Transcranial Direct Current Stimulation to Lower Neuropathic Pain in People With Multiple Sclerosis: a Mechanistic FDG-PET Study
Phase: NA
Conditions: Multiple Sclerosis, Neuropathic Pain
Sponsor: Thorsten Rudroff

 
NCT- 03219073 Study Protocol and Statistical Analysis  
11/2/2022         Last IRB approval 09/19/2019 
Transcranial Direct Current Stimulation to Lower Neuropathic Pain in People With Multiple Sclerosis  
 
 
Purpose 
 
The purpose of this study is to investigate the effects of different intensities of transcranial direct current 
stimulation (tDCS) on neuropathic pain and fatigue in people with MS. We will conduct three different tDCS 
conditions (sham, 2 mA, and 4 mA) on 5 consecutive days each. We will evaluate pain and fatigue with specific 
questionnaires and measure fatigability with an isokinetic device. 
Our research question is whether tDCS can lessen neuropathic pain and increase fatigue resistance in people 
with MS and if a higher intensity stimulation (4 mA) provides additional pain and fatigue improvements. We 
hypothesize less neuropathic pain and increased fatigue resistance after either of the tDCS sessions and that 
the 4 mA condition will better improve pain and fatigue compared with the 2 mA condition. 
 
Significance and Background 
 
People with Multiple Sclerosis (PwMS) are at an over five-fold increased risk of receiving treatment for 
neuropathic pain. This pain type appears to be the primary factor behind the overall increased risk of pain 
treatment for PwMS. However, the management of neuropathic pain syndromes is currently a challenging task 
because only 40% to 60% of patients experience a favorable outcome from pharmacological treatments. 
Several studies have shown that most of the currently available treatments, including antidepressants, opioids, 
and topical anesthetics, have limited long-term effectiveness and are often associated with moderate or even 
severe adverse effects. It is generally agreed that improved therapies are needed for addressing symptoms of 
MS such as neuropathic pain. Furthermore, to fight the opioid epidemic in the US, safer treatments are 
urgently needed. 
 
tDCS has significantly advanced in the past 15 years as a treatment tool and has been successfully used by 
the PI. It has a theoretical advantage when compared with traditional neuropathic pain treatments because it 
directly affects central neural targets, thus having a potentially stronger effect on central sensitization. On the 
other hand, its effects may take longer to appear (i.e., only after 5–10 sessions, subjects may notice pain 
decrease). Because of its relatively low cost, ease of use, and safety profile, tDCS may be a suitable 
alternative treatment of pain in various disorders. 
 
Several preliminary studies have demonstrated initial efficacy of tDCS for pain control. Our own preliminary 
case study on one PwMS, who was resistant to pain medication, using the same tDCS protocol proposed here 
(2 mA condition), showed reduced pain ratings (VAS, NPSI) after the 5 consecutive days. Additionally, 
because pain and fatigue are strongly correlated, we will investigate the effects of tDCS on fatigability in PwMS 
at the same time. Furthermore, because there is a potential to increase the benefits of tDCS by increasing 
stimulation intensity, a comparison of different intensities (2 mA and 4 mA) will also be conducted. 
 
Methods 
 
Prospective participants, men and women with MS, will be recruited. To accomplish this study, 20 participants 
will need to complete 3 randomly ordered blocks of protocols (sham, 2 mA, 4 mA), separated by at least one 
week. Each block involves 5 daily sessions at the INPL. The duration of each session will be approximately 
one hour and will be completed at the same time of day for each subject. We expect data collection to last 6 
months. Each session will be a combination of questionnaires, leg strength assessment, and an isokinetic 
fatigue test. 
 
Leg strength assessment: Isokinetic (concentric/concentric) flexion and extension of the knee at 60°/s will be 
performed five times to determine the more-MS affected leg. When strength difference between the left and 
right legs is less than 10%, the more affected side will be based on the participant’s self-report. 
 
