Extending taVNS Paired With Infant CIMT Into a Home-Based Setting: Technology Development Requisite for a Randomized Trial
Phase: EARLY_PHASE1
Conditions: Cerebral Palsy
Sponsor: Medical University of South Carolina

 
 
 
Extending taVNS Paired With 
Infant CIMT Into a Home-
Based Setting: Technology 
Expansion Requisite for a 
Randomized Trial 
NCT05857527 
PI: McGloon, Kelly.   Date: 12/12/22 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
1.0 
Objectives / Specific Aims 
Newborns who are born premature or suffer brain injury at birth are at risk for motor problems. 
The common motor skills of reaching and grasping that infants have to learn can be weaker on 
one side of the body, depending on the site of the brain injury. These skills are practiced with an 
occupational therapist, to help the infant strengthen these skills. The gold standard rehabilitation 
intervention to address one sided motor weakness is Constraint Induced Movement Therapy 
(CIMT). During CIMT interventions, an infant wears a removable splint or puppet on their 
stronger hand while the therapist engages the infant in various activities targeted to improve 
functioning of the weaker side. CIMT encourages infants to move the weaker arm and hand and 
strengthen the circuits in the brain involved with movement. Even with the high intensity therapy 
program of CIMT, it takes between 40-120 hours total treatment time for most infants to improve 
their motor skills. We hope to improve motor outcomes by pairing CIMT with technology shown 
to improve motor functioning due to brain damage.  
The purpose of this study is to evaluate the safety and effectiveness of using Electromyography 
(EMG) muscle sensors to trigger a non-invasive brain stimulation technique, called 
Transcutaneous auricular Vagus Nerve Stimulation (taVNS) during CIMT in order to improve 
motor outcomes for this intensive rehabilitation intervention. 
 
Explanation of technology:  
• Electromyography (EMG) Sensors: EMG sensors are adhesive electrode sensors that 
detect electrical activity in a muscle, in other words sensors that detect if a muscle is “on 
or off”. In this study we will place EMG sensors over key muscles in the shoulders and 
trunk to automatically detect when an infant is reaching or using their trunk to work on 
activities like sitting or rolling in therapy. When muscles are activated, it will trigger taVNS 
stimulation. Pairing nerve stimulation with movement may boost rehabilitation outcomes 
when paired with motor activities in infants and adults post stroke or brain injury. 
 
• Transcutaneous auricular Vagus Nerve Stimulation (taVNS): taVNS, provides low 
level electrical stimulation (<2.0 mA) to the vagal nerve via an electrode placed on the 
ear. A course of daily vagal nerve stimulation has been shown to be safe and to help the 
brain learn motor tasks in adults and in our study of infants with brain injury or 
prematurity, without side effects. Nerve stimulation has also been used in neonates to 
decrease pain and improve motor function after nerve injury at birth. With electrodes on 
the child’s left ear, the transcutaneous electrical nerve stimulator device will deliver short 
treatments of small electric pulses while he or she is undergoing CIMT with a therapist. 
These devices are FDA approved for pain management on muscles, and FDA-cleared and 
widely available for purchase online without a prescription for home use in adults and 
children. We will use this FDA-approved technology to stimulate the vagus nerve and 
brain pathways involved in motor control.  

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
The FDA has approved transcutaneous electrical nerve stimulation (TENS) therapy for 
pain management. TENS requires placing electrodes directly on the skin of a specific part 
of your body. Small pulsed electrical currents are then delivered to these electrodes, 
which stimulate the underlying muscles and nerves. taVNS is a specific use of this FDA 
approved therapy, and is just another name for TENS therapy on the ear. We think it may 
have different effects than TENS on muscles, because we can stimulate a large nerve, 
called the vagus nerve, in the ear. This nerve connects to the brain and is important in 
many functions. In animals with brain injury, stimulation of the vagus nerve combined 
with specific motor training helps repair the motor areas of the brain. In adults and 
infants, taVNS improves motor function, when paired with a motor task. Using taVNS in 
infants to improve motor skills is experimental, even though the TENS device is cleared 
by the FDA. 
 
Rationale for Pairing EMG triggered taVNS with CIMT.  
Constraint Induced Movement Therapy (CIMT) is the gold-standard in pediatric rehabilitation, 
but it is time intensive (2-5h per day) and unfeasible for many families if delivered in a clinic 
setting. Therefore, we want to maximize functional benefits for the intervention. 
We will test whether EMG muscle sensors can be used to pair experimental taVNS with active 
movement while the child participates in 40 hours of CIMT rehabilitation treatment. CIMT 
encourages the infant to move his or her weaker arm and hand better and strengthen the circuits 
in the brain involved with movement.  
 The data in animals and humans support the premise that both cervically-implanted and 
transcutaneous auricular VNS (non-invasive stimulation method using an electrode on placed on 
the ear) paired with motor rehabilitation improve functioning.18--32 In rats, cervically-implanted 
VNS paired with movement led to a doubling in size of the primary motor cortex associated with 
the movement.18  
 
Our group is the first to show the benefit of using non-invasive taVNS paired with a motor task of 
bottle-feeding in infants with brain injury and oromotor feeding failure. We also recently 
successfully delivered 40 hours of CIMT paired with taVNS to a former premature infant, now 11 
months old, with significant brain injury and left-sided hemiplegia enrolled in our NM4R-funded 
feasibility trial. The infant had little to no spontaneous movement of the left arm, elbow or hand 
prior to study participation, in spite of weekly physical and occupational therapy and home 
exercises with the mother. The infant made rapid progress significantly passing expected outcomes 
expected for CIMT alone. By the 3rd & 4th weeks of therapy mom reported he was regularly 
engaging in bimanual play at home.  
 
After training in taVNS, the therapist was able to deliver taVNS using a manual trigger and engage 
the infant in CIMT. Manually triggering taVNS for every active movement seen during an intensive 
intervention is mentally taxing for the therapist. In this study, we want to trial use of EMG sensors 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
to trigger stimulation. Placing EMG sensors over key muscles in the shoulders and trunk we allow 
us to automatically detect when an infant is reaching or using their trunk to work on activities 
like sitting or rolling. By using EMG sensors we should be able to pair stimulation with movements 
reducing the burden on the therapist and allowing them to focus on facilitating a high quality 
treatment session. Automating the stimulation would make taVNS-paired CIMT more achievable 
in the home-based CIMT programs. Home-based delivery of CIMT is considered best practice for 
pediatric clients so families can be fully engaged, burden for families is reduced, and new skills 
can easily transfer to the natural environment for better carry over of treatment.  
 
Qualifications 
We have a unique collaboration of experts in brain stimulation, pediatric brain injury, 
translational clinical science and pediatric occupational therapy in this pilot project, and we are 
one of the few groups able to rapidly translate this neuromodulatory modality into home-based 
CIMT services. Refining the treatment protocol for home-based taVNS+CIMT and trialing 
incorporation of reliable taVNS triggering by this device we will provide us strong data to submit 
a grant for a randomized trial of home delivered taVNS+ CIMT in infant hemiplegia. 
 
