Combinatorial Treatment of Acute Intermittent Hypoxia and Transcutaneous Electrical Spinal Cord Stimulation to Improve Hand Function in People With Cervical Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injuries
Sponsor: Spaulding Rehabilitation Hospital

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PROTOCOL TITLE: Pairing Intermittent Hypoxia and Transcutaneous Electrical Spinal Cord 
Stimulation to Promote Arm Use After Cervical SCI 
NCT#: NCT04854057 
Date: 29 December 2022 
 
 

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I. BACKGROUND AND SIGNIFICANCE  
Spinal cord injury (SCI) is damage to any part of the spinal cord that interrupts 
communication between the brain and the body. Depending on the level and the extent of the 
damage, individuals with SCI usually have permanent paralysis and disability. Consequently, 
SCI has a life-long, high socioeconomic impact on affected individuals, families, and health 
care systems. Estimated global SCI incidence is 40 to 80 new cases per million population 
per year (WHO, 2013). Each year about 17,700 new spinal cord injuries (SCI) occur in the 
United States (NSCISC, 2020). The estimated direct life-time cost of cervical SCI is between 
$2.3 and $5.0 million that varies depending on the level, severity, and age at injury (Cao, 
Chen, & DeVivo, 2011; NSCISC, 2020). Additionally, indirect costs such as work loss, 
reduced productivity, personal assistance expenses, and the burden on the family is estimated 
an average of $76,000 per year (NSCISC, 2020). 
The majority of spinal cord injuries occur at the cervical level (NSCISC, 2020) that results in 
impairment in motor control and sensory function in the hand and arm. Restoration of upper 
extremity function is consistently rated as the highest treatment priority among people with 
cervical SCI (Anderson, 2004; French, Anderson-Erisman, & Sutter, 2010). The current 
standard of care to restore tetraplegic hand function is limited, and outcomes of these 
approaches are insufficient to improve the ability of self-care and independence. There is a 
need to for novel non-invasive treatment approaches to target plasticity that induce functional 
restoration in persons with chronic, cervical SCI. Brain-derived neurotropic factor (BDNF) 
expression plays a key-role in increasing neuroplasticity (Garraway & Huie, 2016). Daily 
acute intermittent hypoxia (AIH) and transcutaneous electrical spinal cord stimulation 
(TESS) are emerging therapies. Both of these interventions elicit an increase in BDNF. By 
combining these two approaches, augmentation of neuroplasticity could be achieved. 
Daily AIH is a safe and highly promising non-invasive intervention as a plasticity primer for 
task-specific motor training in SCI rehabilitation (Trumbower, Hayes, Mitchell, Wolf, & 
Stahl, 2017; Trumbower, Jayaraman, Mitchell, & Rymer, 2012). Daily AIH upregulates 
BDNF and its high-affinity receptor (TrkB) that induce neuroplasticity (Baker-Herman et al., 
2004). Human trials have demonstrated the efficacy of daily AIH in improving motor 
function both in upper (Trumbower et al., 2017) and lower extremities (Trumbower et al., 
2012) and dynamic balance (Navarrete-Opazo, Alcayaga, Sepúlveda, & Varas, 2017). The 
results of a double blind sham controlled study showed that dAIH paired with task-specific 
training significantly improved hand dexterity, function, maximum hand aperture and muscle 
coordination in all participants compared to baseline (p<0.05) (Trumbower et al., 2017). 
Over the past few years, a novel, non-invasive, transcutaneous electrical spinal cord 
stimulation (TESS) strategy adopting high carrier-frequency waveforms has emerged. This 
new strategy utilizes a unique waveform of biphasic or monophasic, rectangular, 1 ms pulses 
that are delivered at a frequency of 30 Hz. Each pulse is filled with an overlapping frequency 
of 10 kHz, which permits high stimulation intensities to pass through the skin and reach the 
spinal cord without causing discomfort (Gerasimenko et al., 2015). In patients with complete 
SCI, TESS improved lower extremity function in a gravity neutral position and facilitated 
stepping assisted by an exoskeleton (Gad et al., 2017; Gad et al., 2015). TESS is showing an 
exciting potential to restore upper extremity function effectively and non-invasively. Gad and 

