Cranial Nerve Noninvasive Neuromodulation Using the PoNS for Treatment of Symptoms Due to Mild or Moderate Traumatic Brain Injury
Phase: NA
Conditions: Brain Injuries, Traumatic
Sponsor: University of Wisconsin, Madison

 
 
 
Cranial Nerve Noninvasive Neuromodulation Using the PoNSTM for Treatment of Symptoms 
Due to Mild or Moderate Traumatic Brain Injury (AKA TBI Study) 
 
PI: Mitchell E. Tyler, M.S., P.E. 
1550 Engineering Drive 
2156 Engineering Centers Building 
Madison, WI 53706 
metyler1@wisc.edu 
 
12 April 2014 
Modified: 07 August 2014 
 
 
 
        13 November 2014 
 
 
 
 
 25 February 2015 
 
 
    25 June 2015 
 
09 October 2015 
 
22 March 2016 
 
12 Sep 2016 
 
13 Oct 2016 
 
Tactile Communication and Neurorehabilitation Lab (TCNL) 
Department of Kinesiology 
University of Wisconsin 
 
Key Personnel 
• Samuel Acuna, Graduate Student, will be responsible for performing the EMGs under the 
supervision of Prof. Darryl Thelen, PhD. 
• Kristin Caldera, M.D., Co-Investigator, Clinical Advisor, will provide medical consultation for 
subject eligibility and assist with recruitment and identification of potential subjects. 
• Michelle Chiang, Graduate Student, will perform clinical testing, including cognitive assessments. 
• Georgia Corner, DPT, will be primarily responsible for subject training and case report forms. 
• Yuri Danilov, Ph.D., Co-Investigator, will direct the development of the conceptual framework of 
the CN-NINM training program. He will also be chiefly responsible for interpretation and reporting 
of experimental results.  
• Kurt Kaczmarek, Ph.D., has primary responsibility for instrumentation development, statistical 
analysis of experimental data and reporting of experimental results. 
• Danielle McIntosh, B.S., Research Intern, will be responsible for coordinating subject testing and 
training and performing testing. 
• Kelly Miller, B.S. Clinical Monitor, will be responsible for randomization of subjects.  She will also 
be responsible for both monitoring regulatory compliance and reporting unanticipated problems 
and adverse events. 
• Ann Pahnke, B.A., will be responsible for randomization of subjects. 
• Dafna Paltin, B.S., Research Intern, will perform the cognitive assessments. 

 
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• Vivek Prabhakaran, M.D., Ph.D. Co-Investigator, Medical Advisor, will review subject 
neuroradiologic reports, medications, clinical history, monitor for significant adverse events, and 
assist with the recruitment of the targeted patient population.  
• Amy Remm, B.S., Clinical Monitor, will be responsible for regulatory reporting with the US Army 
Clinical Research Monitor (USAMMDA) assigned to the study. 
• Janet Ruhland, M.A., PT, will be primarily responsible for subject training and case report forms and 
will perform subject screening. 
• Kim Skinner, M.S.P.T., will be responsible for performing blinded analysis of the videos for 
Dynamic Gait Index testing. She will also assist in interpretation of experimental results.  
• Darryl Thelen, PhD, M.E., will supervise and serve as consultant for the EMG testing. 
• Mitchell Tyler, M.S., P.E. (Principal Investigator) will direct the overall project, supervise the 
deployment of CN-NINM training and clinical testing, collaborate on development of the Control 
device, assist in interpretation and reporting of experimental results, and report both unanticipated 
problems and adverse events. 
• Yakov Verbny, Ph.D., will be responsible for conducting all physiologic testing and assist in 
interpretation of experimental results. 
 
Summary 
Based on the results of our pilot study in moderate traumatic brain injury (mTBI), we will conduct 
a randomized, controlled study of cranial nerve non-invasive neuromodulation (CN-NINM) in 
individuals with chronic symptoms of mild to moderate traumatic brain injury (mTBI), post-
concussive sequelae, (PCS) and post-traumatic stress (PTS). The study will involve training of 
both balance and gait, with assessments using standardized and relevant metrics to monitor 
changes in these indications, as well as cognitive function, sleep, headache, anxiety, mood, and 
eye-movement control. The training regimen involves using a neurostimulation intervention that 
addresses primary and secondary symptoms associated with mTBI, PCS, and PTS. This 
randomized double blind controlled study will enroll a total of 44 subjects (M & F) in 2 equal 
subgroups: 22 with an Active PoNS™, and 22 with a Control (non-zero, minimally perceivable 
stimulation) device. Subjects will participate in a 3-phase intervention beginning with a 2-week in-
lab training program (ITP) (2 in-lab training sessions and 1 home training session daily), followed 
by 12 weeks of training at home (HTP) (3 home training sessions daily), and a 12-week 
withdrawal period (no training). Subjects will return to the clinic weekly during the at-home phase 
for a single session of retraining and progression, and participate in periodic retesting. All training 
and testing will be performed uniformly across all subjects in both groups. Multiple assessment 
metrics will capture data at the beginning and end of the 2-week in-lab CN-NINM intervention 
period and at 3-week intervals. After completion of the formal training period, subjects will stop 
using the device (withdrawal stage) and will be tested every 3 weeks over an additional 12 weeks 
to monitor and assess changes due to withdrawal of the PoNS. This will yield a total of 10 data 
points for each subject. If successful, this study would indicate that CN-NINM may improve 
rehabilitation outcomes and reduce time required to improve function. 
 
Background 
The Centers for Disease Control and Prevention reports that 5.3 million people live with chronic 
disabilities related to brain injury, costing Americans $76.5 Billion/yr. in medical, rehabilitation 
costs and loss of income. The majority (75-85%) of TBI’s are considered mild or mTBI’s and 

 
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concussion. Current epidemiological reports find that under conditions of similar risk exposure, 
females may have a 2-fold elevated frequency of concussion [West, 2013; Kontos, 2011]. 
At present, the primary approach for treating TBI is through physical medicine. A systematic and 
unified approach is not universally established, and does not include cognitive therapy. Recent 
studies, however, have demonstrated that neuroplasticity and functional benefits are stimulated 
through specific forms of motor-behavioral interventions [Nudo, 2001; Weiller, 1993], while 
others have determined that early, intensive, targeted cognitive skill training after injury, even in 
older adults, are clinically effective [Rohling, 2009; Cicerone, 2000]. Recent studies have 
identified the potential for noninvasive electrical stimulation of the brain to improve patient ability 
to learn and retain a motor task [Reis, 2009; Vines, 2010]. Additionally, there has been an 
emerging call for an integrative approach to developing clinical applications, drawing on the latest 
understanding of the interactive factors affecting the potential for functional physical, cognitive 
and psychological recovery from TBI [Bach-y-Rita, 1990, 2000; Bédard, 2003; Taub, 2002]. 
Traumatic brain injury, and particularly concussive polytrauma due to explosive blast, is a 
signature injury of the Iraq and Afghanistan wars. From 2000 to 2012 the US military reported a 
total of approximately 255,000 military personnel from the OEF/OIF theaters have screened 
positive for TBI, roughly half have been treated for reported indications, and nearly 66,000 (25%) 
are identified as having significant and chronic symptoms [Kontos, 2013]. Personnel in this latter 
group present with problems not only with control of balance, posture, gait, and manual dexterity, 
but also more subtle and insidious difficulties with vertigo, short-term memory, reasoning, 
attention, sensory processing, psychosocial expression and understanding, depression, anxiety, 
aggression, personality changes and social inappropriateness. Faced with little prospect of 
recovery, coupled with the social impact of their functional inability to perform normal activities 
of daily living, chronic symptoms of mTBI frequently lead to social isolation and substance abuse, 
resulting in encounters with law enforcement and social services. [Fabing, 1947] 
CN-NINM uses sequenced patterns of electrical stimulation on the tongue. Our hypothesis is that 
CN-NINM induces neuroplasticity by noninvasive stimulation of two major cranial nerves: 
trigeminal, CN-V, and facial, CN-VII. This stimulation excites a natural flow of neural impulses 
to the brainstem (pons varolli and medulla), and cerebellum via the lingual branch of the cranial 
nerve (CN-Vc), and chorda tympani branch of CN-VII, to effect changes in the function of these 
targeted brain structures, extending to corresponding nuclei of the brainstem – at least in the 
sensory and spinal nuclei of trigeminal nuclei complex and the caudal part of the nucleus tractus 
solitarius. We postulate that the intensive activation of these structures initiates a sequential 
cascade of changes in neighboring and/or connected nuclei by direct collateral connections, 
brainstem interneuron circuitry and/or passive transmission of biochemical compounds in the 
intercellular space. By combining neurostimulation with a specific set of physical, cognitive 
and/or mental exercises, we can further focus brain rehabilitation and target our effort on recovery 
of selected functional damage.  
 
Pilot Study 1: CN-NINM Application to Balance Disorders 
Five subjects (3 males, 2 females, mean age 45.4 yrs.) with a variety of etiologies (1 traumatic 
brain injury, 1 spinocerebellar ataxia, 3 vestibular dysfunction) and moderate balance, gait, and 
visual tracking deficits participated in this study. Each had participated in a variety of unsuccessful 
treatments for problems with balance, gait, vertigo, and nausea. Assessments of balance, gait, 
posture and eye movement were quantified using a number of mechanisms to measure the effects 
of the CN-NINM training regimen.  

 
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• Standardized self-assessment surveys of perceived dizziness and loss of stability via the 
Dizziness Handicap Inventory (DHI) and Activity-specific Balance Confidence scale (ABC). 
• Digital head-based postural stabilography (HPS - similar to standardized force platform 
posturography) to assess changes in posture.  
• Functional magnetic resonance imaging (fMRI) to observe potential changes in the cerebral 
cortex, cerebellum, pons varolli and brainstem. 
After each subject completed baseline testing, they received CN-NINM stimulation while 
simultaneously performing progressively challenging postural control training. Subjects also 
received physical exercise training to develop improved motor coordination and mobility as part 
of the CN-NINM training. Subjects participated in CN-NINM training for 5 consecutive days and 
were retested. 
The results of these tests are shown in Table 1. All subjects exhibited improved scores on the self-
assessment measures, indicating that they perceived themselves as being more stable and less 
'dizzy' after CN-NINM training. Stabilography scores indicate that subjects were more stable. The 
results show that while individual differences varied widely, and are dependent on both the 
subjects’ initial condition and unique symptoms, all 5 subjects improved their postural control. 
 
 
Table 1. Summary of Results from Various Tests of Stability and Gait on 5 Subjects.  
Changes greater than 5% are considered clinically significant. 
 
