operative physical therapy regimens. Further, systemic opioid analgesic use, has 
associated side-effects that can lead to post-operative complications including but not limited to mental-clouding, 
confusion, respiratory depression, interactions with other medications, addiction in some cases, fatigue, and 
gastric motility problems. New analgesic strategies are needed that can be used adjunctively to existing strategies 
with the potential to reduce reliance on opioid analgesia. In two independent pilot studies, the investigators have 
shown that tDCS can reduce post-operative PCA use by as much as 46% while simultaneously reducing 
subjective pain ratings. Thus, there appears to be potential analgesic effects of tDCS for post-procedural and 
post-operative pain. If it proves to be beneficial, this technique could revolutionize current methods for post-
operative pain management. 
Total Planned Enrollment: 120 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
4 
2 
6 
Not Hispanic or Latino 
66 
48 
114 
Ethnic Category: Total of All Subjects* 
120 
Racial Categories 
 
American Indian/Alaska Native 
1 
1 
2 
Asian 
4 
2 
6 
Native Hawaiian or Other Pacific Islander 
1 
1 
2 
Black or African American 
24 
16 
40 
White 
40 
30 
70 
Racial Categories: Total of All Subjects* 
 
 
120 
 
 
 
 
* The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All Subjects.” 
 
 
F. REFERENCES/LITERATURE CITATIONS______________________________________________________ 

 
 
18 of  25 
Version 4, 05/08/2017 
 
List all references. Each reference must include the title, names of all authors, book or journal, volume number, 
page numbers, and year of publication. The reference should be limited to relevant and current literature. It is 
important to be concise and to select only those literature references pertinent to the proposed research. 

 
 
19 of  25 
Version 4, 05/08/2017 
 
 
Literature Cited 
1. 
Orthopedic_Network_News, Hip and Knee Implant Review. CMS MedPar, 2002. pmc-id:  
2. 
Acheson, R.M. and A.B. Collart, New Haven survey of joint diseases. XVII. Relationship between some 
systemic characteristics and osteoarthrosis in a general population. Ann Rheum Dis, 1975. 34(5): p. 379-
387. pmc-id: 1006437 
3. 
Peyron, J., Osteoarthritis. The epidemiologic viewpoint. Clin Orthrop, 1986. 213: p. 13-19. pmc-id:  
4. 
Capdevila, X., Y. Barthelet, P. Biboulet, et al., Effects of perioperative analgesic technique on the surgical 
outcome and duration of rehabilitation after major knee surgery. Anesthesiology, 1999. 91(1): p. 8-15. 
pmc-id:  
5. 
Chelly, J.E., J. Greger, R. Gebhard, et al., Continuous femoral blocks improve recovery and outcome of 
patients undergoing total knee arthroplasty. J Arthroplasty, 2001. 16(4): p. 436-445. pmc-id:  
6. 
Wang, H., B. Boctor, and J. Verner, The effect of single-injection femoral nerve block on rehabilitation and 
length of hospital stay after total knee replacement. Reg Anesth Pain Med, 2002. 27(2): p. 139-144. pmc-
id:  
7. 
Deo, H., G. West, C. Butcher, et al., The prevalence of cognitive dysfunction after conventional and 
computer-assisted total knee replacement. Knee. pmc-id:  
8. 
Talmo, C.T., C.E. Robbins, and J.V. Bono, Total joint replacement in the elderly patient. Clin Geriatr Med. 
26(3): p. 517-529. pmc-id:  
9. 
Samson, A.J., G.E. Mercer, and D.G. Campbell, Total knee replacement in the morbidly obese: a 
literature review. ANZ J Surg. 80(9): p. 595-599. pmc-id:  
10. 
Fregni, F., S. Freedman, and A. Pascual-Leone, Recent advances in the treatment of chronic pain with 
non-invasive brain stimulation techniques. Lancet Neurol, 2007. 6(2): p. 188-191. pmc-id:  
11. 
Rosen, A.C., M. Ramkumar, T. Nguyen, et al., Noninvasive transcranial brain stimulation and pain. Curr 
Pain Headache Rep, 2009. 13(1): p. 12-17. pmc-id: 2697608 
12. 
Williams, J.A., M. Imamura, and F. Fregni, Updates on the use of non-invasive brain stimulation in 
physical and rehabilitation medicine. J Rehabil Med, 2009. 41(5): p. 305-311. pmc-id:  
13. 
George, M.S., Z. Nahas, F.A. Kozol, et al., Mechanisms and the current state of transcranial magnetic 
stimulation. CNS Spectr, 2003. 8(7): p. 496-514. pmc-id:  
14. 
Barker, A., I. Freeston, J. Jarratt, et al., Magnetic stimulation of the human nervous system: an 
introduction and basic principles, in Magnetic Stimulation in Clinical Neurophysiology, C. S, Editor. 1989, 
Butterworth: Boston. p. 55-72. 
15. 
Barker, A.T., R. Jalinous, and I.L. Freeston, Non-invasive magnetic stimulation of human motor cortex. 
Lancet, 1985. 1(8437): p. 1106-1107. pmc-id:  
16. 
Knotkova, H. and R.A. Cruciani, Non-invasive transcranial direct current stimulation for the study and 
treatment of neuropathic pain. Methods Mol Biol. 617: p. 505-515. pmc-id:  
17. 
Mori, F., C. Codeca, H. Kusayanagi, et al., Effects of Anodal Transcranial Direct Current Stimulation on 
Chronic Neuropathic Pain in Patients With Multiple Sclerosis. J Pain, 2009. pmc-id:  