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co-workers studied handgrip force improvements in 6 AIS B and AIS C chronic cervical SCI 
subjects (Gad et al., 2018). They reported that eight sessions of transcutaneous stimulation 
increased maximum voluntary handgrip forces by ~3-fold in the presence of stimulation and 
~2-fold without simultaneous stimulation. In another case study, a subject who had C3 level 
chronic central cord injury improved substantially in terms of motor and sensory function 
(Inanici et al., 2018). Following four weeks of combined stimulation and sensorimotor 
training, the Graded Redefined Assessment of Strength, Sensation, and Prehension test score 
increased 52 points, and the upper extremity motor score improved 10 points. Pinch strength 
increased 2- to 7-fold in the left and right hands, respectively. Sensation recovered on trunk 
dermatomes, and the overall neurologic level of injury improved from C3 to C4. The subject 
began partial self-feeding at home in the second week of the intervention for the first time 
since his injury and continued this activity even after the intervention. Most notably, 
functional gains persisted for over three months of follow-up without further treatment. 
These data suggest that non-invasive electrical stimulation of spinal networks can promote 
neuroplasticity and long-term recovery following spinal cord injury. However, the exact 
mechanism of the electrical spinal cord stimulation remains to be determined. In animal 
studies, electrical stimulation of the nervous system increased BDNF and TrkB expression 
which promotes neuroplasticity (Al-Majed, Tam, & Gordon, 2004; Ghorbani et al., 2020). A 
possible mechanism that increases BDNF expression through electrical stimulation is via 
calcium influx through voltage-gated calcium channels leading to a chemical cascade with an 
increase of BDNF (Vermehren-Schmaedick, Khanjian, & Balkowiec, 2015; Wenjin et al., 
2011). 
 
II. SPECIFIC AIMS  
A major goal of this proposal is to test the efficacy of daily AIH with TESS on restoring hand 
function in persons with chronic incomplete SCI. 
Our fundamental hypothesis guiding this proposal is that daily AIH+TESS engage excitatory 
and inhibitory pathways, which converge on a common plasticity-promoting cascade that 
induces greater recovery of hand function than either one alone. 
Both treatments appear to enhance motor function in persons with cervical SCI. Despite their 
independent effects on promoting functional benefits, we do not yet know if they may 
promote greater functional benefits when combined. To be effective as a long-term 
rehabilitation strategy, it is essential to determine the efficacy of combined protocols of 
recurring AIH+TESS. 
Our specific aims are: 
Aim 1. To investigate the therapeutic effect of combinatorial treatment of TESS and 
dAIH on motor performance. 
We hypothesize that the combination of dAIH and TESS enhances recovery of 
fine motor skills of the hand, strength and muscle coordination that will be 
quantified using Graded Redefined Assessment of Strength, Sensibility, and 
Prehension (GRASSP), pinch-grip force measurements, and muscle coordination 
determined by agonist-antagonist coactivity ratio during grip and release 
movement, respectively. 

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Aim 2. To evaluate the effect of combinatorial treatment of TESS and dAIH on 
excitatory and inhibitory pathways of spinal networks and corticospinal tract. 
We hypothesize that the combination of dAIH and TESS changes the excitability 
in neuronal pathways. To quantify neuronal pathway excitability, we will 
compare F-wave, H-reflex, somatosensory evoked potentials, motor evoked 
potentials and sympathetic skin responses before and after the treatment. 
 