Subject # 
 
 
 
 
 
Calculated % Improvement After CN-NINM Training 
    01     02     03     04     05   Mean    SD 
Activity-Specific Balance Confidence (ABC) 
3 
12 
49 
10 
16 
18.0 16.1 
Dizziness Handicap Index (DHI) 
130 
154 
81 
41 
71 
95.4 41.0 
Head - Postural Stabilogram (HPS) [RMS displacement] 
58.1 33.8 22.9 45.4 57.1 
43.5 15.2 
 
Additionally, three of the subjects reported chronic hypersensitivity to light, visual flow, and/or 
changes in self-motion that severely interfered with activities of daily living such as driving a car, 
grocery shopping, and reading. These individuals reported reduced hypersensitivity to visual 
stimuli and improved image stability after CN-NINM training. Additionally, in subjects with 
reported or observed oscillopsia or nystagmus (3 of 5), we also noted improved eye-motion 
control performance during a simple visual object-tracking task after the 2nd day of CN-NINM 
training. The subject with cerebellar ataxia had the most substantial improvement in the 
smoothness of self-motion (weight transfer, ankle, knee, and hip flexion/extension), and exhibited 
a noticeable improvement in symptoms of dysphonia (speech articulation and volume).   
Functional MRI was performed before the first intervention ('pre') and then 4-6 hours after the last 
training session ('post') of the 5-day CN-NINM intervention, i.e. the subjects did not receive 
tongue stimulation during imaging. A color relief map of the difference in neural activation 
response to dynamic visual stimuli (stereo B/W checkerboards progressing/receding, and rotating 
in pseudorandom motion) is shown in Figure 1. The results shown are composites of the changes 
in cortical and brainstem activation from the 5 subjects (using digital subtraction of post-pre) after 
anatomical correction for region of interest registration. 
The images show increased activity in the visual associative area, both the sensory and motor 
cortices, and especially in both the primary visual area of the occipital lobe and the posterior 
brainstem. The greatest changes (yellow and red) appear in the dorsal pons varolli, medulla 

 
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oblongata, and ventral cerebellum (Figure 1.B). Changes in metabolic activity in these areas are of 
particular interest because these are major sensory integration and control centers for both body 
and eye movement, and therefore primary targets for neuromodulation stimulation. [3-5] 
An apparent decrease in neural activity in the cerebellum following CN-NINM (shown in teal) 
may explain the reductions in frequency and magnitude of oscillopsia observed by all 5 subjects, 
and reported increases in both coordination and continuity of motion that was especially apparent 
in a subject that presented with ataxia due to brainstem microstroke, and vocal modulation 
improvement in a subject with spinocerebellar ataxia.  
 
` 
 
 
A – Whole-brain Activation Map 
 
 
 
 
 
B – Enlarged region of interest from A 
Figures 1 – A & B. Diagrams of ensemble differential neural activity [Post-CN-NINM training minus Pre-training] 
from 5 subjects while viewing dynamic visual stimuli. A - Saggital view of whole brain with head facing to left. B - 
Enlarged region of interest showing detailed activation of the brainstem (medulla, pons, midbrain), and 
cerebellum. Color map indicates relative difference in the magnitude of activation after CN-NINM (p<0.05). Red 
represents the highest increase; teal indicates decreased metabolic activity following CN-NINM intervention. 
[Wildenberg, et. al, 2010, 2011a,b] 
 
 
Pilot Study 2: CN-NINM Application to Traumatic Brain Injury (TBI) 
The results presented below represent the changes in 4 clinical metrics over an initial 5-day period 
of Cranial Nerve Non-Invasive Neuromodulation (CN-NINM) intervention in subjects that had 
suffered moderate traumatic brain injury (TBI). Four female subjects (mean age: 48.3) presented 
with chronic and significant balance and gait deficits due to moderate closed-head, non-
penetrating, Type-2 or 3 concussive injury (9-13 on Glasgow Coma Scale) at initial diagnosis. All 
were approximately 5 years post injury and had previously completed rehabilitative therapy 
programs at their respective primary care facilities.  
Functional Testing.  The results from the gait testing for 4 subjects that participated in the pilot 
study are summarized in Figure 2. The Dynamic Gait Index (DGI) is a clinician-scored index of 8 
facets of gait. Scores range from 0 (worst) to 24 (normal). A score change of 3.0 is generally 
considered clinically significant. The DGI scores indicate significant improvements in stability 
and gait that are retained for as much as 6 hours after completion of the second intervention 
session in the day.  
 

 
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Figure 2. Summary of Results from Dynamic Gait Index for 4 subjects with non-penetrating TBI.  
      Changes greater than 3 points are considered clinically significant improvement in performance. 
The 4 subjects were tested on the NeuroCom® Computerized Dynamic Posturography (CDP) 
Sensory Organization Test (SOT) before and after the week of twice-daily interventions. The SOT 
is an objective, automated measure of sensory-motor integration that evaluates the functional 
contribution of the somatosensory, visual, and vestibular components of balance. A composite 
score is calculated and compared with a database normalized for age and height. Sample pre-post 
scores are shown in Figure 3 for the latter two subjects in this cohort. The composite scores for all 
4 subjects are summarized in Figure 4. 
 
 
 
 
 
 
 
Subject C  
 
 
 
 
 
 
 
 
 
 
 
 
Subject D 

 
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Figure 3.  SOT scores before (upper) and after (lower) for two TBI subjects. Note that the greatest 
functional improvement occurred in the most dynamic and challenging tasks: Condition 5 – Eyes 
closed with platform-induced anterior/posterior sway, and Condition 6 – Eyes open with platform 
and visually-induced anterior/posterior sway. 
 
 
Figure 4. Summary of Results from Computerized Dynamic Posturography Sensory Organization Test 
(SOT). Changes greater than 5 points are considered clinically significant improvement. 
 
We performed electromyogram recording on the legs of one subject. Activation timing of the left 
VL and SOL were abnormal before treatment, and normal after treatment. Note that after 5-days 
of training the muscle activation patterns are more symmetric, agonist-antagonist pairs are 
coordinated, and show significantly less co-contraction. 
 
 
Figure 5.  Electromyogram recorded before (Pre) and after (Post) training. (MG – medial 
gastrocnemius, MH – medial hamstrings). 

 
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Additionally, TBI Subjects C & D were tested for changes in cognitive function, memory, 
attention and mood both before the 5-day intervention began, and within 24 hours of completing 
the training. Their primary indications and scores on the Brief Repeatable Battery of 
Neuropsychological Tests (BRBNT) are summarized in Tables 2 & 3, and the attendant lists 
below each indicate their symptoms and changes. 
Subject ‘C’ - Symptoms: Pre-CN-NINM Intervention 
• Difficulties with concentration, emotions, and physical fatigue. 
• Slow and stuttered speech (significant dysarthria & expressive aphasia). 
• Diplopia & blurred vision, 17˚ visual field deviation requiring corrective lenses 
• Depressed balance & gait test scores. Frequent vertigo and loss of balance 
• Problems with attention span, sustained and divided attention (low scores on word span on Symbol-
Digit and Paced Audio Serial Addition Tests)  
• Depression & emotional lability due to chronic disability   
 
Table 2: Subject C 
Test 
Cycle 
Word 
Span 
Word 
Storage 
Spatial 
Recall 
Symbol- Digit 
PASAT 
PASAT 
Word 
Generation 
Depression 
Scale 
 
(12) 
(11 min) 
(10/36) 
(90 sec) 
(3 sec) 
(2 sec) 
(60 sec) 
 
Baseline 
6 
7 
6.5 
18 
34 
28 
27 
4 (mild) 
2 weeks 
9 
9 
8 
42 
34 
35 
32 
2 
1 month 
10 
11 
9 
53 
52 
36 
33 
2 
 
Results: Post-training 
• Showed statistically and clinically relevant improvement on most of the tests after 1 month 
• Visual field deviation disappeared & vision satisfactory for both day & night driving.  
• Verbal and visual were slow but retrieval intact.  
 
• Able to go to appointments, shopping, cook meals and participate family conversations.   
___________ 
 
Subject ‘D’ - Symptoms: Pre-Intervention 
• Hypersensitivity to sounds, light, motion, or to objects or people moving in environment.  
• Depressed balance & gait test scores; aberrant & asymmetric gait pattern, 
• Chronic fatigue & muscle ache due to co-contraction 
• Showed significant attention impairment (low numbers on all tests) 
• Moderate depression on depression scale, frequent crying 
• Both receptive & expressive aphasia - difficulty participating in conversations 
• Dysarthria - difficulty pronouncing even single-syllable words, stutters. 
 
Table 3: Subject D 
Test 
Cycle 
Word 
Span 
Word 
Storage 
Spatial 
Recall 
Symbol- 
Digit 
PASAT 
PASAT 
Word 
Generation 
Depression 
Scale 
 
(12) 
(11 min) 
(10/36) 
(90 sec) 
(3 sec) 
(2 sec) 
(60 sec) 
 
Baseline 
5 
7 
9 
30 
29 
23 
27 
12 (mod) 
2 weeks 
7 
9 
9 
46 
50 
31 
38 
 5 (mild) 
1 month 
11 
11 
10 
59 
58 
42 
38 
2 
 
 
Results: Post-training 
• Regained normal balance, and able to jog, walk, and stand with eyes closed. 

 
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• Showed significant improvement on all cognitive tests; no signs of depression.   
• Working again part-time, re-engaged in activities of daily living. 
 
We are continuing to monitor the changes in performance in these latter 2 subjects through with 
their referring neurologist, Dr. Charles Davies (Carle Clinic at the University of Illinois). We have 
received report of progressive improvements in eye movement, short-term memory, executive 
function, mood elevation, and progressive reductions in both expressive aphasia and social 
anxiety. 
 
RESEARCH PLAN 
Introduction 
CN-NINM is fundamentally an integrative therapeutic intervention, combining cranial nerve 
electrical stimulation with multiple symptom-specific exercises. Our pilot TBI results suggest that, 
in the absence of identifiable tissue damage, a combination of the neurostimulation and targeted, 
challenging rehabilitation will effect neuroplastic changes, reduce symptoms, and begin 
normalizing function. These changes include rehabilitation and re-establishment of movement 
control (balance, posture, gait, muscular tonus, eyes), cognition (memory, attention, planning, 
decision-making) and potentially mood (depression, aggression, anxiety).  
 
Study Objectives 
The primary objective of the study is to demonstrate that CN-NINM training using the PoNS 
device with normal stimulation is more efficacious than training using a very low but perceivable 
stimulation PoNS device in subjects with symptoms due to a mild to moderate TBI. 
 
In this experimental investigation we will gather data to describe the mean changes in balance and 
gait behavior from baseline for two treatment groups. The results will inform the design and 
power of subsequent, incremental studies investigating the clinical efficacy of this intervention. 
Standardized clinical assessment mechanisms will measure changes in balance, gait, cognition, 
emotional function, headache, eye movement, and sleep in individuals with post-concussive and 
post-traumatic stress complaints in a 14-week rehabilitation program and after a 12-week 
withdrawal period.  
 