 
 
20 of  25 
Version 4, 05/08/2017 
 
18. 
Boggio, P.S., E.J. Amancio, C.F. Correa, et al., Transcranial DC stimulation coupled with TENS for the 
treatment of chronic pain: a preliminary study. Clin J Pain, 2009. 25(8): p. 691-695. pmc-id:  
19. 
Boggio, P.S., S. Zaghi, and F. Fregni, Modulation of emotions associated with images of human pain 
using anodal transcranial direct current stimulation (tDCS). Neuropsychologia, 2009. 47(1): p. 212-217. 
pmc-id:  
20. 
Boggio, P.S., S. Zaghi, M. Lopes, et al., Modulatory effects of anodal transcranial direct current 
stimulation on perception and pain thresholds in healthy volunteers. Eur J Neurol, 2008. 15(10): p. 1124-
1130. pmc-id:  
21. 
Antal, A., N. Brepohl, C. Poreisz, et al., Transcranial direct current stimulation over somatosensory cortex 
decreases experimentally induced acute pain perception. Clin J Pain, 2008. 24(1): p. 56-63. pmc-id:  
22. 
Roizenblatt, S., F. Fregni, R. Gimenez, et al., Site-specific effects of transcranial direct current stimulation 
on sleep and pain in fibromyalgia: a randomized, sham-controlled study. Pain Pract, 2007. 7(4): p. 297-
306. pmc-id:  
23. 
Fregni, F., D. DaSilva, K. Potvin, et al., Treatment of chronic visceral pain with brain stimulation. Ann 
Neurol, 2005. 58(6): p. 971-972. pmc-id:  
24. 
Fregni, F., R. Gimenes, A.C. Valle, et al., A randomized, sham-controlled, proof of principle study of 
transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum, 2006. 
54(12): p. 3988-3998. pmc-id:  
25. 
Avery, D.H., P.E. Holtzheimer, 3rd, W. Fawaz, et al., Transcranial magnetic stimulation reduces pain in 
patients with major depression: a sham-controlled study. J Nerv Ment Dis, 2007. 195(5): p. 378-381. pmc-
id:  
26. 
Borckardt, J., S. Reeves, and M. George, The potential role of brain stimulation in the management of 
postoperative pain. Journal of Pain Management, 2009. 2(3): p. 295-300. pmc-id:  
27. 
Borckardt, J.J., S.T. Reeves, M. Weinstein, et al., Significant analgesic effects of one session of 
postoperative left prefrontal cortex repetitive transcranial magnetic stimulation: A replication study. Brain 
Stimulat, 2008. 1(2): p. 122-127. pmc-id: 2744083 
28. 
Borckardt, J.J., A.R. Smith, S.T. Reeves, et al., A pilot study investigating the effects of fast left prefrontal 
rTMS on chronic neuropathic pain. Pain Med, 2009. 10(5): p. 840-849. pmc-id:  
29. 
Borckardt, J.J., A.R. Smith, S.T. Reeves, et al., Fifteen minutes of left prefrontal repetitive transcranial 
magnetic stimulation acutely increases thermal pain thresholds in healthy adults. Pain Res Manag, 2007. 
12(4): p. 287-290. pmc-id: 2670740 
30. 
Borckardt, J.J., M. Weinstein, S.T. Reeves, et al., Post-Operative Left Prefrontal Repetitive Transcranial 
Magnetic Stimulation (rTMS) Reduces Patient-Controlled Analgesia Use Anesthesiology, 2006. 105: p. 
557-562. pmc-id:  
31. 
Morgan, D., K. Forst-Pineda, and M. Gold, Medical and nonmedical use of prescription opioids: 
Epidemiology and Prevalence. Psychiatric Annals, 2006. 36(6): p. 404-409. pmc-id:  
32. 
Alam, A., T. Gomes, H. Zheng, et al., Long-term analgesic use after low-risk surgery: a retrospective 
cohort study. Arch Intern Med. 172(5): p. 425-430. pmc-id:  
33. 
Greer, S.M., J.A. Dalton, J. Carlson, et al., Surgical patients' fear of addiction to pain medication: the 
effect of an educational program for clinicians. Clin J Pain, 2001. 17(2): p. 157-164. pmc-id:  