III. SUBJECT SELECTION 
Subject Selection and Recruitment: Participants with cervical SCI will be recruited from 
Spaulding Rehabilitation Hospital and Massachusetts General Hospital. Potential subjects 
will be informed about the objectives of the study and must meet all inclusion and exclusion 
criteria. They will be required to read and sign approved consent and HIPAA forms prior to 
participation to allow access to medical information from their physicians. To determine the 
effects of the combinatorial treatment of acute intermittent hypoxia and transcutaneous 
electrical spinal cord stimulation, we propose to carry out a prospective, randomized, double 
blind, cross-over design study involving two alternating treatment arms. Intervention arms 
will consist of TESS and daily dAIH, paired with intensive upper extremity functional 
training. Based on prior recruitment experiences (Hayes et al., 2014), we anticipate a 
withdrawal rate of 20% in SCI. Our predicted sample size is total 10 persons with chronic 
cervical spinal cord injury. We incorporated the International Campaign for Cures of Spinal 
Cord Injury Paralysis (ICCP) inclusion/exclusion criteria recommendations (Tuszynski et al., 
2007) to account for ethical considerations, safety, and potential confounds during subject 
recruitment. 
ResearchMatch.org also will be utilized as a recruitment tool for this protocol. 
ResearchMatch.org is a national electronic, web-based recruitment tool that was created 
through the Clinical & Translational Science Awards Consortium in 2009 and is maintained 
at Vanderbilt University as an IRB-approved data repository (see IRB #090207). 
Inclusion criteria: Participation requirements for individuals with SCI include: 1) 18 to 65 
years old (the latter to reduce likelihood of significant comorbidities); 2) medically stable 
with medical clearance from physician to participate; 3) SCI at or below C3 and at or above 
C7; 4) non-progressive etiology of spinal injury; 5) American Spinal Injury Association 
Impairment Scale (AIS) C-D at initial screen; 6) at least 1 year post-injury (chronic). We plan 
to choose subjects greater that 1-year post-injury to ensure minimal confounding effects of 
natural spontaneous neurological recovery during the experiments. This will mean that 
changes in sensorimotor performance are more likely due to the interventions associated with 
the research study; 7) difficulty independently performing hand functions in activities of 
daily living; 8) able to attend 2 rounds of study sessions for 3 consecutive weeks and 2 
follow-up visits for up to 16 weeks of study involvement; 9) stable medical condition without 
cardiopulmonary disease or frequent autonomic dysreflexia that would contraindicate 
participation in upper extremity rehabilitation or testing activities; 10) adequate social 
support to be able to participate in daily training for 6 weeks and a total of 16 weeks for all 
assessment sessions within the study period; 11) ability to read and speak English or 
communicate via medical interpreter. 

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Exclusion criteria: We will exclude individuals who have: 1) dependence on ventilation 
support 2) implanted stimulator (e.g. diaphragm pacing by phrenic nerve stimulation, vagus 
nerve stimulator, pacemaker, cochlear implant, epidural stimulator, baclofen pump, etc.); 3) 
spinal cord injury related complications including unhealed pressure sore, severe neuropathic 
or chronic pain syndrome, history of frequent autonomic dysreflexia, infection (e.g. urinary 
tract), cardiovascular disease (e.g. deep vein thrombosis), pulmonary disease, heterotopic 
ossification in the upper extremities, severe osteoporosis, unhealed fracture, contracture of 
the upper extremity joints 4) received botulinum toxin injections in upper extremity muscles 
in the prior 6 months; 5) history of tendon or nerve transfer surgery in the upper extremity; 6) 
history of additional neurologic disease, such as stroke, multiple sclerosis, traumatic brain 
injury, peripheral neuropathy (diabetic polyneuropathy, entrapment neuropathy, etc.) or 
peripheral nerve injury in the upper extremity 7) history of concomitant diseases that would 
prevent full participation in intensive exercise therapy, such as uncontrolled hypertension, 
rheumatic diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.), pulmonary 
disease, active cancer, chronic contagious disease, etc.; 8) anticoagulation medication 9) 
pregnancy because of unknown effects of TESS and dAIH, although women of childbearing 
potential will not otherwise be excluded; 10) history of conditions that contraindicate 
transcranial magnetic stimulation. These include history of seizures or epilepsy, unexplained, 
recurring or violent headaches, nausea associated with medical procedures (needles, 
injections etc.), increased pressure inside the skull or significant heart disease, medication 
that may influence chances of having a seizure , and depression or bipolar disorder; 11) 
history of allergic reaction or any skin reaction to use of adhesive electrodes 12) < 24 on 
Mini-Mental Exam (Folstein, Folstein, & McHugh, 1975). 
Inclusion of women and minorities: Of SCI cases, about 78% are male and 59% are non-
Hispanic whites. SCI may affect individuals at any age, and average age at injury is 43 years 
(NSCISC, 2020). Our recruitment of subjects with cervical spinal cord injury and disability 
in their hand and arm function will include women and persons of any ethnicity and race. 
Since we do not have data that show any differences in responsiveness to TESS and daily 
AIH according to the age, gender or race of persons with SCI, we will balance based on age, 
gender, and race. However, women who are pregnant will not take part in this study as the 
effects of TESS and daily AIH on the developing fetus have not been studied. If a woman is 
of childbearing ability, birth control will be recommended for use throughout the study. 
Based on these criteria, the team already has identified ~30 potential subjects eligible to 
participate in the experiments outlined in this proposal (see Human Subjects section for 
details). 
Clinical Ratings: Potential subjects will undergo a screen by one of the licensed study 
clinicians. Physical evaluations will be completed by the study’s licensed physical therapists, 
or occupational therapist, or trained research study staff. 
 