Study Aims 
 
Aim 1: Investigate the feasibility of incorporating automatic triggering of the taVNS device 
using EMG sensors. Rationale: Manual taVNS triggering is mentally taxing for a therapist 
providing intensive, CIMT intervention. Movement based triggering would decrease the mental 
effort for using taVNS allowing the therapist to focus more on the treatment session. Aim specific 
methods: We will systematically test key muscle groups to see if EMG can be used to trigger 
taVNS stimulation at least 75% of the total time for active infant arm and trunk movements 
during CIMT. The first 2 participants will be completed in clinic to allow for updates to EMG 
system real time. After the first 2 participants complete the study we will trial the EMG system 
in the home setting for Aim 2.  
 
Aim 2: To generate proof of concept evidence demonstrating ability to provide high fidelity 
CIMT+taVNS treatment in a home-based setting in 3 infants. Rationale: The strongest level of 
evidence exists for delivery of pediatric interventions in home-based settings. We need to show 
evidence that CIMT +taVNS can be delivered effectively in the home and not just in a research 
clinic. Aim Specific Methods: We will videotape CIMT therapy sessions while the therapist is 
delivering taVNS in the home with EMG triggered taVNS and randomly score 20% of weekly 
session for CIMT treatment fidelity with the published CIMT Fidelity Instrument. Home based 
fidelity will be completed with the last 3 participants.  
 
Project Relevance: Home-based constraint induced movement therapy (CIMT) is the gold 
standard treatment to facilitate arm and hand recovery after pediatric stroke, but it requires a 
large investment of time and energy from therapists and the family.  Non-invasive brain 
stimulation (taVNS) is a promising new technology that may amplify the treatment effect of 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
therapy treatment. Combining home-based CIMT & taVNS may provide families a better return 
on investment in terms of their child’s functional gains from therapy services. This technology 
development pilot project will address important system modifications to automate pairing of 
active movement with taVNS delivers. This automation is needed to decrease the burden of 
pairing taVNS with CIMT and increase likelihood of clinical translation into home-based settings 
 
2.0 Background 
A. 
SIGNIFICANCE Preterm birth and complications in term births result in increased risk for 
intraventricular 
hemorrhage, 
global 
hypoxia-ischemia 
(HIE), 
arterial 
stroke, 
and 
neuroinflammation with white matter injury in newborns1-5. Perinatal CNS injuries may 
significantly disrupt motor circuit development resulting in life-long deficits, such as cerebral 
palsy (CP). Early targeted therapy interventions for high-risk infants may improve neurological 
outcomes by taking advantage of early critical windows for neuroplasticity1,5. 
 
Intensive interventions, such as constraint induced movement therapy (CIMT), are designed to 
ameliorate early motor predecessors of CP in at-risk infants6-12. Standard pediatric rehabilitation 
CIMT programs use high-dose rehabilitation to reinforce activity-dependent neuroplasticity6,7,9. 
Multiple rigorous CIMT studies show functional improvement in motor-impaired children after 
60-120h of treatment. Yet it is difficult for many families10 to complete even the minimally 
effective dose of 40h11 (2 hours/day sessions for 4 weeks). Frequently families will go to great 
lengths to participate in any type of CIMT programming- traveling out of state and staying in 
hotels so their child can participate in a 1-week group based CIMT program for older children. 
But this is not possible for many families that lack extensive social and financial resources. 
Therefore, it is critical to find ways to make CIMT accessible for all families and maximize the 
return on investment for the child.  
 
One way of increasing functional gains with less time and resources, may be pairing CIMT with 
non-invasive vagus nerve stimulation (taVNS). Recent research suggests that even with significant 
brain injury, neuromodulation via vagus nerve stimulation (VNS) delivered during a motor task 
can harness activity-dependent plasticity and lead to improved functional outcomes13-17. 
Encouraged by exciting pilot data, we hypothesize that brain stimulation via taVNS delivered 
during CIMT will boost cortical plasticity of neural circuits, resulting in better functional 
outcomes in a shorter time.  
 
Our team is passionate about developing technology that improves functional outcomes AND 
can be readily translated into practice. This team was previously awarded pilot funding from 
NM4R to develop a taVNS device for testing safety and feasibility of pairing taVNS and CIMT. 
Initial results are encouraging (see data in section C1). However, the current technology requires 
the therapist to manually trigger the taVNS device, distracting from the therapy and necessitating 
additional support personnel. This therapist triggered setup will not work in the home. The goal 
of this technology development project is to refine how the device is triggered, enabling the CIMT 
therapist to deliver taVNS & CIMT in the home-based setting. Translation of this technology into 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
the home is critical for successful implementation of a larger effectiveness clinical trial, as is being 
done in the IAQUIRE trial (NCT3910075). It is also essential for removing barriers of subsequent 
translation into practice.  
 
B. INNOVATION There is a growing body of evidence indicating VNS may amplify the benefits of 
rehabilitation interventions; this is now FDA approved for adult stroke recovery14,15,18-20. Few 
studies have investigated combining neuromodulation and evidence-based pediatric intensive 
therapies such as CIMT, and then only in older children with established CP21-23. We propose 
using taVNS paired with CIMT, in 6–18 month-old infants with unilateral weakness to maximize 
neuroplasticity in the earliest developmental window. Our team is currently conducting a pilot 
study testing the feasibility of pairing CIMT and taVNS in infants with hemiplegia, with 
encouraging results. Based on our experience in our current taVNS and CIMT pilot study, EMG-
triggered automation should greatly increase the likelihood of future clinical translation by 1) 
decreasing the pre-therapy training required for the therapist, 2) decreasing the mental and 
physical demands placed on the therapist, and 3) making treatment translatable to the home 
environment with a single CIMT therapist. 
 
Our group is pioneering taVNS in infants. We designed and instituted using noninvasive taVNS 
paired with a motor task of bottle feeding in infants with feeding failure15,16. We have expanded 
this to include pharmacologic therapy with taVNS in infants refractory to standard taVNS-paired 
feeding. We have seen exciting results in these studies of taVNS to improve bottle feeding for 
infants in the NICU (preliminary results in section C). With our unique collaboration of experts in 
brain stimulation, pediatric translational clinical science and pediatric occupational therapy, we 
have a multidisciplinary team that can rapidly translate this neuromodulatory modality in infants 
with hemiplegia undergoing CIMT treatment. Our team has extensive experience with taVNS 
technology development and translation of the technology into clinic settings (George, Summers, 
Jenkins, Badran), as well as innovative and experienced CIMT therapists (McGloon, Coker-Bolt). 
The proposed technology development project is an exciting innovation for treatment of 
perinatal acquired brain injury. We aim to provide a greater return on investment for intensive 
CIMT interventions while improving equitable care by improving ability to access this promising 
treatment combination in the home-based setting.  
 