Study Design 
The randomized double blind study will enroll up to 44 subjects (males and females) with 
identified balance deficits that will be equally distributed into 2 subgroups: an “Active” CN-
NINM device (PoNS) group, and a “Control” (very low stimulation) device group. Subjects will 
be randomly assigned to one of the two treatment groups by the Clinical Monitor as they are 
recruited using a rolling recruitment method. Cohort assignment will be made by serially selecting 
from a list of 44 randomly generated three-digit subject identification numbers, with 22 assigned 
to both the Active and Control group. 
The study will be a total of 26 weeks, consisting of three stages. The first stage consists of twice-
daily in-lab training (ITP) for 2-weeks (with at-home training during the intervening weekend). 
The intensive CN-NINM training program will focus on balance and gait. This is followed by the 
second stage, which consists of subjects performing the same training for 12 weeks during Stage 2 
– the Home Training Program (HTP). During this second stage, subjects will return to the lab 1 

 
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time per week for a training session. After completion of the second stage, subjects continue in the 
third stage, the withdrawal stage, where they no longer use the PoNS device.  
Multiple assessment metrics will capture data at important points during the study: at the 
beginning and end of the 2-week in-lab CN-NINM intervention period (ITP), every 3 weeks of the 
test/retraining intervals during the home training phase (HTP) and every 3 weeks of the 
withdrawal phase. This will yield a total of 10 data points for each subject on the SOT and gait 
metrics. All training and testing will be performed in a consistent and identical manner across all 
subjects in both groups.  
To preserve the controlled nature of this experiment, each subject will work with three 
experimenters. After completion of screening and enrollment, the subject will be assigned to either 
the active or control group by the Clinical Monitor (CM). The CM will use the randomization list 
provided by the Biostatistics group and the UW Institute for Clinical and Translational Research 
(ICTR) for this study, and will issue the appropriate device (Control or Active). The CM is the 
only person in the study who will know which group to which each subject is assigned. The PI 
will then instruct each subject in the features and use of the PoNS and follow a standardized 
stimulus intensity level setting procedure with the subject. The second investigator, specifically 
the Study Coordinator, will conduct and oversee all testing. A third investigator (Physical 
Therapist) will perform the actual intervention. Subjects will be instructed that they must not tell 
the therapist what they feel on their tongue, or ask questions about the stimulation since the PT 
will not be able to answer these questions. If the subject has questions or feels the need to report 
anything about the device or stimulation, they are to address these only to the PI, in confidence. 
This will prevent treatment and testing bias by ensuring that the therapists and Study Coordinator 
are blinded to the subjects’ treatment group identity.   
To help preserve the controlled nature of this experiment, subjects will also be instructed that they 
must not discuss the stimulation, the group they think they are in, or discuss details of the 
intervention with any other participants in the study or with family members. They may interact 
with other participants as long as their discussions are not related to the study. Subjects will be 
discouraged from congregating or socializing outside of the study in order to maintain blinding. 
Lab study visits will take place at the Tactile Communication Neurorehabilitation Lab (TCNL) at 
455 Science Drive in Madison. Study duration is expected to be 3 years, from time of IRB 
approval to the completion of data analysis. 
An independent, optional sub-study, Characterizing Functional and Structural Brain Changes 
Following Cranial Nerve Noninvasive Neuromodulation (AKA MRI Sub-study), will enroll 26 
subjects (13 subjects in the Active PoNS™ group; 13 subjects in the Control group) who are 
enrolled in the main TBI Study (see Addendum – MRI Sub-study). MRI scans will be performed 
at important points during the study: at the beginning and end of the 2-week in-lab CN-NINM 
intervention period (ITP), at the end of the 12-week home training phase (HTP) and at the end of 
the 12-week withdrawal phase. This will yield a total of 4 data points for each subject. The sub-
study MRI scans will be performed at the Wisconsin Institutes for Medical Research (WIMR), 
1111 Highland Ave., Madison, WI 53705. 
 
Methods 
Subject Population & Selection.  
All subjects will be recruited on a voluntary basis. The study will enroll 44 adults, age 18-65, 
presenting with a chronic balance deficit due to mTBI. Subjects who also present with other 

 
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symptoms, such as gait disturbance, mild to moderate recurrent headaches, sleep, memory, 
attention, or cognitive deficits, will be considered for participation. All candidates will have had a 
closed-head, non-penetrating, blunt, whiplash, or explosive blast-induced brain injury. Subjects 
will be required to provide their most recent neuroradiologic report and evidence of having 
completed a prescribed therapeutic regiment for their symptoms. 
 
Study Inclusion and Exclusion Criteria.  
Inclusion Criteria:  
• All candidates will have a balance disorder as a result of a traumatic brain injury (TBI). 
• All candidates will have a NeuroCom® Sensory Organization Test (SOT) composite score at 
least 8 points below normal after adjustment for age and height [based on normative data].  
• All candidates will be between the ages of 18 and 65 (at the time of screening). 
• If female of childbearing potential, the candidate agrees to use adequate contraception 
throughout participation in the study (from enrollment to completion). 
• 
All candidates must have access to a treadmill.  
• All candidates will be at least 1 year post-injury. 
• All candidates will have a neuroradiologic scan and report after their most recent TBI. 
• All candidates will be ambulatory and able to walk independently for 20 minutes.  
• All candidates, if on medications, will not have had any major changes in type or dosage 
within 3 months of enrollment.  
• All candidates will have participated in a focused physical rehabilitation program for their 
TBI and feel that they have reached a plateau. 
• All candidates will be able to understand and willing to give informed consent. 
 
Exclusion criteria:  
• All candidates that have oral health problems (e.g. gum disease, active cankers, cold sores, 
piercings, oral surgery within the previous 3 months). 
• All candidates with non-removable metal orthodontic devices (e.g., braces) or oral cavity 
piercings that could interfere with PoNS™ use. 
• All candidates who have chronic infectious diseases (e.g. hepatitis, HIV, TB). 
• All candidates with unmanaged hypertension. 
• All candidates with unmanaged diabetes, or complications due to diabetes (e.g. retinopathy, 
neuropathy, renal disease). 
• All candidates with neurological disorders other than those attributed to their primary 
diagnosis (e.g. MS, PD, ALS, AD or other dementia, uncontrolled pain). 
• All candidates with a history of oral cancer. 
• All candidates who have been treated for any type of cancer other than basal cell carcinoma 
within the past year. 
• All candidates who have had a penetrating injury, craniotomy (with the exception of a burr 
hole (trephination) for resolution of acute subdural hematoma), or refractory subdural 
hematoma.  
• Exceptions for other abnormalities identified in neuroradiologic scan reports that are 
asymptomatic and not expected to change may be made on a case by case basis by the 
Medical Advisor. 
• All candidates with chronic use of psychoactive or psychostimulant medications that, in the 
opinion of the investigators, would compromise the subject’s ability to comprehend and 
perform the study activities.  

 
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• All candidates who have a pacemaker, or are identified as at-risk for cardiovascular events. 
• All candidates who are pregnant or lactating. 
• All candidates with a lower extremity biomechanical prosthetic. 
• All candidates with a history of seizures (except those in the acute or post-acute phases, and 
are controlled). 
• All candidates who experienced a loss of consciousness greater than 24 hours as a result of 
their TBI. 
• All candidates with a “severe” score in any of the Attention, Memory, or Executive 
Functions categories on the Cognitive Linguistic Quick Test (CLQT). 
• All candidates who, in the opinion of the investigators, are unable to feel the stimulation and 
successfully complete the device level setting procedure. 
 
Recruitment Process. 
Candidates reporting, suspected of having, or presenting with persistent deficits in balance as a 
result of mTBI are eligible for recruitment for this study. Candidates will be drawn from clinician 
and self-referrals generated from study announcements to clinical colleagues & collaborators, 
posting on clinicaltrials.gov, UW-Madison Division of Information Technology (DoIT) mass 
email (faculty, staff and students), ads in local media such as the Wisconsin State Journal (print 
and online). The recruitment fliers, a list of inclusion/exclusion criteria and/or postings similar to 
the ClinicalTrails.gov listing will be electronically posted on our website, and the websites of 
collaborating institutions, such as the Brain Injury Alliance Additionally, we will provide a 
summary of this research, fliers and postcards to providers that treat this patient population, e.g., 
neurologists and medical physicists at UW Hospitals & Clinics. These providers will help identify 
potentially eligible subjects and will introduce this research to them and may provide a copy of the 
study flyer and/or postcard. Patients interested in participating will be referred to a study team 
member who will provide more information about participation and will assess initial eligibility.  
Potential study candidates who have contacted the TCNL by telephone or email and indicated an 
interest in participation will be scheduled for a phone interview. The study will be described to the 
candidate on the phone. If interested, the candidate will be asked to provide oral consent to answer 
questions related to study eligibility. Persons who meet the eligibility requirements will be asked 
to mail us their MRI/CT report, PT discharge summary, medication list) to help determine 
eligibility. These documents will be reviewed by the study Medical Advisor. If the candidate is 
determined to be ineligible, the documents will be destroyed. Subjects who are eligible will be 
asked to come to the lab, where we will obtain written informed consent and perform the CLQT, 
SOT, and 20-minute walk on treadmill to see if the candidates meet the remaining entrance 
criteria. The MRI/CT report, PT discharge summary and medication list will be filed in a locked 
filing cabinet in a locked room in the TCNL Lab to maintain subject privacy per HIPAA 
regulations. All subject recruitment, interventions, and testing are performed at the Tactile 
Communication Neurorehabilitation Lab, 455 Science Drive, Madison, WI 53711.  
 
Consent Process.  
Candidates who have passed the phone screening will schedule a meeting with the Study 
Coordinator at the TCNL. The Study Coordinator will provide informed consent for the main TBI 
Study, answer questions and obtain informed written consent. Candidates may ask questions 
before signing the informed consent form. After completion of the TBI Study consent, the Study 
Coordinator will also provide informed consent for the MRI Sub-study and explain that 
participation in the sub-study is optional. All candidates will be informed that declining 

 
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participation in the MRI Sub-study will not affect their participation in the TBI Study. The PIs for 
both studies will be available to answer candidates’ questions. All candidates are free to decline 
participation in either study without question if they so choose. Subjects will be given a copy of 
the signed consent form(s). 
 
Subject Screening Procedure.  
Once written informed consent has been obtained, the candidate will complete the Demographic 
Survey, the Subject Health Questionnaire, the CLQT, the SOT, and walk on the treadmill for 20 
minutes. The results will be used to determine if the subject meets the study remaining entrance 
criteria. For those candidates that qualify for study, the SOT performed at screening will be 
recorded as the subject’s baseline score.  
Candidates who meet all screening criteria will be enrolled in the study and assigned a unique 
study identifier. Candidates that fail any portion of the screening will be excused from 
participation. All candidates who choose to enroll in the TBI Study will also be offered the 
opportunity to enroll in the MRI Sub-study.  
 
Confidentiality of Screening Materials. 
For persons who do not meet the entrance criteria, all personally identifiable records used for 
screening will be destroyed. 
 
Compensation for Participation.   
Subjects will be paid for participation at the end of each phase of the study [$800 after Stage 1 (2 
weeks In-Lab), $600 after Stage 2 (12 weeks in HTP), and $600 after Stage 3 (12 weeks in 
withdrawal and 26 weeks total) for a total of up to $2,000]. Subjects will be reimbursed for vehicle 
transportation costs from their residence to the lab for all visits (except screening), and for housing 
during Stage 1 if they live more than 30 miles from the UW-Madison campus. Reimbursement 
will be based on rates published by the University of WI for research subjects during the period of 
participation in the study. If a subject resides greater than 4 hours away from the lab, we will 
reimburse for mileage, if driving, or, if he/she chooses to travel by air, $250 + 25% of the cost of 
round trip airfare for all visits (except screening). Reimbursement for airfare will be based up the 
requirements of the UW Air Travel Policy. 
 