 
 
21 of  25 
Version 4, 05/08/2017 
 
34. 
Compton, W.M. and N.D. Volkow, Major increases in opioid analgesic abuse in the United States: 
concerns and strategies. Drug Alcohol Depend, 2006. 81(2): p. 103-107. pmc-id:  
35. 
Kehlet, H., M. Werner, and F. Perkins, Balanced analgesia: what is it and what are its advantages in 
postoperative pain? Drugs, 1999. 58(5): p. 793-797. pmc-id:  
36. 
Dowman, R., G. Glebus, and L. Shinners, Effects of response conflict on pain-evoked medial prefrontal 
cortex activity. Psychophysiology, 2005. 42(5): p. 555-558. pmc-id:  
37. 
Ginandes, C., P. Brooks, W. Sando, et al., Can medical hypnosis accelerate post-surgical wound 
healing? Results of a clinical trial. Am J Clin Hypn, 2003. 45(4): p. 333-351. pmc-id:  
38. 
Montgomery, G.H., C.R. Weltz, M. Seltz, et al., Brief presurgery hypnosis reduces distress and pain in 
excisional breast biopsy patients. Int J Clin Exp Hypn, 2002. 50(1): p. 17-32. pmc-id:  
39. 
Good, M., G.C. Anderson, S. Ahn, et al., Relaxation and music reduce pain following intestinal surgery. 
Res Nurs Health, 2005. 28(3): p. 240-251. pmc-id:  
40. 
Voss, J.A., M. Good, B. Yates, et al., Sedative music reduces anxiety and pain during chair rest after 
open-heart surgery. Pain, 2004. 112(1-2): p. 197-203. pmc-id:  
41. 
Cheung, Y.L., A. Molassiotis, and A.M. Chang, A pilot study on the effect of progressive muscle relaxation 
training of patients after stoma surgery. Eur J Cancer Care (Engl), 2001. 10(2): p. 107-114. pmc-id:  
42. 
Cheung, Y.L., A. Molassiotis, and A.M. Chang, The effect of progressive muscle relaxation training on 
anxiety and quality of life after stoma surgery in colorectal cancer patients. Psychooncology, 2003. 12(3): 
p. 254-266. pmc-id:  
43. 
Feldman, J.B., The neurobiology of pain, affect and hypnosis. Am J Clin Hypn, 2004. 46(3): p. 187-200. 
pmc-id:  
44. 
Feldman, M., M. MacCulloch, J. Orford, et al., The application of anticipatory avoidance learning to the 
treatment of homosexuality. Developments in treatment technique and response recording. Acta 
Psychiatr Scand, 1969. 45(2): p. 109-117. pmc-id:  
45. 
Gatchel, R.J., Y.B. Peng, M.L. Peters, et al., The biopsychosocial approach to chronic pain: scientific 
advances and future directions. Psychol Bull, 2007. 133(4): p. 581-624. pmc-id:  
46. 
Treede, R.D., D.R. Kenshalo, R.H. Gracely, et al., The cortical representation of pain. Pain, 1999. 79(2-3): 
p. 105-111. pmc-id:  
47. 
Greer, K.R. and J.W. Hoyt, Pain: theory, anatomy, and physiology. Crit Care Clin, 1990. 6(2): p. 227-234. 
pmc-id:  
48. 
Crue, B.L., B. Kenton, and E.J. Carregal, Neurophysiology of pain-peripheral aspects. Speculation 
concerning the possibility of a unitary peripheral cutaneous input system for pressure, hot, cold and tissue 
damage. Bull Los Angeles Neurol Soc, 1976. 41(1): p. 13-42. pmc-id:  
49. 
Dyck, P.J., E.H. Lambert, and P.C. O'Brien, Pain in peripheral neuropathy related to rate and kind of fiber 
degeneration. Neurology, 1976. 26(5): p. 466-471. pmc-id:  
50. 
Staud, R., M.E. Robinson, C.J. Vierck, Jr., et al., Ratings of experimental pain and pain-related negative 
affect predict clinical pain in patients with fibromyalgia syndrome. Pain, 2003. 105(1-2): p. 215-222. pmc-
id:  