C. APPROACH  
C1 Preliminary data We have significant experience from our open-label pilot trial of taVNS-
paired feeding in infants who were refractory to standard of care feeding interventions and were 
slated to receive a G-tube15.  
C1.1 taVNS-paired Feeding study: Treatment Protocol: We deliver taVNS pulses via a left ear 
electrode at 25Hz, pulse width 500μsec at 0.1mA< Perceptual Threshold (PT). Perceptual 
threshold is determined by increasing stimulation level by 0.1 mA until there is some indication 
the infant perceives the stimulation.  Therapists and the parent watch for signs of perception: 
facial grimace, vocalization, bringing hand to the ear, turning the head toward that ear. Once 
Perceptual threshold (PT) is determined stimulation is decreased by 0.1mA to stay below 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
perceptual level. If at any point during the treatment it seems as if the infant is perceiving the 
stimulation (reaching to ear, grimace, etc) a break is taken and then PT is retested to determine 
if stimulation level should be decreased. taVNS treatment is paired with suck-swallowing during 
1 (n=15) or 2 (n=18) oral feeds/day, for 2-3 wks. Results: Efficacy outcomes: 19/35 (54%) infants 
destined for G-tube attained full oral feeds with taVNS-paired feeding in a mean of 2 weeks or 
less. We showed a dose response with twice vs once daily treatments in the increase of daily po 
feeding volumes (F,8.05, p=0.01) & faster time to full po feeds (p<0.05). In secondary outcomes, 
diffusion kurtosis imaging before and after taVNS treatment, showed greater white matter 
plasticity changes in fractional anisotropy (FA) and white matter complexity for Responders 
versus Non-Responders in corpus callosum and external capsule, per week of development. 
Safety outcomes: We observed no bradycardia (HR<80bpm 5sec), no skin irritation. Persistent 
increase in discomfort scores (NIPS >3) occurred in only 3/228 sessions (1.3%) resolving with 
decreasing current. In summary, our first-in-human neonate and infant pilot trial of taVNS paired 
with an oromotor task of bottle feeding, using our custom taVNS system, showed safety and 
feasibility, and achieved encouraging results in >50% of infants slated for G-tube achieving full 
oral feeds in 2 weeks. 
C1.2 CIMT+taVNS Ongoing Safety & Feasibility Pilot  
Pediatric CIMT trained therapists provided 40 hours of 
CIMT paired with taVNS treatment at 0.1mA<Perceptual 
Threshold (PT) over 4 consecutive weeks. Infant’s motor 
abilities are tested prior to therapy start, immediately 
after the 4 weeks of therapy and again 3 months post 
treatement. Primary Outcome: QUEST- an assessment of 
quality of arm/hand movement in infants & children 
with CP.  
RESULTS:  We have completed full study procedures for 
1 infant. Two other infants have completed pre-assessments and the 40 hours of 
treatment intervention but have not completed the 3 month follow-up. All 3 infants 
completed the full intervention with no adverse events. For the first infant, overall, progress 
was better-than-expected using Goal Attainment Scaling (change 28.33 ± 9.83, p 
<0.001). At baseline the infant showed little spontaneous use of his left arm, but 
mom reported he was consistently engaged in bimanual play at home after 4 weeks 
of combined taVNS-CIMT therapy. Significant improvements were seen on the 
QUEST in Dissociated Movement (Pre: 43.75, Post 84.38, Δ=40.63 vs expected 
Δ=5.2 with CIMT alone10) and Grasping (Pre:11.12, Post: 29.62, Δ=18.5 vs 
expected Δ =11.1 with CIMT alone10). At 3-month follow-up Dissociated Movement 
scores were maintained (Post 84.38, Follow-up 85.94) and Grasp scores continued to 
improve (Post 29.62, Follow-up 37.02). 
 
C1.3 Other Achievements that impact this proposal: We recently received FDA Breakthrough 
Device designation for the BabyStrong device, similar to the system proposed in this 
application. Our phase I STTR early RCT with this infant taVNS system is currently being funded 
through an NICHD STTR award. Our infant taVNS feeding data, our early FDA breakthrough 
Figures 1 & 2. CIMT therapist 
assists infant’s trunk control 
while the trigger button is 
attached to her hand with 
flexible wrap (red arrow). 
taVNS device is Velcro 
attached to the infant’s back 
(green arrow). The arm with 
better motor skill is 
immobilized with red flexible 
wrap and a splint. 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
device development for young infants, and other promising studies of taVNS in adults, all 
support the development of this neuromodulatory technique in infants with significant 
hemiplegia after perinatally acquired brain injury. 
 