Isokinetic fatigue test: Participant’s will perform 40 consecutive repetitions of isokinetic concentric/concentric 

flexion and extension of the knee on the more-affected leg at 120 degree/sec. 
 
In the initial session (i.e., Block 1, Session 1) subjects will 1) be consented, 2) complete the Patient 
Determined Disease Steps (PDDS) questionnaire, 3) the Fatigue Severity Scale (FSS), 4) Neuropathic Pain 
Questionnaire (NPQ), 5) Visual analog scale (VAS), 6) perform a leg strength assessment, 7) perform an 
isokinetic fatigue test, and 8) undergo either sham tDCS, tDCS at 2 mA, or tDCS at 4 mA, depending on the 
randomized block. 
 
tDCS treatment protocol: A tDCS device (Soterix) will deliver a small direct current through two sponge surface 
electrodes (5cm × 5cm, soaked with 15 mM NaCL). The positive electrode will be placed over the motor cortex 
representation of the more affected leg, and a second electrode will be placed on the forehead above the 
contralateral orbit. The three protocols blocks (sham, 2 mA, 4 mA) will be performed in randomized order. 
 
tDCS Block: The participant will receive tDCS for 20 min at an intensity of 2 mA or 4 mA while seated 
comfortably and quietly in a room. The intensity will start at 0 mA and will be incrementally increased to 2mA or 
4 mA over the initial 30 seconds. At the 19:30 minute time point, the current will gradually be reduced from 2 
mA (or 4 mA) to 0 mA. 
 
Sham block: Identical to the tDCS block, except the participants will only receive the initial 30 seconds of ramp-
up, after which the current will be set to 0 for the remainder of the 20 minutes. 
 
The remaining sessions of first block (i.e. Block 1, Sessions 2-5) will be as follows: In Sessions 2 and 4, the 
subjects get the tDCS or sham treatment, after which they will complete the fatigue and pain questionnaires 
(FSS and NPQ). Sessions 3 will be the same as Sessions 2 and 4, except that the isokinetic fatigue test will be 
performed at the beginning (i.e., before the tDCS or sham treatment). Session 5 will start with tDCS or sham 
treatment, then the isokinetic fatigue test, and finally the fatigue and pain questionnaires. 
Blocks 2 and 3 will be completed in the same manner as Block 1, except that the subjects will not redo the 
PDDS, VAS, and BDI in Session 1 and the treatment will shift to either tDCS at 2 mA, tDCS at 4 mA, or sham, 
depending on how the blocks were randomized. Block 2 will be randomly assigned based on uncompleted 
stimulation blocks. 
 
Inclusion Criteria: medically diagnosed with Multiple Sclerosis, 18-70 yrs. of age, moderate disability (Patient 
Determined Disease Steps (PDDS) core 2-6), self-reported differences in function between legs, able to walk 
for 6 min, and presenting with chronic, drug-resistant, neuropathic pain. Chronic neuropathic pain will be 
defined as a constant or intermittent sensory symptom with unpleasant feelings or pain, lasting more than 1 
month and having a stereotyped neurological distribution and superficial localization. To differentiate 
neuropathic from spasticity-associated pain, patients need to score greater than 0 on the Neuropathic Pain 
Questionnaire (NPQ) to qualify for the study. A minimum score of 40 (0 = no pain, 100 = worst possible pain) 
on the visual analog scale (VAS) for pain perception at baseline will be required to be enrolled in the study. All 
analgesic medications will be discontinued at least 24 hours before entering the study and not be used until 
study participation is completed. 
 
Exclusion Criteria: relapse within last 60 days, high risk for cardiovascular disease (ACSM risk classification), 
changes in disease modifying medications within last 45 days, concurrent neurological/neuromuscular disease, 
hospitalization within last 90 days, diagnosed depression, and inability to understand/sign informed consent. 
 