PoNSTM Device  
Technical Description 
The portable neuromodulation stimulator (PoNSTM) device is held lightly in place by the lips and 
teeth around the neck of the tab that goes into the mouth and rests on the anterior, superior part of 
the tongue. The paddle-shaped tab of the system has a hexagonally patterned array of 143 gold-
plated circular electrodes (1.50 mm diam., on 2.34 mm centers) created by a photolithographic 
process used to make printed circuit boards (Figure 6, lower right). The system has operational 
limits of 19 V (max) on the tongue (a nominal 5–7 k-ohm load). The biphasic waveform is 
specifically designed to ensure zero net dc current to minimize the potential for tissue irritation.  
The PoNS 2.5 device has 2 user-controlled power buttons: “On” and “Off”. The stimulus intensity 
level for both the Active and Control PoNS v2.5 devices will be set by the PI in cooperation with 
the subject at the first training meeting and cannot subsequently be altered by anyone other than 
the PI. It has stimulation level, time, and date logging capabilities to monitor protocol compliance 
when off site. This feature allows for assessment of stimulus dose response. The system delivers 

 
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triplets of 0.4 - 60µs wide pulses at 5 ms intervals (i.e. 200 Hz) every 20 ms (50 Hz) that has been 
designed to balance stimulus dynamic range and sensation quality [Bach-y-Rita, 1998; 
Kaczmarek, 2000 (a,b), 2012; Tyler, 2009]. At any instant in time, one of the electrodes in each of 
the 16 sectors on the array is delivering stimulation while the remaining electrodes serve as the 
current return path to ground. The voltage and pulse timing to each electrode is programmed in the 
device and cannot be altered.  
The PCB is an industry-standard polyimide composite (P95, Isola Group, Chandler, AZ) that is 
USP Class VI compliant and meets ISO 10993 biocompatibility standards. The edges and top of 
the array tab are subsequently coated with a rugged USP Class VI biocompatible epoxy (Epotech 
302-3M, Epoxy Technology, Billerica, MA). Therefore, the only materials that contact oral tissues 
are the gold electrodes and the biocompatible polymers. The remainder of the PCB and all 
electronic components, including battery, are in a sealed Delrin (USP Class VI compliant) 
enclosure.  
 For regulatory purposes the bottom of the device is labeled as follows: 
"CAUTION - Investigational Device. Limited by Federal (or US) law to investigational use". 
“University of Wisconsin-Madison 
http://tcnl.bme.wisc.edu 
Model number (TBD) 
Version 2.5 S/N 30xx" 
 
The enclosure measures 6.8 cm (w) x 4.4 cm (d) x 2.3 cm (h), and has total mass of 63.6 grams 
that remains outside of the mouth. This configuration produces a downward moment of only 
0.0170 Nm about the front teeth. The paddle shape of the array allows the device to fit behind the 
front teeth of the upper palate and pivot on the lower incisors so that it may be held it in place with 
the lips and virtually no bite force is required. It allows subject with all but the most severe 
problems of bruxism or bite control modulation to hold the device in their mouth without 
difficulty during the training. The device also has a neck strap with a breakaway clasp to prevent it 
from falling from the user’s mouth while not presenting a strangulation hazard. The device should 
be stored and used at temperature between 5 and 50˚C (both in the lab at home by the user), and 
will be disinfected, inspected and tested after completion of use by each subject. A User 
Instructions document will be provided with each device for directions on operation and cleaning. 
 

 
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Figure 6. Image of the PoNS 2.5 device.  The tongue array is on the right. 
Device Deployment 
For each CN-NINM training session, participants will place the tab of the PoNS™ a maximum of 
45 mm into their mouth so that it contacts the anterior, superior surface of the tongue. At the 
outset of CN-NINM training, subjects with the Active device will be instructed to adjust the 
stimulus intensity, to reach their minimum sensation threshold, St, and then the maximum level, 
Sm, without discomfort. The experimental stimulation intensity, Se(A), is calculated and pre-set to a 
value of 75% of the stimulus dynamic range, Sm - St, so that Se(A) = St + 0.75(Sm - St). Sensory 
adaptation occurs after 1-3 minutes of stimulation, requiring a small increase in the absolute 
intensity level. To accommodate for this adaptation and to avoid startle due to sudden onset of 
stimulation at Se, the intensity will ramp up from St to Se over a period of 30 seconds. 
The Control device appears physically identical, but uses a modified stimulus waveform parameter 
set designed to elicit a mild tactile sensation while minimizing the net energy delivered, thereby 
minimizing any neuromodulatory effect. This is accomplished by using a pulse frequency that is 
slowed to approx. 1/2400th that of the Active device. The Control group will be identically 
instructed to determine St and Sm, with the Control experimental stimulus, Se(C) preset [Se(C) = St + 
0.75(Sm - St)], to encourage compliance with the protocol by assuring that the subject can feel the 
stimulation. 
 
Study Procedures & Research Interventions.  
General Testing Plan: Upon enrollment in this research study the following testing will be 
conducted at baseline. These tests will take approximately 3 hours. The primary and secondary 
measures will be used to assess the effect of the intervention on the symptoms of balance and gait 
deficit. The observational measures will provide essential data for potential future studies 
investigating CN-NINM intervention specifically targeted to a particular function deficit. These 
same metrics will be applied during the course of the study according to the schedule in Table 6. 

 
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• 
Primary 
outcome - NeuroCom CDP Sensory Organization Test (SOT) - Measures standing dynamic 
balance. 
• 6-Minute Walk Test - over ground (6MWT) - Measures walking speed. 
• Dynamic Gait Index (DGI) – Assesses walking, walking with head turns, over and around 
obstacles, and stairs. 
• Physiological Stress Test - Resting & post exercise, heart rate, respiration, skin conductance, 
core temperature. 
• Neurobehavioral Symptom Inventory (NSI) - Subjective inventory of TBI symptoms. 
• California Verbal Learning Test (CVLT) – Assesses short- and long-term verbal memory. 
• Brief Symptom Inventory 18 (BSI 18) – Assesses anxiety symptoms. 
• Wechsler Adult Intelligence Scale – Symbol Search and Coding (WAIS-IV) – Assesses 
visual spatial abilities. 
• Pittsburgh Sleep Quality Index (PSQI) - Subjective inventory of sleep habits, duration and 
quality.  
• Headache Disability Index (HDI) – Assesses frequency & severity of headaches 
• Quantitative Gait Assessment and EMG – Measures stride length and width, and muscle 
activation patterns during gait. 
• Computerized video nystagmography (VNG) - Measures eye movement control. 
 
There are items on the BSI 18 designed to identify depression and one item that asks specifically 
about suicide ideation. If the participant endorses this item at the level of "a little bit" or above, we 
will give him/her information about local (or national, if appropriate) suicide prevention resources. 
If the participant scores in the clinical range overall or on the Depression and/or Anxiety Scales, 
we will give him/her information about local or national mental health resources. To minimize 
risks posed by responding to items on the BSI 18, we will score the inventory while the participant 
is still on site. If the participant has a Global Severity Index T score of 63 or higher (according to 
the test norms), we will present him/her with information about local counseling and mental health 
resources. We will also use the BSI 18 norms to determine if the Depression and/or Anxiety scores 
are in the clinical range, and if so, will present the participant with information about resources. 
 
CN-NINM Intervention 
The goal of clinical training is to maximize the subject’s participation in order to optimize the 
potential effects of CN-NINM. Subjects will complete intervention sessions three times per day 
for fourteen weeks (stages 1 and 2). Each 1 to 1.5 hour session may include:  a) therapeutic 
exercise for isolated movement control, b) maximal challenge balance training, c) gait training, 
and d) breathing and awareness training. The intervention intensity in each modality is progressed 
according to each subject’s particular initial symptoms while also being consistent and 
standardized for all subjects.  
In stage 1, subjects will complete the twice-daily training sessions in the lab under the supervision 
of a Physical Therapist. In stage 2, subjects will complete the twice-daily training sessions at home 
for 6 days per week. They will return to the lab once each week for a training session to correct 
and progress their program. Every three weeks they will be re-tested on the primary and two 
secondary metrics. In stage 3, subjects will no longer use the PoNS device. They will return to the 
lab for testing every three weeks. 
Table 4, below, represents the approximate timeline of events that will occur for each subject 

 
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during the study. A typical daily training schedule for the 14-week period of the study for each 
subject is shown in Table 5. Details of how subjects will be trained and the progression of the 
exercises are discussed in each subsection. 
 
A Remote Audio Visual (RAV) training session may be performed in place of the in-lab weekly 
training session for weeks 3, 4, 6, 7, 9, 10, 12 & 13 in the event that the subject does not live 
locally, defined as a distance greater than a 4-hour drive from the lab, or for any instances, made 
on a case-by-case basis by the PI, when extenuating circumstances prevent a subject from 
attending an in-lab training session. In order for this to occur, subjects are required to have 
computerized video communication capability (e.g., Skype, FaceTime), and 2 assistants (one for 
safety and one to handle the video interface). 
 
 
 
 
 
 
 
 
 
 
Table 4 – Event timeline for each subject in the study 
 
 
 
 
Initial Visit  
Stage 1 
(2 weeks) 
Stage 2 
(12 weeks) 
Stage 3  
(12 weeks) 
 
Prior to 
beginning 
intervention 
In lab 
2x/day 
Last P.M. 
of 2nd 
week 
At home 
2x/day 
In lab 
1x/day 
per 
week 
Every 3-
weeks 
Every 3 
weeks 
Screening, Health 
History 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Testing 
X 
 
X 
 
 
X 
X 
CN-NINM Training 
 
X 
 
X 
X 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
 
 
Table 5 - Daily Training Program 
Morning:      Movement Training (warm up) 
 
 
 
10 minutes 
Balance Training with PoNS  
 
 
 
20 minutes 
Gait Training with PoNS  
 
 
 
 
20 minutes 
BAT with PoNS  
 
 
 
 
 
 
 
20 minutes 
- 3 to 4 Hour Break - 
 
Afternoon:  Balance Training with PoNS™  
 
 
20 minutes 
Movement Control Training 
 
 
 
 
20 minutes 
Gait Training with PoNS™ 
 
 
 
20 minutes 
 
Evening:  
BAT with PoNS  
 
 
 
 
 
 
 
20 minutes 
 
 
Movement Training (warm up) 
Movement training has 2 components. The first component is warm up exercises. Subjects 
perform these exercises to prepare the body for work. These include chin retractions, shoulder 
circles, scapular circles, pelvic tilts, pelvic figure 8’s, and single leg figure 8’s. All subjects will be 
trained in these exercises.  

 
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Movement Control Training 
The second component of Movement Training is exercises for motor control. Subjects with 
neurological disorders typically develop compensations resulting in abnormal movement patterns. 
The exercises for this study are targeted to each subject’s gait abnormalities. This targeted training 
helps the subject develop the proper control patterns and synergy needed for correct movement. 
This is accomplished by reinforcing correct vectors of control (speed, force, direction, continuity, 
and range of motion). Emphasis is on quality of movements performed with accurate control.   
 
Exercises to improve gait may include lower extremity isolation, core strengthening, or upper 
extremity movement to improve arm swing. An example of a lower extremity exercise is a heel 
rocker. The subject takes a step, holds the feet in place, and rocks forward and backward. This 
promotes toe lift during heel strike, and ankle range of motion and strength during push off. The 
PT’s will train the subjects in the exercises and monitor their progression. Subjects will be 
progressed to more challenging exercises as they improve. 
 
Subjects may present with a variety of gait abnormalities, although based on prior experience, we 
anticipate that many of them will be similar. We will develop a catalog of movement exercises 
that are most likely to be effective with this population for use in subsequent studies. In the case 
where a subject exhibits normal gait, we will not assign any movement exercises to that subject. 
Regardless of their gait presentation, all subjects will perform gait training for this intervention. 
 