3.0 Intervention to be studied  
General Methods for home-based delivery of taVNS +CIMT The goal of this discovery pilot 
project is to further develop the technical aspects of taVNS+CIMT delivery so that it is practical 
for delivery by a CIMT therapist in a home-based setting. This is essential to prepare for a 
treatment effectiveness study, which by necessity must be home-based because of the minimum 
40-hour time commitment. First, we will use EMG sensors to automatically trigger the taVNS 
device, with the goal of decreasing the burden of treatment for the therapist. We will place the 
EMG sensors on major muscle groups on the shoulder and trunk and refine placement as needed 
to show that EMG-triggering can accurately and effectively trigger stimulation for 75% of total 
time spent in active movements. The therapist will still be able to manually trigger for other 
targeted behaviors (such as grasping). Once our placement of sensors has been tested and meets 
this designated threshold, the EMG-triggered system will be tested in home-based CIMT 
treatment.  
The therapists providing the CIMT treatment are part of the study team. They have received 
specialized training in CIMT and the delivery of taVNS. These therapists were also a part of our 
original CIMT & taVNS study described above in section C1.2. They were part of the team who 
suggested the modifications of using EMG sensors to automate stimulation.  
C2.1.1Inclusion Criteria: Five 6–18 month-old infants, with hemiplegia/motor asymmetry 
qualifying for CIMT, Gross Motor Function Classification System (GMFCS) level I-IV, ability to 
maintain sitting position for 5 minutes with moderate assistance. Exclusion Criteria: Non-English 
literate parents, GMFCS level V, severe motor impairment/ quadriplegic involvement; 
uncorrected blindness or deafness, cardiomyopathy. Infants with cardiac issues will be cleared 
by cardiology before beginning treatment.   
C2.2 Aim 1: Investigate the feasibility of incorporating automatic triggering of the taVNS 
device using EMG sensors. Rationale: Manual taVNS triggering is mentally taxing for a therapist 
providing intensive CIMT intervention. Movement based, EMG-triggering should decrease the 
overall burden allowing the therapist to provide high-quality CIMT. Automation may improve 
pairing of stimulation and motion instead of relying on the therapists to remember to 
activate/terminate stimulation. It may also decrease the number of personnel required. Using 
EMG sensors to track every motion would require extensive set-up and complicate treatment by 
increasing the wires the therapist must manage. Therefore, we aim to use EMG to selectively 
target key muscle groups.  
C2.2.1 Models of pairing stimulation to motor activation Direct pairing of stimulation to 
movement is most effective for functional outcomes14. In adult studies therapists manually 
trigger stimulation for discrete motions that target movement impairments13,20. Infant therapy 
sessions cannot be setup as a series of discrete movements because infants cannot follow 
directions, have short attention spans, and are only beginning to develop isolated arm 
movements. In fact, the kinematic and EMG profiles of young infants’ reaching indicate that 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
healthy infants do not show discrete reaching motions indicated by modulation of EMG 
amplitude until 18 months25. Variability is a key element of infant motor development as infants 
continually trial new movement pattern combinations as they refine skills and learn to adapt 
movements to match the demands of new environments26. Infant reaching kinematic profiles 
instead appear more similar to continuous motions and multistep movements27. While this 
seems like a challenge for automation, it may actually simplify automation, since we want to pair 
taVNS stimulation with active motor planning and execution of general reaching and dynamic 
trunk control and do not need to specifically target one motion. Therefore, we only need to target 
a few key muscle groups that are consistently activated with immature reaching patterns of 
young infants.  
C2.2.2 Targeted Muscle Groups We aim to automate 75% of stimulation time without 
significantly increasing the burden of system set-up/treatment delivery. We will use 2 sets of 
EMG sensors placed on the muscle groups activated in the vast majority of reaching and dynamic 
balance tasks.  
• Reaching- Immature reaching in infants is initially driven by the biceps and triceps28,29. 
As targeted reaching improves there is an increased use of the deltoids and upper 
trapezius as prime movers. Depending on the age/ability of the child we will target 
biceps brachii or anterior deltoid28,29.  
• Trunk control- EMG literature related to development of dynamic sitting balance 
indicates that thoracic level paraspinal muscles are most involved with emerging 
sitting balance and transitions to lumbar paraspinal activation as infants progress to 
more independent sitting balance28-30.  
C2.2.3 Outcome measures for EMG automation taVNS stimulation is most effective when 
directly paired with active movements. Infant movement kinematics are characteristic of 
continuous movements rather than discrete movements. Since motions are not clearly discrete, 
we cannot count the number of stimulations and movements. Instead, a second therapist will 
record the time that the infant is actively engaged in movement tasks and compare that to the 
total time of taVNS stimulation, recorded by data acquisition modules in our taVNS set-up. One 
therapist will be delivering CIMT, a second therapist will be recording active movement time. For 
the first 2 participants, treatments will be completed in the research lab. This will allow the full 
team to be present, making sure that EMG triggered stimulation is occurring at the same time as 
active movement (the screen turns green when stimulation is on). If stimulation is not being 
delivered during active movement, modifications will be made to the system (e.g. changing 
amplification threshold for triggering, adjusting sensor location, etc). If total stimulation time is 
within 75% of total active movement time for therapy sessions in the first 2 infants, then we will 
transition CIMT delivery to the home-based setting for the final 3 infants.   
C2.1.2 Treatment Delivery: CIMT-trained therapist with assistance from a research assistant will 
deliver CIMT for 40 hours (2 hours/day, 5 days/week for 4 weeks) +taVNS delivered via the 
BabyStrong (BS) system, (Soterix taVNS electric pulse generator unit & Neolead® electrodes).  
1) Hydrogel electrodes are placed in front of tragus and inner tragus/cymba chonchae, 
securing the wires behind head with tape. taVNS unit is attached to the baby using 
Velcro cummerbund ( Fig.1, 2).  

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
2) EMG electrodes will be placed on the shoulder (biceps/deltoid m) and on the trunk 
(paraspinus m) and connected to the taVNS unit via a wired interface.  
3) CIMT and BSL therapists establish perceptual threshold (PT) daily, increasing slowly, 
until infant shows signs of tingling sensation. TaVNS is delivered at 0.1mA<PT, 500μsec, 
25Hz, during each CIMT session, timed with movements of the weaker arm /trunk. 
4) A CIMT therapist will deliver CIMT and use the manual trigger if needed for hand 
movements, while a second ‘recording’ therapist will record the active movement time. 
The Data Acquisition (DAQ) interface will record the amount of stimulation time and 
intensity from both EMG and manual triggering.  
5) Good, moderate or poor impedance is constantly displayed on the taVNS unit. With 
poor contact, a beep sounds, and the electrode is adjusted. 
6) Parent and OT will answer weekly questionnaire to assess their perception of ease of 
use, infant tolerance, and any recommendations for improvement of taVNS system or 
delivery. 
 
 
4.0 
Study Endpoints  
Primary Research Question: Can taVNS stimulation be automatically triggered during 75% of the 
total time for active infant arm and trunk movements during CIMT? Primary Outcome measure: 
Percentage of treatment sessions where total stimulation time was 75% of total active movement 
time. 
Limitations and alternative approaches: Trialing EMG system: We will trial the EMG 
sensor system first with two healthy infants in the CHP laboratory setting to trouble shoot set-up 
and connection issues. The BSL and CIMT team will make any necessary modifications to the 
EMG-taVNS set-up. Comparing total movement time to total stimulation time does not ensure 
stimulation is being provided at the appropriate time: The stimulation device changes color when 
stimulation is being provided. Therefore, a second ‘recording’ therapist can monitor if the screen 
is green(‘on’) when also recording active movement.  
 
Aim 2: To generate proof of concept evidence demonstrating ability to provide high fidelity 
CIMT+taVNS treatment in a home-based setting in 3 infants. We will have a second therapist 
videotape CIMT therapy sessions while the CIMT therapist is delivering taVNS in the home with 
EMG triggered taVNS. We will randomly score 20% of sessions for CIMT treatment fidelity with 
published CIMT Fidelity tool. This aim will be completed with the final 3 participants after EMG 
set-up is finalized with first 2 participants.  
 
 Secondary CIMT+taVNS feasibility outcomes: Ability of therapist to operate taVNS 
easily and successfully by earning a “meet or exceed” score (3 or 4) on random therapy sessions 
by CIMT Fidelity Instrument. Ability of infant to tolerate wired ear electrode while remaining 
securely in place during sessions. 
Secondary CIMT +taVNS efficacy outcomes: Change in the functional motor outcomes 
pre and post intervention on the Quality of Upper Extremity Skills Test (QUEST) 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
Inclusion Criteria: Five 6–18 month-old infants, with hemiplegia/motor asymmetry qualifying 
for CIMT, Gross Motor Function Classification System (GMFCS) level I-IV, ability to maintain 
sitting position for 5 minutes with moderate assistance.  
Exclusion Criteria: GMFCS level V, severe motor impairment/ quadriplegic involvement; 
uncorrected blindness or deafness, cardiomyopathy.  
 
 
6.0 &7.0 Number of Subjects and Setting 
We will enroll up to 5 infants. The first two infants will complete all study intervention 
procedures in the pediatric occupational therapy lab (151 Rutledge Ave Building B). This will 
allow for monitoring by the whole team and minor modifications to be made to the set-up 
(adjusting placement of EMG sensors, adding Velcro to keep wires out of the way when 
reaching, etc). Image from on-going taVNS +CIMT study (without EMG triggering).  
 