 
Enrollment and Consent 
 
Prospective participants, men and women with MS, will be recruited from the MS Clinic in the Dept. of 
Neurology at UIOWA (Dr. John Kamholz), through advertisements on UIOWA Campus, and through mass 
email. For those recruited at the clinic, Dr. Kamholz will discuss the study with potential participants and 
provide them with a copy of the informed consent and/or consent summary (if requested) and a copy of the 
recruitment flyer to contact the other study personnel. All other experimental procedures will be performed in 
the INPL (Director: Thorsten Rudroff, PhD, FACSM). Interested individuals from any recruitment source (i.e., 
clinic, flyers, website, email) will contact study personnel and perform an initial phone screening via a 

questionnaire. Contact information for the prospective participant will be accessible only to the research staff 
according to HIPPA regulations. After completion of the phone questionnaire, INPL personnel will schedule the 
participant’s first visit (10 total). 
 
During the first visit, subjects will review the consent summary and consent form before signing the consent 
document. The PI or research staff will answer all questions asked by the potential subject and the subject will 
be informed of all potential risks before the signing the consent document. Subjects will in no way be coerced 
to sign the consent form and will be informed that it is their choice whether to volunteer for this study. Even 
after subjects sign the consent, they are free to withdraw from the study at any time and for any reason. 
 
 
Risks for subjects 
 
Physical well-being: Potential risk include muscle cramps/spasms during strength testing. 
 
tDCS safety: tDCS is a non-invasive brain stimulation technique in which a very weak electrical current is 
applied to the scalp. tDCS has been conducted on humans and animals for many years and no 
evidence has emerged to suggest that it is harmful or has ever induced a serious side effect. However, the 
safety of tDCS is dependent on current strength, electrode size, and stimulation 
duration. Accordingly, these parameters have been investigated to establish safe and effective stimulation 
parameters for tDCS applications in research involving human subjects. However, recently experts in tDCS 
research have indicated that investigation of higher intensity tDCS is warranted (Nitsche et al. 2017) The only 
side effects that have been reported when proper guidelines are followed are temporary tingling, itching, 
headache, or skin redness under the electrodes in some subjects. For example, a 2008 review of the 
approximately 100 human tDCS studies up until that time on healthy adults and patients found that 64 of these 
studies reported no side effects, 24 studies reported a temporary itching or tingling under the electrodes in 
some subjects, and one study reported skin redness. Furthermore, these slight side effects were of equal 
occurrence in subjects that received placebo stimulation in 7 studies. In addition, only two subjects in these 
100 studies reported a mild headache. Similar findings have recently been reported in research and review 
articles (Nitsche et al. 2008; Hummel et al. 2008). 
 
Physiological studies have also assessed the safety of tDCS when applied within the aforementioned 
stimulation guidelines. For example, there was no neuronal damage as measured by serum neuron-specific 
enolase (Stagg & Nitsche, 2011 ) or MRI measures of edema using contrast enhanced and diffusion-weighted 
MRI measures following administration of tDCS (Nitsche et al. 2004). Furthermore, tDCS did not negatively 
alter measures of neuropsychological function and EEG activity (Iver et al. 2005). Accordingly, rat studies 
using tDCS models emulating tDCS applied to humans (Liebetanz et al. 2009 ) showed that the current density 
needed to induce tissue damage or lesions was about 1429 mA/cm^2, whereas the current densities used in 
human studies are between 0.04 and 0.08 mA/cm^2 and in this proposal are 0.029 mA/cm^2 and 0.11 
mA/cm^2. Lastly, safety and tolerability results from two of our recent studies currently under review for 
publication provide evidence that 4 mA tDCS is safe and well-tolerated, with most sensations and sensation 
severities similar to sham and 2 mA tDCS. In conclusion, the tDCS stimulation parameters in this study are 
identical to the most common in the literature and have been proven to be exceptionally safe and well-
tolerated. 
 
The probability is very unlikely that harm may occur (see above). Based on the available literature a slight 
headache should be the worst possible negative effect and should be very rare. In this case, non-prescription 
medication should relieve the headache within 1-2 hours. 
 
PwMS in general have a higher fall risk. 
 
There are no emotional or psychological, financial, legal or social risks. 
 
 
This was a case report: No statistical analysis.