Balance Training (with PoNS) 
Balance training with CN-NINM focuses on developing stable balance during upright standing 
posture, and on establishing a sense of confidence in the subjects’ posture and stability. The goal 
of balance training is to create body awareness, correct postural alignment, and improve balance 
by recalibrating proprioceptive, tactile and vestibular inputs. The balance training begins at 
whatever initial condition the subject can sustain for 2 minutes, e.g. feet at shoulder width on a 
hard surface, eyes open and touching a training table with one or two fingers for tactile-spatial 
orientation. Training will progress from their initial state with increasingly challenging stance 
postures, up to feet together on a soft base with eyes closed and without tactile support. During 
this period, subjects will also receive verbal and physical cues to maintain correct postural 
orientation in order to retrain their nervous system to accept a new postural set point. This is a 
crucial progressive postural awareness and retraining process that will help the subject to 
confidently maintain their center of mass within their base of stability without visual or tactile 
aids.  
Initial balance training requires that the subject perform three progressively challenging 2-minute 
balance trials while using the PoNS™ device to determine their current functional capacity. The 
challenge levels are on a continuum from “able to perform easily” to “able to perform with 
difficulty” in that task. This initial assessment is followed by a 20-minute session in a comfortable 
but challenging position with the PoNS™ device. After the initial training, all subsequent balance 
training consists of a 20-minute session with the PoNS™ in progressively challenging conditions, 
e.g. standing with feet closer together on a stable surface, then progressing to a compliant surface 
(e.g. AirEx foam pad). Foam pads will be supplied to the subject for use during the HTP. Trainers 
will use the Balance Training Flow Chart for balance progression. 
Subjects will use headphones to listen to audio programs with ambient sounds during balance 
training. This will help mask out external environmental noise that may distract the subject from 

 
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their balance task. These audio tracks are installed as MP3 files on TCNL’s iPod. The audio files 
will be supplied to the subject for use on the MP3 or other audio device of their choice during the 
HTP. 
Gait Training (with PoNS) 
Deficits in gait speed and spatiotemporal symmetry are common in people with neurological 
disorders. The goal of gait training is to achieve normal gait. During gait training subjects will 
walk on a treadmill and over ground at progressive speeds and challenges to re-establish 
appropriate dynamic balance and gait patterns. Particular attention is given to symmetry of the gait 
pattern, including dynamic weight transfer, stride kinematics of hip, knee, and ankle 
flexion/extension, and of the stance and swing phases. In-lab gait training will be performed on the 
treadmill for the first week, and on the treadmill and over ground the second week. It is 
recommended that subjects use a treadmill for at least 50% of the HTP to control and monitor their 
training. 
 
Treadmill Training 
The physical therapist will work with the subject to determine an appropriate starting point. As in 
balance training, the appropriate challenge on the treadmill is assigned relative to the subject’s 
baseline.  
On the treadmill, the first 5 minutes are done at a comfortable pace. Every 5 minutes, the 
challenge should be increased. This is done by changing a variable. Variables include:   
• Speed: Increasing the speed increases the challenge.  
• Grade: An incline increases effort and affects the work of ankle dorsiflexors, knee and hip 
flexors.  
• Handrails: Using the handrails allows greater stability. Increase the challenge by decreasing 
hand contact time and force on the rails, with the goal of achieving arm swing 
commensurate with normal gait. 
• Head movement: Turning the head while walking increases the challenge. 
For the last 5 minutes, the subject should work at a challenging but comfortable pace. They should 
be able to maintain good posture and quality of movement. It is expected that each session of gait 
training will start at a higher level than the previous session.  
Over Ground Training 
Subjects will work with the trainer on walking over ground to transfer skills learned on the 
treadmill to regular gait. Trainers will use verbal and tactile cues as needed to correct posture and 
abnormal movement patterns during gait.  
 
Breathing and Awareness Training (BAT) (with PoNS) 
The goal of breathing and awareness training is for the subject to develop relaxed and mindful 
breathing and awareness. A BAT session requires 20 minutes of continuous PoNS™ use with 
relaxed attention, breathing, and concentration. Visualization and breathing are the focus points. 
BAT, also referred to as relaxation training, can have a significant impact on training progress. A 
20-minute BAT session should be performed in a supported body position, uninterrupted with 
eyes closed, and with no distracting sounds. Headphones and MP3s with ambient sounds are 
sometimes used for BAT sessions. 
 

 
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Data Collection  
The scheduled assessments and frequency in which they will be performed is listed in Table 6. If 
any anomalies or unforeseen circumstances occur (e.g., an unexpected delay occurs between 
baseline testing and start of treatment, a significant difference is observed in the assessment results 
from one test point to the next, etc.) additional assessments may be performed. The decision to 
perform additional assessments will be made on a case-by-case basis at the discretion of the PI.  
The following exceptions may also be made on a case-by-case basis at the discretion of the PI: 1.) 
test points 1, 2, 6 and 10 may be performed on more than one day, 2.) test point 2 may not occur 
before the completion of stage 1, but may be performed within 2 days after the end of stage 1, and 
3.) test points 6 and 10 may be performed within 2 days before or after the end of stages 2 and/or 
3. 
Prior to collecting any of the data scheduled in Table 6, all subjects will have been consented into 
the study and completed all of the screening stages. All data to be collected are study-related. This 
investigation will not access any health records of subjects. The health information requested in 
our screening questionnaire is only that which is necessary to correctly ascertain subject eligibility 
for participation in the study. Health information is reviewed with the subject in private by the 
investigators. Subjects are fully clothed at all times.  
Subjects may be videotaped during evaluation or during treatment sessions for use in presentations 
at professional conferences to demonstrate changes in symptoms due to the intervention. Subjects 
will be asked for their permission to be videotaped and their acceptance or rejection of permission 
to do this is obtained during the written informed consent procedure. Subjects will be given the 
option to be recorded but not allow the video to be kept indefinitely. If subjects make this choice 
we will destroy the videotape when study analyses are complete. Subject faces may be 
identifiable, but the subjects will not be identified by name or any other personal identifier in these 
videotapes.  
We are not utilizing computer-generated questionnaires. All data collection materials are coded 
with unique subject identification numbers and the master log of the subject identifiers is stored 
separately from the health information and informed consent documents. Only members of the 
core research team have access to the list that pairs subject names with numbers. Subject data 
folders are maintained in a secure file cabinet where only the core research team has access. Video 
files are stored on encrypted external hard drives. The external hard drives are encrypted with 
password protection and access is limited to the TCNL physical therapy staff. 
 
 
 
 
 
Table 6. Study data to be gathered about each subject:  
 
Assessment  
Data 
Frequency 
General Health 
Questionnaire 
History of brain injury, 
communicable diseases, 
diabetes, oral health, seizures, 
surgeries, medications, rehab, 
major co-morbidities; 
concussion history; ability to 
walk 20 minutes. 
• Screening 

 
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Assessment  
Data 
Frequency 
Demographic Survey 
Name, address, phone, email, 
date of birth, ethnic 
background (optional), 
education, gender 
• Screening 
Cognitive Learning Quick 
Test (CLQT) 
Attention, memory (working, 
procedural, semantic, 
episodic), and executive 
function 
• Screening 
Sensory Organization Test 
(SOT)  
Balance 
• Screening 
• End of stage 1 
• Every 3 weeks during stages 2 
& 3 
6-Minute Walk Test 
(6MWT) 
Gait 
• Screening 
• End of stage 1 
• Every 3 weeks during stages 2 
& 3 
Dynamic Gait Index (DGI) 
Gait 
• Screening 
• End of stage 1 
• Every 3 weeks during stages 2 
& 3 
Quantitative Gait 
Assessment*  
Gait 
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  
Physiologic Stress Test 
Resting & post exercise: 
HR, respiration, skin 
conductance, & core 
temperature 
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  
Neurobehavioral Symptom 
Inventory (NSI) 
TBI symptoms 
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  
California Verbal Learning 
Test (CVLT) 
Short and long term verbal 
memory  
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  
Brief Symptom Inventory 
18 (BSI 18) 
Anxiety symptoms 
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  

 
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Assessment  
Data 
Frequency 
Wechsler Adult 
Intelligence Scale – 
Symbol Search and Coding 
(WAIS-IV) 
Visual spatial abilities 
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  
Pittsburgh Sleep Quality 
Index (PSQI) 
Sleep habits, duration and 
quality - Subjective inventory  
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  
Headache Disability Index 
(HDI) 
Headache frequency & 
severity  
• Baseline 
• End of stage 1  
• End of stage 2  
• End of stage 3  
Video Nystagmography** 
Dynamic oculomotor control 
behavior 
• Baseline 
• 1st day of stage 1 (pre-
treatment) 
• End of stage 1  
• End of stage 2  
• End of stage 3  
 
* Quantitative Gait Analysis: Muscle activation patterns for two 60-second treadmill-walking 
trials and one 60-second period of over-ground walking will be collected using electromyographic 
(EMG) records of bilateral muscle activity on the lower and upper leg. At the same time, 
accelerometers placed at the waist and the heels will be used to index and assess the gait cycle. 
Study personnel will provide stand-by assist to guard for loss of balance. 
 
** Video Nystagmography: Six standardized VNG tests (3 static: Horizontal fixation, Vertical 
fixation, Spontaneous nystagmus; and 3 dynamic: Random saccades, Smooth pursuit, Optokinetic) 
will be used to test and score subject eye fixation stability and movement control. VisualEyesTM is 
the standard for video nystagmographic observation, recording, and playback of ocular 
movements. Because the visual system is a primary contributor to motor, social, cognitive, and 
emotive functions, and oculomotor deficits require a significant, if unconscious, amount of 
attention in persons with TBI. Consequently, oculomotor monitoring methods that can observe 
this demand on the injured brain can be used to quantify any effects of neurorehabilitation due to 
the CN-NINM intervention.  
 
Data Safety and Monitoring Plan 
All study records will be structured and maintained as required under 21 CFR 812.140, and the 
investigators will make reports as required under 21 CFR 812.150.  
Unanticipated adverse device effects  
1. The PI and the Medical Advisor will immediately conduct an evaluation of any unanticipated 
adverse device effect. 

 
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2.  If the investigators determine that an unanticipated adverse device effect presents an 
unreasonable risk to subjects, they shall terminate all investigations or parts of investigations 
presenting that risk as soon as possible. Termination shall occur no later than 5 working days 
after the investigators make this determination and no later than10 working days after the 
investigators first received notice of the effect. 
3. If the investigation was terminated due to unanticipated adverse device effects, the investigation 
may not resume without IRB approval. 
 
Missing Data 
We do not plan to recruit additional subjects to replace dropouts because we have increased the 
sample size to account for potential dropouts. We will make efforts to obtain follow-up data on 
subjects who withdraw from treatment. Due to the pilot nature of the study, we do not plan to do 
imputation for missing data points. Instead we will do a complete case analysis as well as a 
sensitivity analysis to examine the effect of the missing outcome data. 
 
Compliance 
We will respect the principle of Intention to Treat and will not remove subjects for protocol non-
compliance. We have established the following a priori definition of compliance:  
Subjects who miss more than 20% during any one-week period will be considered 
noncompliant with the training protocol.  
 