This new study should only require minor changes to the set-up (adding wires for EMG muscle 
sensors). After completing 2 infants in the lab which should provide more than enough 
opportunity to modify set-up issues. The remaining 3 participants will complete study 
interventions in their home.  A specially trained pediatric therapist will deliver all treatment 
sessions.  A second study team member will also accompany the therapist to assist with 
therapy, video tape sessions, and monitor the infant.  
 
 
 
 
 
 
 
 
 
 
 
8.0 Recruitment Methods 
We have IRB approval for two pilot studies (#67997, #103800) in preterm and term stroke/HIE 
infants with taVNS paired with feeding using similar taVNS study procedures as proposed in this 
application. The taVNS system has a non-significant risk device designation from MUSC’s IRB in 
these two pilot trials.  
 
Dr. Jenkins will screen for infants in the nursery with known brain injury that will likely lead to 
hemiparesis or weakness, such as perinatal arterial stroke, HIE, severe IVH, PVL or cerebellar 
infarct, regardless of sex or race. The clinical team will inform the parents of the potential to 
Figures 1 & 2. CIMT therapist 
assists infant’s trunk control 
while the trigger button is 
attached to her hand with 
flexible wrap (red arrow). 
taVNS device is Velcro 
attached to the infant’s back 
(green arrow). The arm with 
better motor skill is 
immobilized with red flexible 
wrap and a splint. 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
participate in the study. Dr. Jenkins will then explain the study to the parents and give them 
contact information if they are interested, to initiate screening and consent procedures when 
their infant reaches 6-8months of age. Infants are also referred directly to Dr. Coker-Bolt and 
McGloon specifically for CIMT from a wide region of the southeast. Because some parents 
travel great distances to get these services, we may obtain referrals from other care providers 
out of our region.  We will perform phone screening and obtain Econsent prior to patient arrival 
for patients whose parents cannot meet in person prior to the first treatment session, to be 
able to get services fully prepared for the visit. We will use the approved REDcap system to 
obtain consent. Dr. Jenkins or other approved study personnel will go over the entire consent 
document on the phone with the parent to ensure comprehension and to confirm identity. 
Parent will be given a copy of the completed, signed consent form in person or by email or fax. 
 
Volunteers of all ethnicities and racial categories will be accepted into this study protocol. No 
preference will be given based on race, gender or ethnicity. Young infants who had perinatal 
complications leading to perinatally acquired brain injury may be considered vulnerable 
populations and are the target of this proposal. 
 
The parents of infants who present for CIMT are highly motivated, and willing to commit to the 
time and effort commitment for CIMT. Most of the study procedures occur during the active 
treatment period. Therefore, we anticipate >95% retention to completion of the immediate 
outcome measures. For the 3 months follow-up assessment, we will call every month to discuss 
infant progress with the mother/caregiver. All of these infants will also have regular 
developmental follow-up in MUSC’s or other high-risk clinic, and we will collect this data with 
parent consent, though it is not part of the primary or secondary outcomes for the phase I trial. 
 
 
9.0 
Consent Process 
Drs. Jenkins, Coker-Bolt, or McGloon (PI and Co-Investigators) will explain the study to these 
parents by phone or conference call and obtain written informed consent when they and their 
infants present to the Occupational therapy department for CIMT. Based on our 87% consent 
rate in the pilot taVNS-feeding study, and the ready parental acceptance of taVNS, we anticipate 
no significant parental concerns that would impact enrollment. We will not have a Spanish 
language consent. 
We will perform phone screening and obtain eConsent prior to patient arrival for patients whose 
parents cannot meet in person prior to the first treatment session, to be able to get services fully 
prepared for the visit. We will use the approved REDcap system to obtain consent. Dr. McGloon 
or other approved study personnel will go over the entire consent document on the phone with 
the parent to ensure comprehension and to confirm identity. Parent will be given a copy of the 
completed, signed consent form in person or by email or fax. 
 
10.0 
Study Design / Methods 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
Overall Study Design: The goal of this discovery pilot project is to further develop the technical 
aspects of taVNS+CIMT delivery so that it is practical for delivery by a CIMT therapist in a home-
based setting. This is essential to prepare for a treatment effectiveness study, which by necessity 
must be home-based because of the minimum 40-hour time commitment. First, we will use 
EMG sensors to automatically trigger the taVNS device, with the goal of decreasing the burden 
of treatment for the therapist. We will place the EMG sensors on major muscle groups on the 
shoulder and trunk and refine placement as needed to show that EMG-triggering can accurately 
and effectively trigger stimulation for 75% of total time spent in active movements. The 
therapist will still be able to manually trigger for other targeted behaviors (such as grasping). 
Once our placement of sensors has been tested and meets this designated threshold, the EMG-
triggered system will be tested in home-based CIMT treatment. 
 
This study will determine the feasibility of using EMG sensors to trigger taVNS stimulation 
paired with CIMT therapy in n=5, 6-18month old infants with hemiplegia after perinatally 
acquired brain injury. We will measure the effect of active taVNS paired with 40 hours of CIMT 
on infant motor skills before and after treatment over a month, and follow up the motor skills 
over 3 months. All infants will receive active taVNS treatment. CIMT treatment is a non-research 
procedure, and motor and developmental testing are non-research procedures. taVNS is a 
research procedure. CIMT sessions will be videotaped, to measure the fidelity of CIMT delivery 
while the therapist is delivering taVNS to determine feasibility.   
The alternative treatment is the usual and customary occupational therapy services. If parents 
wish, they may pursue CIMT therapy with local therapists, but there are very few qualified 
therapists in the area. Also, although CIMT is considered a gold standard intervention, it is often 
not covered by insurance due to the time intensity required.  
We will monitor for and mitigate following risks are present with this study: Risk of skin 
irritation, risk of discomfort, risk of slightly decreased heart rate, and risk of loss of 
confidentiality.  
Risk of skin irritation: we will monitor the skin on the inner aspect of the left ear before and 
after each session, and will switch to the right ear if redness is present, and decrease the 
stimulation if redness persists. 
Risk of discomfort: We will protect against the risk of discomfort by close monitoring. We will 
use the mother’s perception of infant discomfort and infant signs of discomfort to determine 
the perceptual threshold, and then treat at 0.1mA less than this level of perception. If any 
infant seems to be in discomfort during the CIMT taVNS session, we will decrease the 
microcurrent by 0.1mA, as in our feeding taVNS trial in infants. We will use facial expression 
change, fidgety movements and infant vocalization as signs of behavioral discomfort, to 
indicate need for decreasing the microcurrent during the taVNS session. 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
We will not continuously monitor heart rate during the taVNS session, as our extensive HR data 
in infants show no bradycardia and no decrease in HR beyond 60 seconds after starting 
stimulation. 
Risk of loss of confidentiality: We will check the infant’s medical records to gather the following 
information: gestational age at birth, ventilator support, head ultrasound and MRI results, 
bottle feeding, infection, neonatal condition during labor and delivery, infant’s treatments and 
conditions, and developmental progress.  
We will assign study numbers to each participant, keep CRF and consent forms in locked offices. 
Database files with names and contact information will be password protected and stored on 
the MUSC Pediatric server. All other data files related to this study will be identified by 
participant number only, without link to standard identifiers. We will publish the aggregate 
data only.  
11.0 Specimen Collection and Banking  
Videotapes will be stored for future use, by Drs. Coker-Bolt and McGloon in a password 
protected file on the pediatric server, behind MUSC’s firewall Future use will include education 
and teaching sessions and in presentations to describe the combined CIMT and taVNS 
treatment. They will be deidentified as much as possible although the therapist may use the 
infants name during CIMT. Only Drs. Coker-Bolt, McGloon and Jenkins and study personnel will 
have access to subject identities. Only coded identifiers will be used to store and linked to 
videotapes. If parents wish to withdraw the infant videotapes at any age prior to 18 years, they 
may request to do so in writing, and withdraw any future use of the child’s videotape. 
Videotapes will not be released to other parties not directly involved in research.  
 
