Effect of Transcranial Direct Current Stimulation on Proprioceptive and Vibratory Sensation: Potential Benefit for Patients With Peripheral Neuropathy
Phase: NA
Conditions: Peripheral Neuropathy
Sponsor: Johns Hopkins University

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Effect of Transcranial Direct Current Stimulation 
on Proprioceptive and Vibratory Sensation: 
Potential Benefit for Patients with Peripheral 
Neuropathy. 
 
 
 
3/01/2020 
NCT03073759 
 
 
PI: Mohammad Khoshnoodi, M.D. 
Assistant Professor, Neurology 
Neuromuscular Division 
600 N.Wolfe St., Meyer building, 5-119b 
Baltimore, MD, 21287 
Phone: 410-955-5406 
Fax: 410-955-1961 
Email: mkhoshn1@jhmi.edu 
 
 
 
 

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Contents 
 
1. INTRODUCTION ................................................................................................................................4 
1.1. Indication ......................................................................................................................................... 4 
1.2. Background and Rationale ........................................................................................................... 4 
2. STUDY OBJECTIVES AND ENDPOINTS .....................................................................................7 
2.1. Objectives ........................................................................................................................................ 7 
2.2. Endpoints ........................................................................................................................................ 7 
3. STUDY DESIGN .................................................................................................................................7 
4. SUBJECT SELECTION ....................................................................................................................8 
4.1. Inclusion Criteria ............................................................................................................................. 8 
4.2. Exclusion Criteria ........................................................................................................................... 8 
5. STUDY PROCEDURE .......................................................................................................................9 
6. ASSESSMENTS .................................................................................................................................9 
6.1. Clinical Assessment ....................................................................................................................... 9 
6.2. Outcome Assessments ................................................................................................................. 9 
6.2.1. Proprioception Measurement ................................................................................................ 9 
6.2.2. Measurement of Vibratory Threshold ................................................................................. 10 
6.2.3. Time to Sway ......................................................................................................................... 10 
6.2.4. Timed Walk Test ................................................................................................................... 10 
6.3. Safety and Risk Assessments .................................................................................................... 10 
7. ADVERSE EVENT REPORTING ..................................................................................................11 
8. DATA ANALYSIS/STATISTICAL METHODS ............................................................................11 
8.1. Sample Size Determination ........................................................................................................ 11 
8.2. Analysis of Primary and Secondary Endpoints ........................................................................ 11 
9. QUALITY CONTROL AND QUALITY ASSURANCE ................................................................12 
10. DATA HANDLING AND RECORD KEEPING ..........................................................................12 
10.1. Case Report Forms/Electronic Data Record .......................................................................... 12 
10.2. Record Retention ....................................................................................................................... 12 
11. ETHICS ............................................................................................................................................12 
11.1. Institutional Review Board (IRB) .............................................................................................. 12 