 
 
22 of  25 
Version 4, 05/08/2017 
 
51. 
Burns, J.W., A. Kubilus, and E. Michael, Cognitive-Behavioral Factors in the Management of Chronic Low 
Back Pain: Conceptualization and Evidence of Treatment Efficacy. Curr Rev Pain, 1999. 3(4): p. 300-307. 
pmc-id:  
52. 
Giardino, N.D., M.P. Jensen, J.A. Turner, et al., Social environment moderates the association between 
catastrophizing and pain among persons with a spinal cord injury. Pain, 2003. 106(1-2): p. 19-25. pmc-id:  
53. 
Atkinson, J.H., M.A. Slater, D.R. Wahlgren, et al., Effects of noradrenergic and serotonergic 
antidepressants on chronic low back pain intensity. Pain, 1999. 83(2): p. 137-145. pmc-id:  
54. 
Brooks, J.C., T.J. Nurmikko, W.E. Bimson, et al., fMRI of thermal pain: effects of stimulus laterality and 
attention. Neuroimage, 2002. 15(2): p. 293-301. pmc-id:  
55. 
Davis, K.D., Neurophysiological and anatomical considerations in functional imaging of pain. Pain, 2003. 
105(1-2): p. 1-3. pmc-id:  
56. 
Lorenz, J., S. Minoshima, and K.L. Casey, Keeping pain out of mind: the role of the dorsolateral prefrontal 
cortex in pain modulation. Brain, 2003. 126(Pt 5): p. 1079-1091. pmc-id:  
57. 
Seminowicz, D.A. and K.D. Davis, Cortical responses to pain in healthy individuals depends on pain 
catastrophizing. Pain, 2006. 120(3): p. 297-306. pmc-id:  
58. 
Theunissen, M., M.L. Peters, J. Bruce, et al., Preoperative Anxiety and Catastrophizing: A Systematic 
Review and Meta-analysis of the Association With Chronic Postsurgical Pain. Clin J Pain. pmc-id:  
59. 
Zubieta, J.K., J.A. Bueller, L.R. Jackson, et al., Placebo effects mediated by endogenous opioid activity 
on mu-opioid receptors. J Neurosci, 2005. 25(34): p. 7754-7762. pmc-id:  
60. 
Wager, T.D., J.K. Rilling, E.E. Smith, et al., Placebo-induced changes in FMRI in the anticipation and 
experience of pain. Science, 2004. 303(5661): p. 1162-1167. pmc-id:  
61. 
Tsubokawa, T., Y. Katayama, T. Yamamoto, et al., Treatment of thalamic pain by chronic motor cortex 
stimulation. Pacing Clin Electrophysiol, 1991. 14(1): p. 131-134. pmc-id:  
62. 
Tsubokawa, T., Y. Katayama, T. Yamamoto, et al., Chronic motor cortex stimulation for the treatment of 
central pain. Acta Neurochir Suppl (Wien), 1991. 52: p. 137-139. pmc-id:  
63. 
Lefaucheur, J.P., G. Jarry, X. Drouot, et al., Motor cortex rTMS reduces acute pain provoked by laser 
stimulation in patients with chronic neuropathic pain. Clin Neurophysiol. 121(6): p. 895-901. pmc-id:  
64. 
Peyron, R., I. Faillenot, P. Mertens, et al., Motor cortex stimulation in neuropathic pain. Correlations 
between analgesic effect and hemodynamic changes in the brain. A PET study. Neuroimage, 2007. 
34(1): p. 310-321. pmc-id:  
65. 
Garcia-Larrea, L. and R. Peyron, Motor cortex stimulation for neuropathic pain: From phenomenology to 
mechanisms. Neuroimage, 2007. 37 Suppl 1: p. S71-79. pmc-id:  
66. 
George, M.S., Z. Nahas, F.A. Kozel, et al., Mechanisms and state of the art of transcranial magnetic 
stimulation. J Ect, 2002. 18(4): p. 170-181. pmc-id:  
67. 
Roth, B.J., S. Momen, and R. Turner, Algorithm for the design of magnetic stimulation coils. Med & Biol 
Eng & Comput, 1994. 32: p. 214-216. pmc-id:  
68. 
Stanton, P.K. and T.J. Sejnowski, Associative long-term depression in the hippocampus induced by 
hebbian covariance. Nature, 1989. 339(6221): p. 215-218. pmc-id:  