 
IV. SUBJECT ENROLLMENT 
a) 
Methods of enrollment, including procedures for patient registration and/or 
randomization: Our study coordinator, study physicians, physical therapists, PI (Trumbower), 

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and research collaborators will recruit subjects using a variety of strategies shown effective in the 
past. First, the team will identify potential subjects using Institutional Review Board (IRB)-
approved resources to inform persons with SCI that are currently admitted to inpatient 
rehabilitation/outpatient units of Spaulding Rehabilitation Hospital and Massachusetts General 
Hospital. Subjects also will be recruited by word of mouth and flyers at these facilities. 
Potential individuals with SCI will be identified by the following sources: 
1. Attending physicians or therapists may refer their subjects to the study. We will provide 
physicians, therapists, and clinics with study information sheets, letters, and flyers. 
Prospective subjects will be encouraged to contact the study co-investigators. 
2. Flyers posted in public areas across the Boston-land region, in the outpatient specialist 
clinics, or other private locations with given permission. 
3. Possible subjects might also be identified through their medical records and their 
physicians might be asked to inform the subjects about the study. 
4. Presentations at local, state hospitals, and rehabilitation facilities that include public and 
VA medical centers in the U.S. Northeast. 
5. Attending public forums, conferences, or events at which the co-investigator will distribute 
IRB approved recruitment materials. 
6. Partners Rally http://rally.partners.org 
7. We also will provide a description of the study on http://www.ClinicalTrials.gov, 
8. We will contact patients who have consented to be added to the Spaulding Rehabilitation 
Hospital’s Spinal Cord Injury Model Systems (SCIMS) Database who have identified that 
they wished to be contacted for additional research studies. Research staff recruiting from 
the SCIMS database are also added as study staff on the SCIMS protocol. 
9. ResearchMatch.org also will be utilized as a recruitment tool for this protocol. 
ResearchMatch.org is a national electronic, web-based recruitment tool that was created 
through the Clinical & Translational Science Awards Consortium in 2009 and is 
maintained at Vanderbilt University as an IRB-approved data repository (see IRB 
#090207). 
 
b) 
Procedures for obtaining informed consent: Prospective subjects also will be informed 
of the methods, inclusion/exclusion criteria, and purpose of the study. We will provide a 
description of this study on ClinicalTrials.gov, as required by U.S. law. In all cases, recruitment 
will not be coercive, will not involve undue inducements, and will accurately reflect the study. 
Eligible subjects will be screened at the designated site facilities (i.e., INSPIRE Laboratory, 
Spaulding Rehabilitation Hospital). At the screening visit, subjects will be informed of this project, 
their potential involvement, the possible benefits and risks, and their right to terminate 
participation at any time without penalty. Qualifying subjects in agreement with the study details 
will be asked to sign the informed consent and HIPAA form approved by Partner’s IRB. All 
potential subjects will enter the study according to the inclusion/exclusion criteria above and 
following medical clearance. Experiments will be conducted at the Spaulding Rehabilitation 
Hospitals (Boston, Cambridge). 
c) 
Treatment assignment, and randomization: Simple randomization of the participants 
will be used to assign for the cross-over order of the dAIH and sham treatments. 
 