12.0 
Data Management  
Analysis and Statistical plan: We will compare the change in score on functional measures 
between CIMT+ taVNS via repeated measures ANOVA from pre- to immediately and 30 days 
post- treatment via ANOVA. Power analysis on primary outcome is not valid with 5 
participants. However, for reference in infants treated with 60 vs 120h intensive CIMT8, the 
QUEST grasp mean changed from 4.50±2.6 to 5.25±3.1 with 3h/day CIMT (∆=0.75), versus 
4.14±2.6 to 5.73±3.0 with 6h/day CIMT (∆=1.59). We estimate 40h of CIMT+taVNS, 2h/day 
CIMT+taVNS will be similar to 3h CIMT, ∆grasp =0.75.8  
Keeping Data Confidential: We will assign study numbers to each participant, keep CRF and 
consent forms in locked offices. Database files with names and contact information will be 
password protected and stored on the MUSC Pediatric server. All other data files related to 
this study will be identified by participant number only, without link to standard identifiers. 
We will publish the aggregate data only.  
 
13.0 
Provisions to Monitor the Data to Ensure the Safety of Subjects  
Data and Safety Monitoring Plan 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
The participants who receive active taVNS involved with this proposal will be infants whose 
participation is agreed to by their parent/guardians in written consent. The principal 
investigator will be responsible for monitoring the safety of the proposed experiments. Dr. 
McGloon and Jenkins will also execute the Data Safety Management (DSM) plan and provide 
any necessary progress reports to the IRB, including but not limited to subject demographics, 
recruitment rates, retention rates, quality assurance issues, and adverse events or significant 
adverse events. Dr. Jenkins or her designee, should she be unavailable, will be responsible 
for reporting all unanticipated problems or AEs to the IRB. The PI or Co-I will be present for 
patient visits and the OT Research Assistant will discuss any perceived AE with them. Dr. 
McGloon will be responsible for reporting any unanticipated device- related AE's to FDA. All 
screening data will be kept in a binder in Dr. McGloon’s locked office. Screening data 
collected from participants who do not qualify for the study will be securely destroyed. 
 
Dr. Mark George, who is a board-certified neurologist and psychiatrist, and Phillip Summers 
will oversee the use of the taVNS system. Dr. Jenkins will be immediately available to the RA 
to monitor safety and adverse events. 
 
An independent Safety Monitoring Committee (SMC) will be formed to advise the study 
investigators. The SMC will review and evaluate accumulated study data to ensure safety, as 
in the pilot trial. They also will make recommendations concerning continuation, 
modification, or termination of any of the taVNS studies. It will be composed of Dr. Steve 
Kautz PT PhD and NM4R PI, Dr. Michelle Woodbury, OT PhD; and Dr. Jeff Borckardt, MUSC 
associate professor psychiatry and assistant provost with extensive VNS, TMS, and tDCS 
experience. The SMC and IRB will be notified immediately of any and all SAE's. 
 
Drs. Jenkins, McGloon and Coker-Bolt will obtain informed consent for mother and infant to 
participate, during which participants’ guardians are fully advised on the research procedures 
to be used, the amount of time required of them, the possible risks and benefits of the 
procedures, their right to refuse their infant’s participation in the study without prejudice, 
their right to terminate participation of their infant at any moment without prejudice, and 
the name and telephone number of the principal investigator. 
 
Regarding confidentiality, subjects’ guardians are informed that the information they 
provide, as well as participation in the study, will be kept strictly confidential, with access 
limited to the research staff. All paper records (consents, CRFs, study tools) will be kept in Dr. 
McGloons’ locked office in the College of Health Professions The identity of subjects in 
databases will be protected with alphanumeric codes. All data will be kept in locked office or 
on secure servers designed for use and access by Brain Stimulation and Neonatology, and OT 
Lab members only. 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
 
14.0 
Withdrawal of Subjects  
Parents may withdraw their infants at any time. Reasons may include excessive 
demands of time for CIMT or family pressures. Infants may be withdrawn without 
parental consent, if taVNS is poorly tolerated. If either occur, parents will be referred 
for clinical CIMT, of if this is not possible within the parent’s home structure, other 
occupational and physical therapy as appropriate. We will continue to collect follow-up 
data on motor skills even with early termination, if infants continue with MUSC OT 
department. 
15.0 
Risks to Subjects 
 
Risks of taVNS  
taVNS is transcutaneous electrical stimulation of the auricular branch of the vagus nerve that 
innervates the ear. Although this novel therapeutic modality is still in the development and 
optimization process, few risks are expected by the peripheral taVNS in adults and infants. TENS 
devices are FDA approved for pain relief and are available over the counter. The main risks 
associated with TENS are electrical hazards that may result in user discomfort or injury. The unit 
used in these studies (Soterix) is a custom modified, FDA-cleared electrical stimulator that meets 
the standards of the FDA for investigational use. Skin irritation, redness, or inflammation may 
occur under the stimulating electrodes, but these have not been observed with short term use. 
 