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11.2. Ethical Conduct of the Study .................................................................................................... 12 
11.3. Subject Information and Consent ............................................................................................ 13 
12. REFERENCES ................................................................................................................................13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION 
1.1. Indication 
The purpose of this study is to assess effect of transcranial direct current stimulation (tDCS) on 
vibratory and proprioceptive sensation in patients with peripheral neuropathy. 
1.2. Background and Rationale 
Distal symmetric polyneuropathy (DSP) is a common disease and it can occur in up to 30% of 
those between ages 70 and 80 years, especially those with diabetes or other diseases that can 
cause neuropathy[1]. Older individuals even without diabetes or other coexisting disease have 
increased prevalence of PN that puts them at a significantly increased rate of falling and fall-
related injury as compared to similarly aged populations without neuropathy[2-4]. Peripheral 
nerve dysfunction contributes to age related mobility loss and susceptibility to accidental falls 
due to several factors including impaired proprioception and muscle weakness[5]. 
Biomechanical gait analyses have shown that patients with PN walk at slower speeds, with 
shortened stride lengths and greater base widths, stride times and double support times than 
age-matched healthy controls[6, 7]. Falls among older adults place a significant cost on the US 
health care system, resulting in over 662,000 hospitalizations and a total cost of over $30 billion 
annually[8]. In a prospective follow up study of 32 patients with peripheral nerve dysfunction, 20 
had at least one fall over a period of one year. Fourteen of these patients suffered a fall related 
injury[9]. Ankle proprioception was reduced in all of the patients with fall. Proprioception is likely 
to be affected early in the disease process, because it is a complex system that requires 
integration of sensory input from many receptors 
Somatosensory in conjunction with visual and vestibular systems convey information about limb 
and body movement, force, pressure, tension, and movement in space that is needed for motor 
control[10]. The somatosensory system is responsible for the neural representation of 
proprioception. Proprioception is usually defined as the ability of the central sensory processing 
system to identify the position of the body segments and movements in space based on the 
sensory signals received from sensory receptors[11]. Mechanoreceptors located in joint 
capsule, ligaments, menisci, musculotendinous unit, and in the skin are involved in sending the 
proprioceptive feedback signal to the central somatosensory processing areas. Individuals who 
are deprived from such signals temporarily or permanently due to damage to the sensory 
nerves show a significant disturbance in movement planning and execution despite having a 
fully functional motor pathway. Precise ankle proprioceptive thresholds allow earlier perception 
of a perturbation that is necessary for stabilization or swing limb positioning to prevent falls. 
Additionally, Standing balance control relies substantively on ankle proprioception. Disrupting 
proprioception during standing increases body sway that has become part of routine bedside 
neurologic examination of gait and balance. It has been estimated that ankle proprioception has 
between 60-70 % contributions to body sway when deprived from other source of sensory 
feedback such as visual signal[12-14].  
Exploring the neural correlates of maintaining balance during upright stand and walking and role 
of ankle proprioception has been difficult due to the fact that functional imaging are mostly done 

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with subjects lying down and immobile. The first brain mapping of ankle proprioception-related 
neural differences in young and older adults was provided in 2011. In this study, stimulating key 
proprioceptors (i.e., muscle spindles) in the feet with tendon vibration was done during fMRI. In 
young and older individuals, muscle spindle related neural activity was identified in brain areas 
that included primary and secondary sensorimotor cortices, secondary associative areas, and 
basal ganglia[15]. Another fMRI study focused on finding areas in the brain that their activity 
during proprioceptive stimulation shows high correlation with performance of the subjects in a 
complex balance task. Areas that were found to have high correlation were right anterior insula, 
right inferior frontal gyrus (BA 44/45), orbital frontal cortex (BA 47), and the right basal ganglia 
(pallidum and putamen)[16]. It has been tried to examine the neural correlates of balance 
control using mental imagery of standing upright while lying supine in an fMRI scanner. 
Reported areas of activation from these studies include premotor cortex, pre-SMA, dorsolateral 
prefrontal areas, precuneus, inferior parietal lobe, insula, and cingulate, among others[17, 18].  
Objective quantification of proprioception may improve early detection of proprioceptive loss and 
help quantify this loss with aging. Present methods of proprioception quantification 
predominantly involve measurement of kinesthesia (ability to detect movement) and joint 
position sense (JPS). A common measure of kinesthesia is the threshold for perception of slow 
passive movement. Determining the error associated with active or passive reproduction of a 
joint angle assesses JPS. The most common used measures are passive or active matching 
and minimum detectable change in position. For example, one method that has been used to 
measure the proprioception at the ankle is to place one foot on a footpad that is tilted using a 
torque machine with a fixed speed. Subjects are asked to report as soon as they feel any 
movement in their ankle and the direction of the move. The angle when the patient pushes the 
button is used as threshold of proprioception. The other way of measuring it has been putting 
the ankle in a range of angles and use the angle that the subjects can report the direction of 
movement correctly more than 75% of trials as the threshold. Matching technique is asking the 
patient to reproduce an angle in the joint, either on the same side or on the other side. All of 
these measures have their own downsides and studies have tried to validate them with 
controversial results. Overall, it appears that threshold reporting is more sensitive than matching 
techniques. Functional measures such as time to sway and times walk have also been used to 
evaluate the effect of treatments such as physical therapy and balance training[19-21]. 
Currently there is no cure for most of the cases of PN and management is mostly focused on 
rehabilitation programs. Dynamic balance training has shown to have a modest effect on 
functional stability in patients with diabetic neuropathy but there is no accepted guidelines 
regarding a rehabilitation regimen that improve balance and prevent falls in these patients. 
There is little evidence that proprioception can be improved by exercise or bracing. Biofeedback 
strategies have only just started to be investigated in patients with PN and the results have not 
been convincing. Providing proprioceptive signal has not received much attention in developing 
prosthetic limbs or brain-compute interface protocols until more recently. Few studies have used 
BCI protocols to provide a tactile signal to prosthetic hands to improve the grip accuracy, but 
this has not been implemented for gait or balance[8, 10, 22-24].  