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V. STUDY PROCEDURES 
a) Study timeline: 
The length of each arm of the study for each participant will last 8 weeks (up to 16 weeks 
total for both arms.) Figure 1 illustrates the stages of study timeline: 
Figure 1. Study design and timeline 
 
b) Repeated measurements: 
Measurements will be conducted at baseline, once at the end of each intervention week and at the 
end of one-month follow-up period. 
 
c) Outcome measures: 
1. GRASSP test. This test is validated for the tetraplegic population to quantify hand and 
arm function (Kalsi-Ryan et al., 2016; Kalsi-Ryan, Curt, Verrier, & Fehlings, 2012). Sub-
scores of the GRASSP test include: a) Strength: manual muscle testing of 10 upper 
extremity muscles (i.e. deltoid, triceps, biceps, wrist extensors, finger flexors, finger 
abductors, extensor digitorum, opponens pollicis, flexor pollicis longus, and first dorsal 
interossei) on each side using Medical Research Council Motor Strength Scale; b) 
Sensation: Semmens-Weinstein monofilament testing of dorsal and palmar sensation of 
the fingers and thumb; c) Qualitative prehension: movement and active/passive 
positioning of finger-hand-forearm to form three prehension patterns, i.e. cylindrical 
grasp, lateral key pinch and tip to tip pinch; d) Quantitative prehension: scoring the 
performance during 6 pre-defined tasks, i.e. 9-hole peg test, pouring water, opening a jar, 
placing and turning a key in a lock, putting coins in a slot, and separating nuts from bolts. 
2. Pinch and grip forces will be measured for both the right and left hands using standard 

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clinical dynamometer to quantify strength (Angst et al., 2010). To avoid tenodesis grip 
and pinch movement, tests will be performed in a standardized way with subjects seated 
upright against the back of a chair, shoulder adducted and neutrally rotated, elbow flexed 
90 degrees, forearm in neutral position, when possible. Verbal encouragement will be 
provided to the subjects to exert maximum force. The average of three measurements per 
test session will be recorded. 
 
d) Treatment Protocols: 
1) Participants will receive intensive upper extremity functional training paired with 
TESS. Intensive training will consist of progressive functional task practice for upper 
extremity motor training. A total of 24 treatment sessions, which will last 45 minutes per 
session, will be completed in 3 weeks (4 days/week) per crossover arm. The functional 
task practice protocol is described previously and shown to be effective for enhancing 
functional performance and strength in chronic SCI (Beekhuizen, 2005; Beekhuizen & 
Field-Fote, 2005; Gomes-Osman, Tibbett, Poe, & Field-Fote, 2017; L. Hoffman & Field-
Fote, 2013; L. R. Hoffman & Field-Fote, 2010). Functional task practice training will 
include repetitive unimanual (15 minutes each side) and bimanual (15 minutes) activities 
of gross upper extremity movement, isolated finger movements, simple and complex 
pinch and grip performance. For each category, 8-10 activities with various difficulty 
levels are designated and the subject will perform 1-2 activities within the same category 
in each treatment session. Activities in each category will be chosen according to the 
subject’s ability and will be changed/modified as function progresses over time. For 
instance, the size of the coins will be reduced for simple pinch task or resistance level 
will be increased for TheraPutty exercises. Typical movement patterns will be 
encouraged by guidance and giving feedback (Vergara, Sancho-Bru, Gracia-Ibanez, & 
Perez-Gonzalez, 2014). When subjects have little to no voluntary movement, active 
assistance will be provided. 2-3 minute rest periods will be allowed between activities 
and when needed. 
2) Transcutaneous electrical spinal cord stimulation (TESS): We will deliver TESS to 
the cervical spinal cord utilizing the experimental device developed by SpineX, Inc 
(Transcutaneous Electrical Spinal Cord Neuromodulator - TESCoN). The stimulator 
delivers programmable electrical current waveforms that are comprised of two modulated 
frequencies: (1) base frequency and (2) overlapping frequency, on up to four independent 
channels. 
This current waveform is adapted from kilohertz-frequency muscle stimulation, and 
permits high amplitude stimulation without discomfort (Ward, 2009; Ward & 
Shkuratova, 2002). Thus, stimulation over the skin can reach the spinal cord to activate 
spinal networks (Hofstoetter, Freundl, Binder, & Minassian, 2018). The rationale for the 
high overlapping frequency is that unmyelinated C-fibers in the skin can be selectively 
blocked by using high-frequency waveforms (Joseph & Butera, 2011; Joseph, Haeffele, 
& Butera, 2007; Ward & Robertson, 1998), and stimulation may penetrate more deeply 
due to lowering of the tissue impedance (Medina & Grill, 2014). 
We will use an electrical current waveform for transcutaneous spinal cord stimulation 
that is biphasic, 1 millisecond pulse width, 30 Hz base frequency, with a 10 kHz 
overlapping frequency (Fig 2). 