 
 
23 of  25 
Version 4, 05/08/2017 
 
69. 
Malenka, R.C. and R.A. Nicoll, Long-term potentiation--a decade of progress? Science, 1999. 285(5435): 
p. 1870-1874. pmc-id:  
70. 
Wang, H., X. Wang, and H. Scheich, LTD and LTP induced by transcranial magnetic stimulation in 
auditory cortex. Neuroreport, 1996. 7(2): p. 521-525. pmc-id:  
71. 
Wassermann, E.M. and J. Grafman, Recharging cognition with DC brain polarization. Trends Cogn Sci, 
2005. 9(11): p. 503-505. pmc-id:  
72. 
Lefaucheur, J.P., X. Drouot, Y. Keravel, et al., Pain relief induced by repetitive transcranial magnetic 
stimulation of precentral cortex. Neuroreport, 2001. 12(13): p. 2963-2965. pmc-id:  
73. 
George, M.S. and E.M. Wassermann, Rapid-rate transcranial magnetic stimulation and ECT. Convuls 
Ther, 1994. 10(4): p. 251-254; discussion 255-258. pmc-id:  
74. 
Wagner, T., F. Fregni, and S. Fecteau, Transcranial direct current stimulation: a computer based human 
model study. Neuroimage, 2007. 35: p. 1113-1124. pmc-id:  
75. 
Wagner, T., A. Valero-Cabre, and A. Pascual-Leone, Noninvasive human brain stimulation. Annu Rev 
Biomed Eng, 2007. 9: p. 527-565. pmc-id:  
76. 
Miranda, P.C., M. Lomarev, and M. Hallett, Modeling the current distribution during transcranial direct 
current stimulation. Clin Neurophysiol, 2006. 117(7): p. 1623-1629. pmc-id:  
77. 
Nitsche, M.A. and W. Paulus, Sustained excitability elevations induced by transcranial DC motor cortex 
stimulation in humans. Neurology, 2001. 57(10): p. 1899-1901. pmc-id:  
78. 
Nitsche, M.A., L.G. Cohen, E.M. Wassermann, et al., Transcranial direct current stimulation: State of the 
art 2008. Brain Stimul, 2008. 1(3): p. 206-223. pmc-id:  
79. 
Antal, A., T.Z. Kincses, M.A. Nitsche, et al., Manipulation of phosphene thresholds by transcranial direct 
current stimulation in man. Exp Brain Res, 2003. 150(3): p. 375-378. pmc-id:  
80. 
Lang, N., H.R. Siebner, Z. Chadaide, et al., Bidirectional modulation of primary visual cortex excitability: a 
combined tDCS and rTMS study. Invest Ophthalmol Vis Sci, 2007. 48(12): p. 5782-5787. pmc-id:  
81. 
Migita, K., T. Uozumi, K. Arita, et al., Transcranial magnetic coil stimulation of motor cortex in patients 
with central pain. Neurosurgery, 1995. 36(5): p. 1037-1039; discussion 1039-1040. pmc-id:  
82. 
Tamura, Y., S. Okabe, T. Ohnishi, et al., Effects of 1-Hz repetitive transcranial magnetic stimulation on 
acute pain induced by capsaicin. Pain, 2004. 107(1-2): p. 107-115. pmc-id:  
83. 
Rollnik, J.D., S. Wustefeld, J. Dauper, et al., Repetitive transcranial magnetic stimulation for the treatment 
of chronic pain - a pilot study. Eur Neurol, 2002. 48(1): p. 6-10. pmc-id:  
84. 
Pleger, B., F. Janssen, P. Schwenkreis, et al., Repetitive transcranial magnetic stimulation of the motor 
cortex attenuates pain perception in complex regional pain syndrome type I. Neurosci Lett, 2004. 356(2): 
p. 87-90. pmc-id:  
85. 
Lefaucheur, J.P., X. Drouot, and J.P. Nguyen, Interventional neurophysiology for pain control: duration of 
pain relief following repetitive transcranial magnetic stimulation of the motor cortex. Neurophysiol Clin, 
2001. 31(4): p. 247-252. pmc-id:  
86. 
Lefaucheur, J.P., X. Drouot, I. Menard-Lefaucheur, et al., Neurogenic pain relief by repetitive transcranial 
magnetic cortical stimulation depends on the origin and the site of pain. J Neurol Neurosurg Psychiatry, 
2004. 75(4): p. 612-616. pmc-id: 1739005 