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Transcranial direct current stimulation (tDCS) is a commonly used non-invasive form of brain 
stimulation for studying brain functions in health and disease[25, 26][25, 26][25, 26][25, 26][25, 
26][25, 26][25, 26][25, 26][25, 26][25, 26][25, 26][25, 26][25, 26][25, 26][25, 26][25, 26][25, 
26][25, 26][25, 26][25]. It involves attachment of surface electrodes to the head through which 
very small electric currents (1 or 2mA) are applied via a current regulated device that is powered 
by a 9 volt battery.  The currents are so small that they do not produce any sensation.  
Importantly, when the electrode is placed over the cortex, the small currents appear to affect the 
excitability of the neural tissue. For example, after anodal tDCS over the motor cortex, the 
amplitude of the motor evoked action potential is increased[27].  That is, a given external input 
to the motor cortex produces a greater magnitude of muscle activity after application of tDCS. 
This suggests that anodal tDCS tends to increase the excitability of the cortical region that it is 
applied to, making it so that a given amount of ‘input drive’ will produce a greater amount of 
neural activation. In contrast, cathodal tDCS stimulation of the cortex reduces is excitability. 
Since a tDCS device is relatively small and elicits no acoustic noise and muscle twitching 
compared with other brain stimulation techniques, it is suitable for sham-controlled clinical 
studies.  
Usefulness of tDCS in modulating sensory functions has been reported before. For example, it 
has been shown that anodal stimulation of S1 can increase somatosensory evoked potential 
(SEP) while cathodal stimulation will reduce it[28]. It has been shown that performance of 
healthy subjects as well as patients with multiple sclerosis (MS) in a tactile task can be 
enhanced by anodal stimulation of S1[29]. It has also been reported that stimulation of M1 
cortex with tDCS can increase SEP. Stimulation of motor cortex has also been shown to 
enhance the thermal and mechanical sensation as tested by quantitative sensory testing[30]. 
Additionally a dual hemispheric protocol -during which S1 on one side is stimulated and on the 
other side is inhibited to block the interhemispheric inhibitory pathways- has been tested in 
healthy individuals and has been shown to improve performance in tactile spatial discrimination 
tasks[31]. Interestingly, the effects of tDCS on sensation can last for several minutes[32]. 
Effects of tDCS on gait and balance as well as improving tactile and proprioceptive sensation 
has been tested mostly in patients with stroke or spinal cord injury[33-37]. There is no 
experiment to our knowledge that has examined the effect of stimulating motor and sensory 
cortices on enhancing the proprioceptive signal in patients with PN. Enhancing this signal by 
stimulating cortical areas, theoretically can enhance the impaired proprioceptive signal from the 
ankle and potentially improve the balance problems caused by it. tDCS has been used before in 
patients with PN safely and with various degree of success for treatment of neuropathic pain, 
but no study has ever reported any measures of proprioception or balance[26]. 
In the current study, we plan to test the hypothesis that tDCS of somatosensory, motor or 
prefrontal cortices can enhance the proprioceptive feedback received from the ankle joints or 
other sensory feedback signals important for controlling balance and gait and improve these 
measures in patients with PN. We plan to recruit patients with PN and measure the 
proprioception sense of the ankle using joint position sense as well as functional measures such 
as timed walk and time to sway to compare in these subjects before the stimulation and after 
the real and sham stimulation.  