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Stimulation intensity will be adjusted between 0 and 130 milliamperes (mA) due to dose 
response curves obtained during the first stimulation session. We will use two 2.5 cm 
round self-adhesive hydrogel surface electrodes as cathodes and two 5 x 10 cm 
rectangular self‐adhesive hydrogel electrodes as anodes (Axelgaard Manufacturing Co., 
Ltd., USA). Cathode electrodes will be placed midline on the skin of the neck, one above 
and one below the injury level with the guidance of the occipital inion and spinous 
processes as landmarks. Anode electrodes will be placed symmetrically over the iliac 
crests of the pelvis. 
We will determine the optimal stimulation parameters for each participant based on the 
motor responses that will be tested using surface electromyography (EMG) electrodes 
(multichannel EMG system, Bortec AMT-8) placed on eight upper extremity muscles 
(deltoid, triceps, biceps, extensor digitorum, flexor digitorum, first dorsal interosseous, 
abductor pollicis brevis, and abductor digiti minimi) on each side. Subthreshold 
stimulation intensity will be used for therapeutic stimulation. Monophasic and biphasic 
stimulation waveforms activate neural circuits differently (Wang, Millard, Zheng, & 
Stanley, 2012), and both waveforms will be tested for their ability to enable functional 
movements. We will increase the stimulation intensity in increments of 5 mA until we 
reach direct muscle activation detected by surface EMG recordings. 
Stimulation will be delivered for up to 45 minutes during each session of stimulation 
paired with training (6 weeks, 4 days/week). During the first week of the intervention 
period, participants will get only TESS paired with training. During the second and third 
weeks of the intervention period, TESS paired with training will be applied after daily 
AIH or SHAM (Figure 1). For safety precautions, we will closely monitor heart rate and 
blood pressure throughout each session along with blood oxygen saturation throughout 
AIH and SHAM sessions. Stimulation parameters will be re-adjusted as needed 
throughout the intervention phase of the study. For example, if stimulation interferes with 
the coordination of fine motor skills, the intensity will be lowered, or it will be increased 
for strengthening exercises if needed. 
3) Daily Acute Intermittent Hypoxia (dAIH) and normoxia (SHAM): Each participant 
will be exposed to 4 sessions (1-week) of daily AIH and 4 sessions (1 week) of SHAM 
with a randomized alternating order. The order will be reversed for the second arm of the 
study. Daily AIH and SHAM treatment will precede the delivery of TESS paired with 
training on the second and third weeks of the intervention period (Figure 1). Each session 
 
Figure 2. (A) Current waveform, (B) Cathode and anode electrode placement sites that 
will be used for TESS 
Biphasic
Catode electrodes:
C3-4
C6-7
Anode electrodes:
R&L anterior iliac crests
A
B