 
 
24 of  25 
Version 4, 05/08/2017 
 
87. 
Canavero, S. and V. Bonicalzi, Central pain syndrome: elucidation of genesis and treatment. Expert Rev 
Neurother, 2007. 7(11): p. 1485-1497. pmc-id:  
88. 
Khedr, E.M., H. Kotb, N.F. Kamel, et al., Longlasting antalgic effects of daily sessions of repetitive 
transcranial magnetic stimulation in central and peripheral neuropathic pain. J Neurol Neurosurg 
Psychiatry, 2005. 76(6): p. 833-838. pmc-id: 1739662 
89. 
Borckardt, J.J., S.T. Reeves, W. Beam, et al., A Randomized, Controlled Investigation of Motor Cortex 
Transcranial Magnetic Stimulation (TMS) Effects on Quantitative Sensory Measures in Healthy Adults: 
Evaluation of TMS Device Parameters. Clin J Pain. pmc-id:  
90. 
Nitsche, M.A., A. Seeber, K. Frommann, et al., Modulating parameters of excitability during and after 
transcranial direct current stimulation of the human motor cortex. J Physiol, 2005. 568(Pt 1): p. 291-303. 
pmc-id: PMC1474757 
91. 
Antal, A., D. Terney, S. Kuhnl, et al., Anodal transcranial direct current stimulation of the motor cortex 
ameliorates chronic pain and reduces short intracortical inhibition. J Pain Symptom Manage. 39(5): p. 
890-903. pmc-id:  
92. 
Lavoie, B.A., H. Devanne, and C. Capaday, Differential control of reciprocal inhibition during walking 
versus postural and voluntary motor tasks in humans. J Neurophysiol, 1997. 78(1): p. 429-438. pmc-id:  
93. 
Devanne, H., B.A. Lavoie, and C. Capaday, Input-output properties and gain changes in the human 
corticospinal pathway. Exp Brain Res, 1997. 114(2): p. 329-338. pmc-id:  
94. 
Ridding, M.C. and J.C. Rothwell, Stimulus/response curves as a method of measuring motor cortical 
excitability in man. Electroencephalogr Clin Neurophysiol, 1997. 105(5): p. 340-344. pmc-id:  
95. 
Bachmann, C.G., S. Muschinsky, M.A. Nitsche, et al., Transcranial direct current stimulation of the motor 
cortex induces distinct changes in thermal and mechanical sensory percepts. Clin Neurophysiol. pmc-id:  
96. 
Jurgens, T.P., A. Schulte, T. Klein, et al., Transcranial direct current stimulation does neither modulate 
results of a quantitative sensory testing protocol nor ratings of suprathreshold heat stimuli in healthy 
volunteers. Eur J Pain. 16(9): p. 1251-1263. pmc-id:  
97. 
Borckardt, J.J., M. Bikson, H. Frohman, et al., A pilot study of the tolerability and effects of high-definition 
transcranial direct current stimulation (HD-tDCS) on pain perception. J Pain. 13(2): p. 112-120. pmc-id:  
98. 
Johnson, S., J. Summers, and S. Pridmore, Changes to somatosensory detection and pain thresholds 
following high frequency repetitive TMS of the motor cortex in individuals suffering from chronic pain. 
Pain, 2006. 123(1-2): p. 187-192. pmc-id:  
99. 
Leo, R.J. and T. Latif, Repetitive transcranial magnetic stimulation (rTMS) in experimentally induced and 
chronic neuropathic pain: a review. J Pain, 2007. 8(6): p. 453-459. pmc-id:  
100. 
Craig, A.D., K. Chen, D. Bandy, et al., Thermosensory activation of insular cortex. Nat Neurosci, 2000. 
3(2): p. 184-190. pmc-id:  
101. 
Davis, K.D., C.L. Kwan, A.P. Crawley, et al., Functional MRI study of thalamic and cortical activations 
evoked by cutaneous heat, cold, and tactile stimuli. J Neurophysiol, 1998. 80(3): p. 1533-1546. pmc-id:  
102. 
Borckardt, J.J., J. Romagnuolo, S.T. Reeves, et al., Feasibility, safety, and effectiveness of transcranial 
direct current stimulation for decreasing post-ERCP pain: a randomized, sham-controlled, pilot study. 
Gastrointest Endosc. 73(6): p. 1158-1164. pmc-id:  
103. 
Taylor, R., P.F. Lovibond, M.K. Nicholas, et al., The utility of somatic items in the assessment of 
depression in patients with chronic pain: a comparison of the Zung Self-Rating Depression Scale and the 