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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
Primary Objective:  
To evaluate the effect of tDCS on proprioception, defined as the minimum detectable angle of 
dorsiflexion or plantar flexion at the ankle.  
Secondary Objectives:  
1. To evaluate the effect of tDCS on the proprioception threshold of the big toe. 
2. To evaluate the effect of tDCS on vibratory sensation threshold; 
3. To evaluate the effect of tDCS on time to sway when standing with feet together and eyes 
closed. 
4. To evaluate the effect of tDCS on timed walk test;   
2.2. Endpoints 
Primary Endpoint  
Minimum detectable angle of dorsiflexion and plantar flexion of the ankle. 
Secondary Measures and Efficacy Endpoints 
1. Time to sway when standing with feet together and eyes closed; 
2. Vibratory threshold as measured by Rydel Seiffer graduated tuning fork;  
3. Distance walked in a timed walk test; 
3. STUDY DESIGN 
This study will be performed in patients with peripheral neuropathy who are walking 
independently, but have complains of balance problems such as recent falls or difficulty walking 
and show reduced vibratory and proprioceptive sensation during routine neurologic 
examination. These patients will be tested for proprioceptive and vibratory threshold at the toes 
and ankles before, during and after receiving anodal tDCS over sensory and motor cortices, as 
well as sham stimulation. Patients will be blinded and won’t know if they are receiving actual 
stimulation or sham stimulation. Subjects will be asked to participate in 2 sessions. In one of the 
sessions, decided randomly, the sham stimulation will be applied and during the other session 
the real tDCS stimulation will be applied. Similar sets of assessments will be performed before, 
during and after application of real or sham stimulations.  
 

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4. SUBJECT SELECTION 
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into consideration 
when deciding whether this protocol is suitable for a particular subject.  
4.1. Inclusion Criteria 
Subject eligibility should be reviewed and documented by an appropriately qualified member of 
the investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legal representative) has been informed of all pertinent aspects of the 
study; 
2. Subjects who are willing and able to comply with scheduled visits, and study 
procedures and are able to read and participate in all study assessments; 
3. 
Subjects 
with 
axonal 
predominantly 
sensory 
large-fiber 
distal 
symmetric 
polyneuropathy confirmed with EMG/NCS.  
4. Subjects who are walking independently without sue of cane or walker. 
5. Subjects with impaired proprioception and/or vibration at the toes/ankle on routine 
neurologic examination.  
6. Age older than 18 years; 
4.2. Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study:   
1. Subjects with weakness in ankle dorsiflexion or plantar flexion; 
2. Subjects with other etiologies for gait and balance disorder such as cerebellar ataxia, 
history of stroke, spinal canal stenosis, untreated B12 deficiency;   
3. Subjects who are not able to walk independently; 
 
4. History of seizure or a family history of epilepsy; 
 
5. Cardiac pacemakers; cochlear implants; implanted medication pump. 
 
6. Metal implants in the head, except for dental fillings or implants. 
 
7. Increased intracranial pressure; 

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8. Pregnancy; 
 