Two studies have used TENS on neonates to try to prevent or mitigate painful procedures (39- 
40). The TENS was administered at acupuncture sites with increasing current from 1-3.5 mA, and 
Hz from 2-10 in 30 healthy infants <3 days old. (39) In a subsequent study, this investigative team 
randomized 162 term neonates to TENS (3.5mA, 10Hz) or usual care to prevent pain from lancet 
heelsticks for blood sampling (40). These TENS parameters were safe and did not cause 
discomfort in the neonates. TENs has also been used with passive stretching in neonatal torticollis 
at 8Hz, 0.2mA for 30 minutes continuously (41) and in brachial plexus nerve injuries starting at 6 
weeks of age to improve motor function of the hand, in conjunction with constraint induced 
movement therapy (42). Neither study reported adverse effects of electrical stimulation. TENS 
has also been used in peroneal and sacral nerve stimulation for dysfunctional voiding and stooling 
(44- 45). Finally, the routine sweat test employed in newborns and infants to confirm the 
diagnosis of cystic fibrosis uses transcutaneous electrical stimulation to deliver pilocarpine via 
iontophoresis (43). From the product brochure of the Nanoduct™ Neonatal Sweat Analysis 
System (Discovery Diagnostics, Canada), the nominal current is 0.5 (± 0.02) mA to 5 mA for 2.5 
minutes (± 0.2 sec).  
 
taVNS also has associated risks that may arise from the direct brain effects stimulating the 
vagus nerve. The transient decrease in heart rate is a well described risks associated with 
neuromodulation of the parasympathetic nervous system that we have also observed in infants 
in the administration of noninvasive taVNS. The decrease in heart rate of 20±10bpm from a 
baseline HR of 160bpm occurs within 30 seconds of onset of stimulation and resolves in 60 
seconds. 
 
There have been multiple studies in which taVNS has been used on humans, none of them 
reporting significant adverse events. A simple PubMed search for “transcutaneous auricular 
vagus nerve stimulation” shows more than 100 peer-reviewed articles, most of which have been 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
published within the past 5 years. An extremely through review of all tVNS literature has been 
performed and no harm or adverse events have been observed and any side effects were 
resolved by decreasing current intensity. There also is currently a commercial tVNS device 
available 
for 
purchase 
on 
the 
European 
market 
(Cerbomed 
- 
Nemos 
device; 
www.cerbomed.com) that is marketed as a take- home treatment for epilepsy. 
Not only does the current literature show a lack of harm done by tVNS, the side effects 
of implanted VNS of alteration of voice, coughing, pharyngitis, hoarseness, headache, and 
nausea, have not been reported with taVNS. Cardiac evaluations have been made on 
hundreds of VNS, and more recently taVNS patients, with no changes in cardiac function 
(Handforth et al, 1998; Sackeim et al, 2001b; Morris and Mueller, 1999) with long-term safety 
confirmed in recent large sample retrospective studies (Menascu et al, 2013; Ryvlin et al, 
2014; Choi et al, 2013). 
We performed taVNS paired with feeding in 35 infants in our pilot study without adverse 
effects and with potential benefit. A summary of potential risks in infants include the risk of 
skin irritation, discomfort, transiently decreased heart rate, and loss of confidentiality. 
Bradycardia: Our own safety studies designate a transient measurable change in heart rate (-
20 to  10bpm), lasting <60 seconds, which is not clinically significant in infants with baseline 
HR of 140- 160bpm in our pilot study (Badran BW, 2020, Frontiers in Human Neuroscience). 
Given the minimal risk of taVNS FDA approved/cleared devices, we anticipate that taVNS 
paired with CIMT will be a very safe procedure in infants. The potential risks will be clearly 
outlined in the informed consent document, as in our prior infant taVNS study. MUSC’s IRB 
has previously determined our taVNS system to be minimal risk device. Nevertheless, there 
may be unknown risks with experimental procedures. 
 
Risk of loss of confidentiality: We will assign study numbers to each participant, keep CRF and 
consent forms in locked offices. Database files with names and contact information will be 
password protected and stored on the MUSC Pediatric server. All other data files related to 
this study will be identified by participant number only, without link to standard identifiers. 
We will publish the aggregate data only.  
This study will involve research on vulnerable subjects: mothers and their infants with 
perinatal brain injury, potentially as a result of maternal conditions during pregnancy.  
 
16.0 
Potential Benefits to Subjects or Others 
The infants with perinatally acquired brain injury constitute a vulnerable populations, but the 
procedures in this protocol are all minimal risk procedures (CIMT, motor assessments). Other 
than the novelty of using taVNS in infants, taVNS also involves little risk: equivalent TENS units 
are widely available on the internet for home purchase and use in all ages. 
The intervention of pairing taVNS and CIMT could offer considerable benefit to both families 
and infants. taVNS paired with CIMT training may enhance infant motor skills in infants who 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
have one-sided weakness, and enable the infants to achieve greater upper extremity function 
with less time commitment than the maximum CIMT protocols that are 2 to 3 times as long as 
our taVNS-paired CIMT protocol. 
However, there may be no direct benefit to the participants. 
 
17.0 
Sharing of Results with Subjects 
Results of all motor skills test will be shared with parents as soon as the scoring is 
completed.  
 