 
Data Access and Management 
The TCNL will work with ICTR to develop a database in OnCore® that will capture test scores 
(both written and electronic), and associate the unique identifier to the file for each subject. The 
PI, Study Coordinator, Clinical Monitor, PTs and designated study staff will have access to the 
database during the course of the study. It will be the responsibility of the PI to ensure data are 
entered into the OnCore database in a timely and consistent manner. Data are recorded on data 
collection forms, transcribed onto case report forms (CRFs) and entered into the OnCore database 
by study staff. An independent staff member reviews the data collection forms, CRFs and verifies 
that data were entered correctly. Treatment group and personal identifying information will not be 
entered into the OnCore. These records will be maintained in a separate secure file location to 
maintain control of the study and avoid potential experimenter bias. 
Data captured on all source documents from the study (demographics, Health Questionnaire, 
CRF's, ADE's, SAE's, assessments) will be entered into an OnCore database managed by the Data 
Monitoring Committee (DMC) of the Institute for Clinical and Translational Research (ICTR), an 
NIH-funded program comprising UW faculty not associated with the funding source or TCNL and 
knowledgeable in the Neurorehabilitation field. A US Army Medical Department Medical 
Research and Materiel Command (USAMRMC) Monitor has been assigned to protocol 2014-0002 
and will perform site visits and review study data. The USAMRMC Monitor will compare data on 
data collection forms and case report forms (CRFs) with data entered in OnCore, including but not 
limited to accrual, study data, adverse events, serious adverse events and protocol deviations. Any 
discrepancies will be issued and resolved using the querying functionality in OnCore. Results of 
the monitoring performed by the USAMRMC Monitor are available for DMC review. 
Additionally, the study will be monitored annually by the DMC. The DMC members will review 
protocol-specific reports created by statisticians using data pulled from the ICTR OnCore clinical 

 
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research management system.  The ICTR DMC will meet with the Investigators to review data, 
analysis, subject accrual including rate and origin of subject referrals, and any adverse events. An 
interim analysis of study results may be performed and source documents may be reviewed to 
allow the DMC to independently judge whether the overall integrity and conduct of the protocol 
remain acceptable based on data provided and reported by the Principal Investigator. The DMC 
will make recommendations to the Principal Investigator that could include actions of 
continuation, modification, or termination.  The ICTR DMC will review all manuscripts prior to 
submission for publication. Written minutes of the ICTR DMC meeting in which this study is 
reviewed will be prepared and provided to the investigators and the SMPH Office of Research and 
Graduate Studies." 
 
Confidentiality 
The PI will keep records of the subjects’ participation in the research. To protect subject privacy, 
all research-related records will be labeled with a coded identifier that is unique to that research 
participant and will not include the subject's name, service, or social security number. The PI will 
keep a separate file that creates the only link between participant identifier and research records in 
a locked file in a locked records room. Video files are stored on encrypted external hard drives. 
The external hard drives are encrypted with password protection and access is limited to the 
TCNL study team.  We use VeraCrypt and the lab’s unique secure key code. All TCNL 
evaluation and/or treatment related records used for the research study or any of research-related 
records necessary for evaluation will be secured in HIPAA compliant medical records in the 
TCNL.   
Details regarding identities of the participants will be protected per HIPAA regulations regarding 
Protected Individual Information. Physical files fill be stored in a separate locked file in the locked 
records room for 7 years. Video files are stored on encrypted external hard drives.  
To protect subject privacy during RAV training sessions, Skype and FaceTime call are only made 
using a TCNL account and physically secure TCNL computer. Both the accounts and the 
computer are password-protected and accessible only by study PTs, the Study Coordinator and PI. 
Contact information (e.g., subject name and phone number) may be required to perform RAV 
training sessions. The PT only creates user accounts for the subjects participating in RAV training 
and provides the information necessary to access calls from the TCNL. Security certificates are 
issued when the call is made from the TCNL and can only be received and accessed by an 
authenticated user (the study subject). The call stream is made using a secure protocol and 
encrypted by both Skype and FaceTime. 
Study staff may use e-mail to communicate with research subjects. Prior to any email exchanges, a 
study staff member will review the Guidelines for Using Email and the subject must agree to use 
email communication by signing a Provider-Patient Email Information and Consent form. The 
information contained in emails will be limited to training program information, such as a 
summary any changes to training program, answers to any questions that were asked regarding 
training during a training session and/or a copy of the subject's home exercise program. The 
subject home exercise training program contains the exercises/physical therapy training to be 
performed by the subject during the at home training stage and may include a description and/or 
photographs of the subject performing the exercises/physical therapy training. Images used in the 
training programs will not contain full-face photographs. All emails to subjects will be sent from 
UW/wisc.edu accounts; personal or home email accounts will not be used. 

 
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When the results of the research are published or discussed in conferences, no information will be 
included that would reveal the subjects’ identity to others.  
Authorized representatives of the following groups may need to review this research as part of 
their responsibilities to protect research participants: 
• U.S. Army Medical Research & Materiel Command (MRMC) Institutional Review Board 
• U.S. Army Human Research Protections Office and other DOD offices charged with 
oversight of human research 
• U.S. Army Medical Materiel Development Activity 
• U.S. Department of Health & Human Services Office for Human Research Protections 
• University of Wisconsin – Madison Health Sciences Human Subjects IRB. 
• University of Wisconsin –Institute for Clinical and Translational Research – Data 
Monitoring Committee. 
 
Coded data (results only) will be shared with the MRMC via secure email for purposes of 
informing future studies.  
 
Statistical Considerations  
Sample Size Estimation   
This study will be an experimental investigation and will employ descriptive statistics to discover 
the mean changes from baseline for Control and Active, and then calculate true effect sizes and 
corresponding variances both within and between the two treatment groups. It is a first step in an 
iterative, incremental process to generate enough data to make reasonable power calculations in 
subsequent controlled studies. We believe this approach is justified because we have a very small 
data set from which to draw estimates of effect size, and none regarding a control group response. 
Our estimates are based on large changes in SOT scores in the previous pilot study involving 4 
civilian subjects with mild to moderate concussive TBI using an Active device.  
For this study we have assumed that the Control group response will be half that of the active 
group. Using a two-sample t-test to estimate the sample sizes of the experimental group and the 
control group, and assuming equal variances in the two treatment groups with σ = 0.5; a 2-tailed 
significance level, α = 0.05; the true difference of the means = 0.5, and setting the power at 0.80, 
we calculate that a cohort of 17 subjects in each arm is sufficient. Based on our previous 
experience in two controlled pilot studies, we estimate a drop-out rate of not more than 25%. In 
using this conservative estimate, we believe the study is sufficiently powered at 22 subjects per 
treatment group (44 subjects total) to generate the data necessary to calculate effect sizes and 
cohorts in the future.  
 
Primary Endpoints and Observational Measures  
The primary outcome measure is the Composite SOT score. Observational measures are the 
Neurobehavioral Symptom Inventory, California Verbal Learning Test, Brief Symptom Inventory, 
Wechsler Adult Intelligence Scale – Symbol Search and Coding, Pittsburgh Sleep Quality Index, 
Headache Disability Index, Physiologic Stress Response, Quantitative Gait Assessment using 
EMG, 6 minute walk test, Dynamic Gait Index, and Computerized Video Nystagmography. The 
observational measures will provide essential data for potential future studies investigating CN-
NINM effects on a particular functional deficit. 
 
Data Analysis  

 
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An interim analysis will be performed when 22 subjects have completed the second phase (At-
Home Training), and a full investigation at the completion of the study.  
 
• Interim Analysis: In compliance with the request from the funding agency (US Army Medical 
Research and Materiéls Command), a single independent interim analysis will be conducted under 
a Statistical Analysis Plan (SAP) developed for this study and reviewed by the Biostatistics Group 
at ICTR. The primary independent measure: Active vs. Control PoNS. The interim analysis will be 
performed after 22 subjects have completed the 6th data point (at 14 weeks - the completion of the 
At-Home phase of the study) 
The primary analysis will be conducted under the intention-to-treat principal, and all data will be 
included. We will not conduct a missing data imputation analysis. Every attempt will be made to 
obtain follow-up data on subjects who withdraw from treatment.  
The interim analysis will be performed using the primary efficacy endpoint for the data of first 22 
subjects that have completed the Week 2 and Week 14 visits. The two treatment groups will be 
listed only as "Group 1" and "Group 2" to maintain the blinding of the treatments. 
The number of subjects (most likely 11), and both the Mean and standard deviation (SD) for each 
group will be calculated by the study statistician. Student’s t-test will be used to compare the two 
means. A p-value will be generated but no decision will be made at the interim analysis time, and 
the trial will continue to completion unless there are serious safety concerns. 
The study statistician will present the interim analysis results (n, Mean, and SD) by treatment 
group in unblinded fashion including the p-value to the DSMC.  
Also, the statistician will present these results to the sponsor of the study but in the blinded fashion 
by identifying the treatment groups only as Group 1 and Group 2. 
 
• Final Analysis: A repeated-measures ANOVA will be performed on the data derived from the 10 
outcome measures gathered for each subject. Both individual (n=1) and cohort data set (n=22) 
analysis will be conducted to identify both specific and generalizable effects of the intervention 
methods. Sub-analysis by gender and age in both treatment groups will also be performed to 
assess the relative response of females and males.  
Evidence of efficacy will be determined by significant differences in outcome measures both 
within and between groups after both the two-week intensive phase and at conclusion of the 14 
weeks. Changes of 8 points in the SOT are considered clinically significant. 
Data logs for each individual will be entered into the OnCore Data Management System used by 
ICTR for independent analysis and experimental verification.  
 
Risks/Benefits Assessment 
Potential Risks 
1. Electrotactile Stimulation.   The sensation could become uncomfortable at high intensity levels, 
which could be distressing to the subject. Some subjects have reported a mild tingling 
sensation that lasts from several minutes up to an hour after the stimulus is turned off. 
Although this sensation may feel unusual, it is not reported to be annoying and does not 
interfere with normal activities. 

 
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2. Excess Salivation. Subjects may experience excess salivation due to the presence of the PoNS 
in the mouth. 
3. Disease Transmission. Because more than one subject may use the same device, there is a 
potential for disease transmission.  
4. Falls.  Subjects will be performing balance and gait tasks that may cause them to lose their 
balance or fall.  
5. Decreased Performance or No Improvement in Symptoms. There is a risk that when subjects 
stop using the device, they will not retain any improvements they may have gained while 
doing CN-NINM training and their function will return to its prior level. There is also the 
possibility that CN-NINM training will not improve their symptoms. 
6. Confidentialty. There is a risk that someone who is not involved in performing or monitoring 
this study could view study information.  
 
Minimizing Risk 
1. 
PoNS Stimulation. The experimental apparatus cannot deliver a dangerous level of 
electric current. Furthermore, subjects will pre-set the intensity level to within the preferred 
stimulus intensity range, between sensation threshold and maximum level without discomfort. 
Subjects can remove it from their mouth if it does not feel comfortable. 
Although no data are available on the effects of long-term electrotactile stimulation in the 
mouth, we have never observed, nor had report of any tissue irritation following tongue 
stimulation on over 300 subjects and conducted under UW-Madison HS-IRB Protocols 
H2000-0119, H2000-0527, H2001-364, H2004-375, H2005-0192, H2007-0251, H2008-0057, 
H2010-0405, H2011-0335, and 2012-0482. We do not anticipate any problems here. 
2. 
Excess Salivation. Salivation is a natural response to the presence of anything in 
the mouth. Subjects typically learn to regulate saliva by learning to swallow with the device in 
their mouth. This is less a risk than a side effect. 
3. 
Disease Transmission. This risk is reduced to an extremely small level by two 
mechanisms. First, subjects reporting transmittable diseases, or having apparent oral lesions or 
inflammation will not be allowed to participate in the study. Secondly, the electrode array will 
also be cold sterilized according to the protocol developed & approved by UWHC Infection 
Control Office.  
4. 
Falls.  Subjects will be protected from falls wherever possible. During in-lab 
balance training the subject is surrounded on 3 sides by a custom laboratory bench designed 
for this purpose, while the treadmill has a handrail that surrounds the participant on 3 sides. 
Additionally, subjects may be required to wear a safety belt during gait tests and training to 
prevent falls. 
For RAV training sessions, two additional assistants must be present. The first assistant 
protects the subject from injury during performance of the various tasks (balance, gait, 
exercise). The second assistant handles the computer or video interface, and directs the camera 
angle at different positions in order for the physical therapist (PT) to observe the training as it 
occurs. The training session is interactive and the PT instructs the first assistant how and when 
to support the subject. The interaction that occurs in the RAV session with the PT, the 
assistant, and the subject will minimize the risk of falls in a manner equivalent to that of an in-
lab training session. 