9. History of head trauma; 
 
10.  Subjects who are taking neuroleptic medications. 
5. STUDY PROCEDURE 
The tDCS portion of the experiment will begins with DC current (maximum of 2 mA) 
stimulation delivered through surface electrodes (TransQE from IOMED®, surface area: 25 
cm2) using a Phoresor® II Auto (Model No. PM850, IOMED®, Salt Lake City, Utah 84120, 
USA). One electrode will be positioned above the left or right primary motor cortex, the other 
electrode over the forehead [27].  
For sham stimulation the electrodes will be placed in the same way as for real tDCS in the 
absence of real stimulation, this means stimulation will be increased to a current strength near to 
perception threshold and will be decreased afterwards and set to 0 mA output for the period of 20 
min. With this procedure participants are usually unable to differentiate between tDCS and sham 
stimulation [38] .  
6. ASSESSMENTS 
6.1. Clinical Assessment 
Patients will have a complete neurologic examination by the PI and their medical records will be 
reviewed including EMG/NCS. A documentation of the disease onset, potential cause, onset of 
balance problem, most recent fall, examination of muscle strength, reflexes and sensory exam 
will be done by the PI.  
6.2. Outcome Assessments 
6.2.1. Proprioception Measurement 
Both minimum detectable change in joint position and position matching techniques will be 
used.  
For minimum detectable change in joint position of the ankle, subject’s foot will be placed on a 
foot pad with adjustable angle. The starting angle will be parallel to the floor. The angle will be 
changed by 2 degrees in each step and subject will be asked to report as soon as they feel a 
movement in their ankle with their eyes closed. Direction of movement will be at both 
dorsiflexion and plantar flexion.  
For the matching position of the ankle, the footpad will be positioned in various angles ranging 
from 5 degree to 45 degree and will be asked to try to match the ankle on the other side with 
their eyes closed. The angle on the other foot will be measured and recorded. For the same-

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side matching, subjects will be asked to remember than angle and try to reproduce it after the 
ankle is returned to the neutral position.  
For measuring proprioception at the big toe, the experimenter will move the toe with steps of 2 
degrees at a time and will ask subject to report any change as soon as felt with their eyes 
closed.  
6.2.2. Measurement of Vibratory Threshold 
Vibratory threshold is measured by a Rydel Seiffer graduated tuning fork. The two arms of this 
tuning fork bear calibrated weights at their extremities. A triangle and an arbitrary scale from 0 
(minimum score) to 8 (maximum score) imprinted on the weights allow assessment of vibration 
thresh- old. Once the arms are swinging, the fork vibrates at 64 Hz and the triangles on the 
weights appear double. The intersection of these two virtual triangles moves from 0 to 8 in an 
exponential way with decreasing vibration amplitude of the arms. The vibration extinction 
threshold is considered as the nearest value to the apparent point of intersection of the virtual 
triangles when the subject indicates that vibration is no longer perceived. 
6.2.3. Time to Sway 
With patient staying with their feet together, they will be asked to close their eyes. Time until the 
onset of a postural sway will be recorded. 
6.2.4. Timed Walk Test 
Subjects will be asked to walk a marked, pre-defined 6-meter distance at a normal speed and 
the time required for time walk will be recorded. 
6.3. Safety and Risk Assessments 
Weak direct currents can be applied non-invasively, transcranially and painlessly. Such 
application leads to transient changes in corticomotor excitability that is fully reversible. 
There are no known risks of percutaneous, transcranial DC stimulation of the brain, other than 
mild local discomfort at the electrode sites (much less than TMS for example). In the current 
published studies on humans [27, 38-42], the following objective safety data were reported:  
• 
 No heating of electrodes  
• 
 No demonstrable changes in the skin underlying electrode placement after a stimulation 
period similar to the one proposed in this protocol.  
• 
 Mild itching sensation in the absence of pain. Never led to stopping a study in any of the 
previous reports.  
• 
No change in serum neuron-specific enolase (NSE, marker for neuronal damage) in 5 
subjects immediately and 1 hour after exposure to 13 min of 1 mA anodal DC to motor 
cortex  
• 
No changes in diffusion weighted or contrast-enhanced MRI and in EEG after exposure 
to tDCS.  