18.0 Drugs or Devices  
The Soterix device and electrodes, hand-held trigger will be stored in Dr Coker-Bolt’s or 
McGloon’s  office when not in use, and in a locked cabinet when in daily use for a 
participant.  Only authorized investigators will have access to this locked cabinet. 
The Soterix units is a custom device based on an taVNS device that is FDA cleared for 
investigational use. (see Soterix letter) 
References  
1. Rocha-Ferreira E, Hristova M. Plasticity in the Neonatal Brain following Hypoxic-Ischaemic 
Injury. 
Journal 
of 
neural 
transplantation 
& 
plasticity. 
2016;2016:4901014-16. 
doi:10.1155/2016/4901014 
2. Duerden EG, Foong J, Chau V, et al. Tract-Based Spatial Statistics in Preterm-Born 
Neonates Predicts Cognitive and Motor Outcomes at 18 Months. American journal of 
neuroradiology : AJNR. 2015;36(8):1565-1571. doi:10.3174/ajnr.A4312 
3. O’Shea TMTM, Allred EE, Kuban KCKKCK, et al. Elevated concentrations of inflammation-
related proteins in postnatal blood predict severe developmental delay at two years in 
extremely premature infants. The Journal of pediatrics. 2011;160(3):395-401.e4. 
doi:10.1016/j.jpeds.2011.08.069 
4. Yanni D, Korzeniewski SJ, Allred EN, et al. Both antenatal and postnatal inflammation 
contribute information about the risk of brain damage in extremely preterm newborns. 
Pediatr Res. Oct 2017;82(4):691-696. doi:10.1038/pr.2017.128 
5. Dammann O, Leviton A. Inflammation, brain damage and visual dysfunction in preterm 
infants. Seminars in Fetal and Neonatal Medicine. 2006/10/01/ 2006;11(5):363-368. 
doi:https://doi.org/10.1016/j.siny.2006.02.003 
6. Ramey SL, Coker-Bolt P, DeLuca S. Handbook of Pediatric Constraint-induced Movement 
Therapy (CIMT): A Guide for Occupational Therapy and Health Care Clinicians, Researchers, 
and Educators. AOTA Press, Ther american Occupational Therapy Association, Incorporated; 
2013. 
7. DeLuca SC, Ramey SL, Trucks MR, Wallace DA. Multiple Treatments of Pediatric 
Constraint-Induced Movement Therapy (pCIMT): A Clinical Cohort Study. Am J Occup Ther. 
Nov-Dec 2015;69(6):6906180010p1-9. doi:10.5014/ajot.2015.019323 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
8. Case-Smith J, Frolek Clark GJ, Schlabach TL. Systematic review of interventions used in 
occupational therapy to promote motor performance for children ages birth-5 years. Am J 
Occup Ther. Jul-Aug 2013;67(4):413-24. doi:10.5014/ajot.2013.005959 
9. DeLuca SC, Trucks MR, Wallace DA, Ramey SL. Practice-based evidence from a clinical 
cohort that received pediatric constraint- induced movement therapy. J Pediatr Rehabil Med. 
2017;10(1):37-46. doi:10.3233/prm-170409 
10. Reidy TG, Carney J, Whiston N, Naber E. Infant constraint induced movement therapy: 
Lessons learned from clinical implementation. J Pediatr Rehabil Med. 2017;10(1):61-67. 
doi:10.3233/prm-170411 
11. Ramey SL, DeLuca S, Stevenson RD, Case-Smith J, Darragh A, Conaway M. Children with 
Hemiparesis Arm and Movement Project (CHAMP): protocol for a multisite comparative 
efficacy trial of paediatric constraint-induced movement therapy (CIMT) testing effects of 
dosage and type of constraint for children with hemiparetic cerebral palsy. BMJ Open. Jan 15 
2019;9(1):e023285. doi:10.1136/bmjopen-2018-023285 
12. Kwon JY, Chang WH, Chang HJ, et al. Changes in diffusion tensor tractographic findings 
associated with constraint-induced movement therapy in young children with cerebral palsy. 
Clin Neurophysiol. Dec 2014;125(12):2397-403. doi:10.1016/j.clinph.2014.02.025 
13. Redgrave JN, Moore L, Oyekunle T, et al. Transcutaneous Auricular Vagus Nerve 
Stimulation with Concurrent Upper Limb Repetitive Task Practice for Poststroke Motor 
Recovery: A Pilot Study. J Stroke Cerebrovasc Dis. Jul 2018;27(7):1998-2005. 
doi:10.1016/j.jstrokecerebrovasdis.2018.02.056 
14. Porter BA, Khodaparast N, Fayyaz T, et al. Repeatedly pairing vagus nerve stimulation with 
a movement reorganizes primary motor cortex. Cereb Cortex. Oct 2012;22(10):2365-74. 
doi:10.1093/cercor/bhr316 
15. Badran BW, Jenkins DD, Cook D, et al. Transcutaneous Auricular Vagus Nerve Stimulation-
Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot 
Study. Front Hum Neurosci. 2020;14:77. doi:10.3389/fnhum.2020.00077 
16. Badran BW, Jenkins DD, DeVries WH, et al. Transcutaneous auricular vagus nerve 
stimulation (taVNS) for improving oromotor function in newborns. Brain Stimul. Sep-Oct 
2018;11(5):1198-1200. doi:10.1016/j.brs.2018.06.009 
17. Kimberley TJ, Pierce D, Prudente CN, et al. Vagus Nerve Stimulation Paired With Upper 
Limb 
Rehabilitation 
After 
Chronic 
Stroke. 
Stroke. 
Nov 
2018;49(11):2789-2792. 
doi:10.1161/strokeaha.118.022279 
18. Meyers EC, Solorzano BR, James J, et al. Vagus Nerve Stimulation Enhances Stable 
Plasticity and Generalization of Stroke Recovery. Stroke. Mar 2018;49(3):710-717. 
doi:10.1161/strokeaha.117.019202 
19. Khodaparast N, Hays SA, Sloan AM, et al. Vagus nerve stimulation delivered during motor 
rehabilitation improves recovery in a rat model of stroke. Neurorehabil Neural Repair. Sep 
2014;28(7):698-706. doi:10.1177/1545968314521006 
20. Hays SA. Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation. 
Neurotherapeutics. Apr 2016;13(2):382-94. doi:10.1007/s13311-015-0417-z 

Title: Extending taVNS Paired with Infant CIMT into a Home-Based Setting: Technology 
Development Requisite for a Randomized Trial 
PI: Kelly McGloon 
 
21. Gillick B, Rich T, Nemanich S, et al. Transcranial direct current stimulation and constraint-
induced therapy in cerebral palsy: A randomized, blinded, sham-controlled clinical trial. Eur J 
Paediatr Neurol. May 2018;22(3):358-368. doi:10.1016/j.ejpn.2018.02.001 
22. Kirton A, Andersen J, Herrero M, et al. Brain stimulation and constraint for perinatal stroke 
hemiparesis: The PLASTIC CHAMPS Trial. Neurology. May 3 2016;86(18):1659-67. 
doi:10.1212/wnl.0000000000002646 
23. Nemanich ST, Rich TL, Chen CY, et al. Influence of Combined Transcranial Direct Current 
Stimulation and Motor Training on Corticospinal Excitability in Children With Unilateral 
Cerebral Palsy. Front Hum Neurosci. 2019;13:137. doi:10.3389/fnhum.2019.00137 
24. !!! INVALID CITATION !!! 24; 
25. Van der Fits IB, Otten E, Klip AW, Van Eykern LA, Hadders-Algra M. The development of 
postural adjustments during reaching in 6- to 18-month-old infants. Evidence for two 
transitions. Exp Brain Res. Jun 1999;126(4):517-28. doi:10.1007/s002210050760 
26. Hadders-Algra M. Variation and variability: key words in human motor development. Phys 
Ther. Dec 2010;90(12):1823-37. doi:10.2522/ptj.20100006 
27. Boxum AG, La Bastide-Van Gemert S, Dijkstra LJ, Furda A, Reinders-Messelink HA, 
Hadders-Algra M. Postural control during reaching while sitting and general motor behaviour 
when 
learning 
to 
walk. 
Dev 
Med 
Child 
Neurol. 
May 
2019;61(5):555-562. 
doi:10.1111/dmcn.13931 
28. Harbourne RT, Lobo MA, Karst GM, Galloway JC. Sit happens: Does sitting development 
perturb reaching development, or vice versa? Infant Behavior and Development. 2013/06/01/ 
2013;36(3):438-450. doi:https://doi.org/10.1016/j.infbeh.2013.03.011 
29. Vieira da Fonseca M, Oliveira ALS, Figueiredo RM, Lima RTF, Toledo AM. How Has 
Electromyography Been Used to Assess Reaching in Infants? A Systematic Review. J Mot 
Behav. 2021;53(1):117-127. doi:10.1080/00222895.2020.1723476 
30. Rachwani J, Santamaria V, Saavedra SL, Woollacott MH. The development of trunk control 
and its relation to reaching in infancy: a longitudinal study. Frontiers in human neuroscience. 
2015;9:94-94. doi:10.3389/fnhum.2015.00094 
31. Case-Smith J, DeLuca SC, Stevenson R, Ramey SL. Multicenter randomized controlled trial 
of pediatric constraint-induced movement therapy: 6-month follow-up. Am J Occup Ther. Jan-
Feb 2012;66(1):15-23. doi:10.5014/ajot.2012.002386