 
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During in-lab training, the PT will provide stand by assist during testing and training. Subjects 
must demonstrate safe, independent performance of all at-home training tasks before they are 
assigned these activities to be performed at home. The at-home training program is designed 
for each individual study subject, specifically to reduce the risk of falls 
5. 
Decreased Performance or No Improvement in Symptoms. Subjects will be 
educated in regards to awareness of symptoms and the potential for a return to their prior level 
of symptoms once they stop using the device.   
6. 
Confidentiality. The PI will keep records of the subjects’ participation in the 
research. To protect subject privacy, all research-related records will be labeled with a coded 
identifier that is unique to that research participant and will not include the subject's name, 
service, or social security number. The Clinical Monitor will keep a separate file that creates 
the only link between participant identifier and research records in a locked file in a locked 
records room. Video files are stored on encrypted external hard drives. The external hard 
drives are encrypted with password protection and access is limited to the TCNL study team. 
We use VeraCrypt and the lab’s unique secure key code.  All TCNL evaluation and/or 
treatment related records used for the research study or any of research-related records 
necessary for evaluation will be secured in HIPAA compliant medical records in the TCNL. 
Details regarding identities of the participants will be protected per HIPAA regulations 
regarding Protected Individual Information. Physical files fill be stored in a separate locked 
file in the locked records room for 7 years. Video files are stored on encrypted external hard 
drives.  
E-mail communication with research subjects will be performed in compliance with UW 
Policy and Procedure 8.6 E-mail Communications Involving Protected Health Information. All 
emails will be sent from UW/wisc.edu accounts; personal or home email accounts will not be 
used. The information contained in emails will be limited to training program information, 
such as a summary any changes to training program, answers to any questions that were asked 
regarding training during a training session and/or a copy of the subject's home exercise 
program. The subject home exercise training program contains the exercises/physical therapy 
training to be performed by the subject during the at home training stage and may include a 
description and/or photographs of the subject performing the exercises/physical therapy 
training. Images used in the training programs will not contain full-face photographs. 
When the results of the research are published or discussed in conferences, no information will 
be included that would reveal the subjects’ identity to others.  
 
In the event that a subject is injured while participating in the study, the investigators will follow 
the established standard UW HS-IRB protocol for handling and reporting accidents and injuries.   
The PT will be 'hands-on' in all aspects of the training, and will review both daily and weekly 
progress of each patient for the two weeks of study training. The PI will also review both daily and 
weekly progress of each patient for the 14 weeks of the study. If at any time there are indications 
that the patient is in distress, the training session will be stopped, and both the circumstances and 
the plans for progression will be evaluated and discussed with the patient. Because the primary 
interest is in maximizing beneficial outcome for all subjects, we will take whatever actions 
necessary to ensure their safety and wellbeing.   
 

 
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Potential Benefits 
Based on our preliminary results, we anticipate that some subjects may derive some improvement 
in symptoms from participation. If successful this treatment could reduce rehabilitation time, 
improve return toward normal health status, and enhance retention through reintegration. 
 
Risk/Benefit Ratio 
The anticipated benefits from this intervention include symptom improvement that will affect the 
subject’s quality of life and functional capacities. These benefits far outweigh the risks associated 
with the study. With proper instruction and monitoring, these risks are managed and minimized.  
Benefits to Society: If successful, this treatment could improve the rehabilitation outcomes of 
people with chronic symptoms due to a TBI. Recovery from symptoms and improvement in 
function will allow this population to return to normal social interaction, participate in activities, 
and contribute to society.  
The scientific benefit is that the results obtained will likely far exceed those already obtained, and 
will lend greater credibility to future applications of the intervention. 
 
Adverse Events, Unanticipated Problems 
Adverse Events  
The most likely adverse events are detailed in the section “Risks/Benefits Assessment,” above. All 
possible adverse events are identified and characterized in the appended PoNS Investigators 
Brochure and the PoNS Device Safety Chart. 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others, Serious Adverse Events 
and Deaths.  
All unanticipated problems involving risk to subjects or others and all serious adverse events will 
be promptly reported by the PI and the Medical Advisor according to proscribed procedure: 
http://my.gradsch.wisc.edu/hrpp/10122.htm 
 
Withdrawal from Study Participation 
Subjects are free to withdraw from the study at any time without penalty or explanation. The 
intervention is relatively rigorous in terms of degree and continuity of effort. Some participants 
may find it more challenging than expected.  

 
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Normalizes Activity Within the Motion-Sensitive Brain Network in Balance-Impaired Subjects as Revealed by 
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NeuroImage, 56:2129-2137. 
 
 

 
Addendum – MRI Sub-study 
 
Title:  Characterizing Functional and Structural Brain Changes Following Cranial Nerve 
Noninvasive Neuromodulation (AKA MRI Sub-study). 
 
 
PIs:  Mitchell E. Tyler, M.S., P.E. 
 
 
1550 Engineering Drive 
 
 
2156 Engineering Centers Building 
 
 
Madison, WI 53706 
 
 
metyler1@wisc.edu 
 
 
 
Vivek Prabhakaran, MD, PhD 
 
 
600 Highland Avenue - E3 CSC, Mail Box 3252 
 
 
Madison WI 53792 
 
22 March 2016 
 
Modified: 12 September 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13 October 2016 
 
 
Key Personnel 
• Jenelle Fuller, MRI technologist, will be performing the MRI scans. 
• Kelli Hellenbrand, MRI technologist, will be performing the MRI scans. 
• Sara John, MRI technologist, will be performing the MRI scans. 
• Danielle McIntosh, B.S., Research Intern, will be performing informed consent. 
• Kelly Miller, B.S., Clinical Monitor, will be responsible for randomization of subjects.  She will also 
be responsible for both monitoring regulatory compliance and reporting unanticipated problems 
and adverse events. 
• Veena Nair, PhD, will be accompanying participants to the MRI scans and perform statistical 
analysis of the MRI Sub-study data. 
• Vivek Prabhakaran, M.D., Ph.D., Co-PI, will direct the overall project, assist in interpretation and 
reporting of experimental results, review images for adventitious findings and report both 
unanticipated problems and adverse events.  
• Alexander Remsik, PhD, will be accompanying participants to the MRI scans and perform statistical 
analysis of the MRI Sub-study data. 
• Amy Remm, B.S., Clinical Monitor, will be responsible for regulatory reporting with the US Army 
Clinical Research Monitor (USAMMDA). 
• Kim Skinner, M.S.P.T., Co-Investigator, Study Coordinator, will be responsible for performing  
screening.  
• Mitchell Tyler, M.S., P.E., Co-PI, will direct the overall project, assist in interpretation and reporting 
of experimental results, and report both unanticipated problems and adverse events. 
 
 
 

 
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Study Objectives 
The primary objective of this sub-study is to investigate the cortical and non-cortical changes 
induced by CN-NINM training in patients with symptoms due to a mild to moderate TBI. In this 
sub-study, we will use functional magnetic resonance imaging (fMRI) tasks to identify the 
anatomical locations of the modulated neural activity induced by the tongue stimulation and how 
these changes can produce the behavioral and subjective improvements seen in patients with 
balance disorders after therapy with CN-NINM. A secondary objective is to evaluate the 
relationship between changes in brain and behavioral measures over time. We will evaluate the 
hypothesis that CN-NINM induces greater neuroplasticity in the Active than the Control group in 
areas involved in balance processing as well as by evaluation of major cranial nerves involving the 
tongue: trigeminal, CN-V, and facial, CN-VII and CN XII. An optic flow fMRI task will be used 
to evaluate areas involved in balance processing. A jaw-clenching fMRI task will be used to 
evaluate CN-V; A Tongue-thrust fMRI task will be used to evaluate CNV, VII, and CN-XII. This 
stimulation also has a cascading effect on neural activity in the brainstem (pons varolli and 
medulla), and cerebellum and higher order cortical structures such as the anterior cingulate. 
Neuroplasticity changes will be measured by task fMRI activation changes. 
In addition to traditional task fMRI we will also use advanced neuroimaging methods to 
characterize functional and structural brain connectivity patterns in this population. Resting state 
fcMRI (rs-fcMRI) refers to the temporal coherence between different brain regions indicated by 
spontaneous blood-oxygen-level dependent fluctuations in the absence of any active task 
performance, i.e., when the brain is “at rest” [1-3]. Strong coherence has been identified between 
clinically relevant networks such as the somatomotor, visual, language, memory, and other 
functional networks and several studies have demonstrated test-retest reliability of rs-fcMRI 
measures. In a group of TBI patients in the sub-acute to chronic stage, Bonelle and colleagues 
recently showed that abnormality in default mode network (DMN) function is a sensitive marker 
of impairment of sustained attention [4].  
To identify abnormal structural connectivity patterns in the concussed brain we will collect 
Diffusion Tensor Imaging (DTI) data. DTI evaluates integrity of the white matter (WM) by 
exploiting the fact that water diffuses faster along the main axis (λ1) of fibers compared with 
diffusion perpendicular to fibers (λ2 and λ3) [5-8]. Neuroplasticity changes over time from pre- to 
post-stimulation will be measured by functional connectivity as measured by rs-fcMRI and 
diffusivity and tractography measures as measured by DTI. 
 
Methods 
Sub-study Inclusion and Exclusion Criteria.  
In addition to the inclusion and exclusion criteria in the main study, we will also exclude any 
subjects with contraindications to MR (e.g., claustrophobia, metal implants, etc.). 
 
 
Subjects must also complete the MRI Screening Form (UWH# SR301436-DT [Rev. 02/17/14]) to 
determine final MRI Sub-study eligibility. The MRI Screening Form will be reviewed with 
subjects prior to each scanning session for any changes that could affect eligibility. 
 
 

 
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Total Subjects.  
The sub-study will enroll 26 subjects (13 subjects in the Active PoNS™ group; 13 subjects in the 
Control group). 
 
Consent Process.  
After completion of the TBI Study consent, the Study Coordinator will also provide informed 
consent for the MRI Sub-study and explain that participation in the sub-study is optional. All 
candidates will be informed that declining participation in the MRI Sub-study will not affect their 
participation in the TBI Study. The PIs for both studies will be available to answer candidates’ 
questions. All candidates are free to decline participation in either study without question if they 
so choose. Subjects will be given a copy of the signed consent form(s). 
 
Compensation for Participation.  
Subjects are eligible for the main TBI Study compensation; there is no additional compensation 
for completion of the MRI Sub-study. 
Data Points 
The imaging scans performed in this sub-study will coincide with the 4 major data collection 
points in the main study (Table 1): (1) at baseline (after enrollment but before training has begun); 
(2) at the end of the 2-week in-lab training period; (3) at the end of the 12-week at-home training 
period; and (4) at the end of the 12-week withdrawal period. For data consistency, every attempt 
will be made to schedule MRIs on the exact dates listed in Table 1 or within 2 business days after 
that date. If any anomalies or unforeseen circumstances occur (e.g., inability to schedule MRI 
scans due to scheduling conflicts, etc.) MRIs may be performed at the next closest in-lab training 
session or scheduled test point. The decision to perform MRIs outside of the visit schedule listed 
in Table 1 will be made on a case-by-case basis at the discretion of the PI. 
 