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Several hundred subjects so far without reporting any side effects apart from a slight 
itching under the electrode and a short phosphene if the stimulation was switched on or 
off abruptly.  A review paper discussed the safety of tDCS in human. tDCS applications 
over motor and non-cortical areas in healthy individuals, migraine patients, post-stroke 
patients, and tinnitus patients ,etc. revealed the most common adverse effect after tDCS 
was a mild tingling sensation, followed by fatigue, then a light itching sensation under the 
stimulation electrodes. Not as common, but mentioned, were headache, nausea, and 
insomnia. The review paper concluded that tDCS is associated with very minor adverse 
effects in healthy humans and patients with varying neurological disorders[43]. Even 
higher intensities of current has been used for tDCS safely without complications[44, 45]. 
7. ADVERSE EVENT REPORTING 
All serious adverse events will be reported to the IRB immediately by the PI.  
Expected adverse events due to tDCS or TMS that will be reported in annual reviews:  
• 
 Itching sensation under the electrode (tDCS)  
• 
Phosphene-like visual phenomenon if the DC stimulation will be switched on or off 
rapidly  
• 
Slight discomfort lasting less than a second on the scalp near the TMS coil  
• 
Twitching of the face and jaw due to the magnetic pulse, which may be unpleasant but 
usually not painful  
• 
 Transient headache  
Exceptional adverse events due to tDCS that will be reported immediately  
     • Skin burn 
• Seizures  
8. DATA ANALYSIS/STATISTICAL METHODS 
8.1. Sample Size Determination 
Based on the review of the literature, a sample size of 15-20 patients often time has been used 
to investigate the effect of tDCS. We plan to recruit 20 patients in this study.  
8.2. Analysis of Primary and Secondary Endpoints 
A repeated measure ANOVA will be used to compare the outcome measures before the 
stimulation, after the real stimulation and after the Sham stimulation. 

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9. QUALITY CONTROL AND QUALITY ASSURANCE 
The study site may be subject to review by the Institutional Review Board (IRB). It is important 
that the investigator and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. 
10. DATA HANDLING AND RECORD KEEPING 
10.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included subject. The investigator has 
ultimate responsibility for the collection and reporting of all clinical and safety data entered on 
the CRFs and any other data collection forms (source documents) and ensuring that they are 
accurate, 
authentic/original, 
attributable, 
complete, 
consistent, 
legible, 
timely 
(contemporaneous), enduring and available when required.  The CRFs must be signed by the 
investigator or by an authorized staff member to attest that the data contained on the CRFs is 
true.  Any corrections to entries made in the CRFs, source documents must be dated, initialed 
and explained (if necessary) and should not obscure the original entry.  
10.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records), 
all original signed informed consent documents, copies of all CRFs, safety reporting forms, 
source documents, and adequate documentation of relevant correspondence (eg, letters, 
telephone calls reports).  The records should be retained by the investigator according to 
International Conference on Harmonization (ICH), local regulations, or as specified in the 
Clinical Study Agreement (CSA), whichever is longer. 
11. ETHICS 
11.1. Institutional Review Board (IRB) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB.  All correspondence with the IRB should 
be retained in the Investigator File.   
The only circumstance in which an amendment may be initiated prior to IRB approval is where 
the change is necessary to eliminate apparent immediate hazards to the subjects.  In that event, 
the investigator must notify the IRB in writing immediately after the implementation. 
11.2. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical Research 
Involving Human Subjects (Council for International Organizations of Medical Sciences 2002), 

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Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World Medical Association 
2008).  
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
11.3. Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.  
Subject names, address, birth date and other identifiable data will be replaced by a numerical 
code consisting of a numbering system in order to de-identify the trial subject 
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements. 
The informed consent document used in this study, and any changes made during the course of 
the study, must be prospectively approved by the IRB before use. 
The investigator must ensure that each study subject, or his/her legal representative, is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.   
The investigator, or a person designated by the investigator, will obtain written informed consent 
from each subject or the subject's legal representative before any study-specific activity is 
performed.  The investigator will retain the original of each subject's signed consent document. 
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