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will consist of 15 episodes of 1.5 min hypoxia (fraction of inspired oxygen – [FIO2] = 
0.09 ± 0.02, i.e. 9% O2) for AIH or normoxia (FIO2 = 0.21 ± 0.02, i.e. 21% O2 or room 
air) for SHAM with 1 min intervals of room air. 
Gas Delivery Methods: Intermittent gas mixtures will be delivered via manual 
adjustment of one- way valves attached to a hypoxia generator (HYP123, Hypoxico Inc., 
USA). The generator will fill reservoir bags attached to a non-rebreathing facemask worn 
by subjects (Hayes et al., 2014; Trumbower et al., 2012). We will deliver preset air 
mixtures of FIO2 = 0.09 ± 0.02 (hypoxia) or FIO2 = 0.21 ± 0.02 (normoxia). Oxygen 
concentration will be continuously monitored (OM-25RME; Maxtec Inc). 
Participants will receive 4 treatment sessions of daily AIH and 4 daily SHAM per week 
throughout two consecutive weeks with an alternative order. A single AIH session 
consists of 15, 90 seconds episodes of breathing at a fraction of inspired oxygen (FIO2) of 
0.09 ± 0.02 with 60 seconds intervals of 0.21 ± 0.02 FIO2 (room air) (Figure 3). While a 
single daily SHAM session consists of 15, 90 seconds episodes of 0.21 ± 0.02 FIO2 with 
60 seconds intervals of 0.21 ± 0.02 FIO2 (room air). We provide the treatments via a 
custom air delivery system; see (Hayes et al., 2014; Trumbower et al., 2017; Trumbower 
et al., 2012) [10, 23, 32–34] for details. In brief, the delivery system directs a known air 
mixture from either a pressure-swing adsorption (PSA) system [HYP-123; Hypoxico Inc., 
USA] or a blower source to the non-rebreather facemask. PSA is a method that 
concentrates nitrogen from room air. For safety, oxygen concentration within the 
breathing circuit is continuously monitored [OM-25RME; Maxtec Inc]. Additionally, we 
continuously monitor blood oxygen saturation (SpO2) and heart rate (HR) at 1-s intervals, 
and blood pressure (BP) every 5th breathing interval using a MASIMO system 
[MASIMO rainbow SET, Irvine, CA]. 
 
Figure 3. Acute Intermittent Hypoxia (AIH) protocol (FIO2 - fraction of inspired oxygen) 
 
e) Devices to be used 
1. Transcutaneous Electrical Spinal Cord Stimulator 
• Transcutaneous Electrical Spinal Cord Neuromodulator (TESCoN) - Clinical 
Study Device, SpineX, Inc. Northridge, CA 
2. Daily Acute Intermittent Hypoxia 
• Pressure-swing adsorption (PSA) system - HYP123, Hypoxico Inc. 
37.5 min
t = 1.5 min
t = 1 min
N = 15 episodes
FIO2 = 0.09 (hypoxia)
FIO2 = 0.21 (normoxia)

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• Oxygen concentration monitor - OM-25RME; Maxtec Inc. 
• Blood oxygen saturation (SpO2), heart rate (HR) and blood pressure (BP) monitor 
- MASIMO rainbow SET, Irvine, CA. 
 
VI. BIOSTATISTICAL ANALYSIS 
Mixed-effects regression will be used to estimate and compare the rates of improvement in 
each performance measure and neurophysiologic parameter throughout the duration of each 
treatment phase.  
Fixed effects will include time and treatment group, with the interaction of these two effects 
forming the primary indicator of a statistically significant treatment effect. Demographic and 
other patient characteristics will be assessed for a potential confounding relationship with 
treatment effect and outcome and will be added as fixed effects to each model as necessary. 
Since mixed-effects regression can accommodate and compensate for missed assessments 
and subject drop-out, no cases will be excluded from the analysis for this reason. A two-sided 
alpha of 0.05 will be used to determine statistical significance, and all p-values will be 
adjusted for the experiment-wise error rate due to multiple correlations per Holm-Bonferroni. 
Although the daily sessions throughout both 3-week study arms require substantial 
commitment, we do not expect more than 20% drop-out rate, based on our team’s prior 
recruitment experiences with the spinal cord injured population (Hayes et al., 2014). 
Given the early stage of research on combinatorial treatment of transcutaneous spinal cord 
stimulation and daily acute intermittent hypoxia for restoring upper limb function, power 
analysis and sample size are not computed. 
 
 

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