 
 
25 of  25 
Version 4, 05/08/2017 
 
Depression Anxiety Stress Scales in chronic pain and clinical and community samples. Clin J Pain, 2005. 
21(1): p. 91-100. pmc-id:  
104. 
Faravelli, C., G. Albanesi, and E. Poli, Assessment of depression: a comparison of rating scales. J Affect 
Disord, 1986. 11(3): p. 245-253. pmc-id:  
105. 
Tanaka-Matsumi, J. and V.A. Kameoka, Reliabilities and concurrent validities of popular self-report 
measures of depression, anxiety, and social desirability. J Consult Clin Psychol, 1986. 54(3): p. 328-333. 
pmc-id:  
106. 
Gould, J., A psychometric investigation of the standard and short form Beck Depression Inventory. 
Psychol Rep, 1982. 51(3 Pt 2): p. 1167-1170. pmc-id:  
107. 
Reynolds, W.M. and J.W. Gould, A psychometric investigation of the standard and short form Beck 
Depression Inventory. J Consult Clin Psychol, 1981. 49(2): p. 306-307. pmc-id:  
108. 
Beck, A.T. and A. Beamesderfer, Assessment of depression: the depression inventory. Mod Probl 
Pharmocopsychiatry, 1974. 7(0): p. 151-169. pmc-id:  
109. 
Beck, A.T., N. Epstein, G. Brown, et al., An inventory for measuring clinical anxiety: psychometric 
properties. J Consult Clin Psychol, 1988. 56(6): p. 893-897. pmc-id:  
110. 
Daut, R.L., C.S. Cleeland, and R.C. Flanery, Development of the Wisconsin Brief Pain Questionnaire to 
assess pain in cancer and other diseases. Pain, 1983. 17(2): p. 197-210. pmc-id:  
111. 
Tan, G., M.P. Jensen, J.I. Thornby, et al., Validation of the Brief Pain Inventory for chronic nonmalignant 
pain. J Pain, 2004. 5(2): p. 133-137. pmc-id:  
112. 
Gagliese, L. and J. Katz, Age differences in postoperative pain are scale dependent: a comparison of 
measures of pain intensity and quality in younger and older surgical patients. Pain, 2003. 103(1-2): p. 11-
20. pmc-id:  
113. 
Zalon, M.L., Comparison of pain measures in surgical patients. J Nurs Meas, 1999. 7(2): p. 135-152. 
pmc-id:  
 
 
H. FACILITES AVAILABLE____________________________________________________________________ 
Describe the facilities available for this project including laboratories, clinical resources, etc. 
 
The PI (an independent investigator in the Brain Stimulation Laboratory) possesses the tDCS 
machine described in this protocol. Participants will be involved in a standard clinical protocol and will 
have all of the resources available to them and to manage their post-operative disposition that all 
patients would have at VAMC.