 
 
 
 
 
 
 
Table 1 – Event timeline for each subject in the study 
 
 
 
Initial Visit  
Stage 1 
(2 weeks) 
Stage 2 
(12 weeks) 
Stage 3  
(12 weeks) 
 
Prior to beginning 
intervention 
Last day 
of 2nd week 
Last day 
of 12th week 
Last day 
of 12th week 
Informed Consent 
X 
 
 
 
fMRI Sub-study 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 

 
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Sample size consideration: Power calculation is based on 2-sample t-test using the standard 
G*Power 3.1.9.2 package [9, 10]. With n = 13 patients in the Active PoNS group, and n=13 in the 
healthy control group, at a two-sided significance level of 0.05, we will have 85% power for 
detecting an effect size of 1.2 standard deviations (see figure below) in our primary outcome 
measure 
of 
signal 
change in task fMRI. 
Our data from our 
preliminary 
study 
with N=12 subjects 
was 
sufficiently 
powered to detect a 
significant effect of 
the intervention on 
brain 
changes 
as 
assessed by similar 
task fMRI [11] as 
proposed in this study.  
 
Functional MRI 
Scanning and Analysis 
All MRI data will be acquired with the University of Wisconsin-Madison Department of 
Radiology’s 3T MRI scanner (GE Healthcare, Waukesha, WI) using an 8-channel brain coil. The 
T1-weighted anatomical scans will be acquired with a 3D-SPGR pulse sequence (TR= 10 ms, TE= 
3 ms, 94 slices, 0.938 x 0.938 x 1.5 mm resolution). One functional scan will be acquired with a 
T2*-weighted gradient-echo echo-planer imaging sequence (time repetition = 2000 ms, acquisition 
time = 1800 ms, echo time = 30 ms, flip angle = 75 degrees) to acquire BOLD signal in a 128x128 
matrix over a 12cm2 FOV and 10 slices giving a resolution of 0.938 x 0.938 x 2.0 mm3 centered 
over the brainstem and cerebellum. This increase in resolution will allow for multiple 
measurements of BOLD signal in each brainstem nuclei, which are on the order of 3x3x3 mm3, 
smaller than a single voxel at standard fMRI resolutions [12]. A second functional scan will be 
acquired with a T2*-weighted gradient-echo echo-planer imaging sequence (time repetition = 
2000 ms, acquisition time = 1800 ms, echo time = 30 ms, flip angle = 75 degrees) to acquire 
BOLD signal over 30 axial slices (3.75 x 3.75 x 4.5 mm resolution) covering the entire brain. 
 
Rs-fcMRI data: A 10 minutes eyes closed, whole brain resting state scan will be collected using 
gradient-echo echo-planar imaging with the following parameters: TR = 2.6 s, TE = 22 mms, field 
of view = 22.4 cm, flip angle = 60°, 40 sagittal slices, acquisition matrix = 64 x 64, 3.5 mm 
isotropic voxel size, 162 time-points. T1-weighted anatomical images will be collected for 
overlaying the fMRI data using a FSPGR BRAVO sequence (TR = 8.132 ms, TE = 3.18 ms, TI = 
450 ms) over a 256 x 256 matrix and 156 slices (flip angle = 12°, FOV = 25.6 cm, slice thickness 
= 1 mm). 
Resting data will be preprocessed as in our earlier studies [13]  using FSL and AFNI [14-16]. Data 
will be motion and slice-time corrected, spatially smoothed using a Gaussian kernel of 6 mm 
FWHM, and scaled to the grand mean. Time series will be band-pass filtered (0.005 – 0.08 Hz), 
linear and quadratic trends removed. To control for participant head motion and physiological 
noise, motion parameters, white matter and CSF signal will be regressed from the time series. The 

 
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residual time series will be demeaned, re-sampled to 3 mm3, registered to MNI152 standard space 
using FSL’s FLIRT program.  
Seed-based connectivity analyses: Time courses will be extracted from 160 seed regions of interest 
(ROIs) previously defined in the literature that were generated from meta-analyses focused on 
tasks involved in high level cognitive and motor functions [17]. The time series from these 
spherical seed-regions, each 6 mm radius, will be extracted from the spatially standardized 
residuals for every EPI scan. The resulting time series for each seed-region per scan per subject 
will be then imported into Matlab (Mathworks) and correlated against every other seed-region, 
creating 160x160 roi-to-roi connectivity matrices containing correlation coefficients for each 
subject. Correlation coefficients will be z-transformed using Fisher’s r-to-z transformation to 
normalize the distribution and will be used as inputs to the NBS [18, 19] toolbox (as in the 
preliminary study [20]). NBS is a non-parametric approach that controls for family-wise error 
(FWE) in mass-univariate testing of an N x N ROI-to-ROI connectivity matrix and identifies 
networks of regions that is significantly different between groups. 
 
DTI data: Diffusion Tensor Imaging (10 minute) scans will be collected using single shot 
diffusion weighted EPI images, 21 contiguous slices[b=0 sec/mm2 and b=1000sec/mm2], with 
TR=4500 ms, TE=71.8 ms, FOV = 24 x 24 cm, 3mm slice thickness, amplitude of diffusion 
gradient = 40 mT/ applied in 56 non-collinear directions uniformly distributed in three-
dimensional space. 
DTI data will be processed using FSL (v5.0) [21] with the following steps: 1) correction for 
motion and eddy current distortion; 2) head-motion correction for gradient direction vectors; 3) 
image registration and brain mask extraction; 4) estimation of tensor diffusion and generating 
diffusivity measures; 5) registration of standard white-matter atlases (JHU-ICBM-FA-2mm.nii.gz 
and JHU-ICBM-labels-2mm.nii.gz) to each patient’s native space; 6) estimation of diffusivity 
measures for specific tracts of interest. 
 
Task fMRI: 1) In order to evaluate regions involved in balance processing, a checkerboard pattern 
will be used as the basis for a 2-dimensional visual stimuli in an optic flow task. A static 
checkerboard of alternating black and white squares will be used (CBstat) as the control stimulus. 
A rotating checkerboard (CBrot) will also be employed, in which the image appears to cyclically 
approach and recede relative to the observers' viewpoint, as well as rotate about the center of the 
viewfield [22]. During the scan, subjects will be shown the visual stimuli using a pseudo-
randomized block-design paradigm. Each stimulus will be displayed for twelve seconds in blocks 
of three to six repetitions. Within a block, the stimulus presentations will be separated by six 
seconds of fixation to reduce the contamination of neural responses from one stimulus 
presentation into the next [23]. Each block will be separated by six seconds of fixation. The order 
of stimulus presentation will be the same for all subjects. Task scan will be approximately 7-8 
minutes. 2) In order to evaluate CNV, subjects will perform a jaw-clenching task, in which 
subjects will alternate between 20 seconds of jaw-clenching and 20 seconds of rest for a total of 6 
cycles or 4 minutes. 3) In order to evaluate CNV, VII, CNXII, subjects will perform a tongue 
thrust task in which they will alternate between thrusting their tongue to the roof of the mouth for 
20 seconds and 20 seconds of rest for a total of 6 cycles or 4 minutes. We will also evaluate 
relationship of these brain MRI measures with balance and gait measures for the two treatment 
groups at each of the four time-points. 
 

 
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Each fMRI sub-study scan will take approximately 60 minutes to complete. All MRI scans will be 
performed at the Wisconsin Institutes for Medical Research (WIMR), 1111 Highland Ave., 
Madison, WI 53705. 
 
Statistical Analysis 
 
Task MRI Outcomes: Percent signal change will be computed for specific ROIs based on our 
previous work [11]. A repeated measures ANOVA will be used with Time (pre-intervention, stage 
1, 2 3) as factor to examine change in percent signal over time in the patient group. To assess 
specific changes due to our intervention, we will perform paired t-tests (pre-intervention & stage 
1; pre-intervention & stage 2 etc.). 2-sample t-tests will be used to compare differences between 
the Active PoNS group and control group.  
 
Resting fcMRI Outcomes: The output from the NBS toolbox is a network of brain regions that 
are significantly impaired between groups (identified using 2-sample t-test) and networks that are 
significantly influenced by the intervention over time ((identified using paired t-test) [18, 19]. For 
each significant network, the toolbox provides a list of all pairwise regions and their connection 
strengths and the t-statistic associated with each connection. 
 
DTI outcomes: DTI analysis will yield whole brain fractional anisotropy (FA), and diffusivity 
measures (radial, axial, and mean diffusivity). A repeated measures ANOVA will be used with 
Time (pre-intervention, stage 1, 2 3) as factor to examine change in FA and diffusivity measures 
over time. 2-sample t-tests will be used to compare differences in these measures between the 
Active PoNS group and control group. 
 
Brain Behavior correlations: A Pearson correlation or Spearman rank correlation test, as 
appropriate, will be used for correlation analyses between brain measures (task fMRI derived 
percent signal change, resting fcMRI derived connectivity measures, DTI FA and diffusivity 
measures) and behavioral outcome measures 
 
Potential Risks and Benefits 
Functional MRI: MRI, a Class II device, is recognized as a Non-Significant Risk (NSR) device by 
the FDA.  All the systems, features, and accessories that will be used in the scanning of subjects 
under this protocol will be operating outside the limits identified by the FDA as “Criteria for 
Significant Risk Investigations.”   
 
Risks 
1. MRI: Aside from the standard risks associated with persons with certain metallic implants 
discussed above, no known risks of MRI exist. We know of no risks or adverse effects from 
the magnetic fields or radio waves used in the standard MRI pulse sequences. A small increase 
in risk may be associated with rapid gradient waveform switching times associated with fast 
MR imaging. In certain situations, the rapid switching of gradient waveforms has caused 
peripheral nerve stimulation in subjects. Significant nerve stimulation, however, has not 
occurred as long as the imaging system has been programmed to stay within certain limitations 
of gradient strength and switching time (dB/dt). The MR scanners currently being used at the 
UW stay within these guidelines, and any additional pulse sequences which we program in our 

 
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laboratory will be designed to stay within the current guidelines for dB/dt established by the 
FDA.  
Occasionally some individuals experience feelings of claustrophobia during an MR exam. 
The following instructions will be given to the subjects: Support will be provided to keep you 
from becoming uncomfortable, and you will be able to stop at any time. Using a microphone 
built into the MR scanner, a technologist will be able to hear you if you need assistance at any 
time. Please inform the technologist of any discomfort you may experience during the MR 
exams. 
2. Pregnancy: Women who are pregnant or breastfeeding are excluded from the study. Although 
there is no evidence that MR exams can cause harm, there may be risks that are not known at 
this time. For this reason, this sub-study is not approved to enroll pregnant women or those 
that are breastfeeding. 
 
Adverse Events, Unanticipated Problems 
The most likely adverse events are detailed in the “Risks” section above. All unanticipated 
problems involving risk to subjects or others and all serious adverse events will be promptly 
reported by the PIs according to proscribed procedure: 
http://my.gradsch.wisc.edu/hrpp/10122.htm. 
 
Adventitious Findings 
The images collected for all subjects will be reviewed for adventitious findings by Co-PI, Dr. 
Prabhakaran. Subjects will be informed of all findings of clinical significance. During informed 
consent, subjects will be provided with the option of whether they will also be informed of 
findings of uncertain or no known clinical significance and whether any findings should be 
released to their primary care physician. 

 
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