Clinical Impact of Respiratory-Swallow Training on Refractory Dysphagia in OP HNC
Phase: NA
Conditions: Head and Neck Cancer, Dysphagia
Sponsor: VA Office of Research and Development

 
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Clinical Impact of Respiratory-Swallow Training on Refractory Dysphagia in OP HNC  
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Agency: VA RR&D (Merit) 
Principal Investigator/Study Chair: Bonnie Martin-Harris, PhD, CCC-SLP, BCS-S, ASHA 
Honors 
Version #15 
 
 

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Abstract 
 
Despite important advancements in medical and surgical cancer treatments that prolong 
survival, Veterans and non-Veterans with head and neck cancer (HNC) are faced with chronic, 
intractable dysphagia resulting in persistent drastic alterations in diet, the need for feeding 
tubes, and increased risk for aspiration pneumonia – a life threatening infection. We must 
devote research and clinical efforts to mitigate these devastating impairments because currently 
our rehabilitative intervention options are severely limited. As such, and in keeping with the 
VHA’s Blueprint for Excellence Transformative Actions, the need for the development of 
effective swallowing interventions that show potential for rapid translation to clinical practice 
is imperative. Respiratory-swallow coordination is an essential element of airway protection 
during swallowing and facilitates many key aspects of swallowing physiology. This key 
coordinative event is significantly disrupted in patients who are dysphagic following medical and 
surgical treatments for HNC. Our preliminary trial tested an innovative swallowing treatment 
approach developed in our clinical laboratory, respiratory-swallow training (RST), that targets 
respiratory-swallow coordination directly and resulted in compelling improvements in physiologic 
swallowing outcomes in Veterans and non-Veterans suffering from dysphagia that persisted 
long after traditional behavioral swallowing intervention(s). The goal of this proposed trial is to 
extend our preliminary study using a rigorous, randomized cross over design and determine the 
impact and durability of RST on clinical outcomes essential for eating, drinking, health, and 
quality-of-life in patients with HNC. As such, positive results from the proposed trial have high 
significance and clinical relevance for patients’ health and well-being.  
 
A total of 51 participants will be recruited with the goal of 40 participants enrolled. Participants 
will be randomly assigned 1:1 to either RST (intervention arm) or no active treatment (control 
arm), which is considered standard of care in this patient population. The participants in the 
control arm will have no active treatment for 4 weeks and will then participate in RST as a cross-
over design. Data obtained will be used to evaluate clinical efficacy and durability The primary 
efficacy endpoint is physiologic function metrics of the oropharyngeal swallow, and the 
secondary endpoint will be respiratory-swallow phase patterning. We will also elaborate on the 
impact of RST by detailing the physiological, airway protective, and morphometric changes that 
occur. We will use reproducible, reliable, and validated metrics that include the Modified Barium 
Swallow Impairment Profile, Penetration-Aspiration Scale, and Computational Analysis of 
Swallowing Mechanics to distinguish the mechanistic effects of RST. Further, adherence to a 
novel HP component using self-guided practice will be introduced and tested for feasibility and 
contribution to the degree and durability of the RST intervention effect.  
 
Our overarching goal is to provide two parallel tracks of knowledge generation: 1) provide 
immediate clinical translation of experimental findings to improve the lives of Veterans and non-
Veterans, and 2) drive model generation on fundamental mechanisms of motor 
coordination. Basic knowledge will drive clinical application and vice-a-versa. As such, this is an 
ideal experimental and clinical context that will fuel knowledge generation in this highly 
significant area of science and clinical practice. 

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Specific Aim 1. Directly train optimal respiratory-swallow phase patterning using RST and test 
the clinical efficacy and durability of the effect measured by change in physiologic metrics of the 
oropharyngeal swallow. Hypothesis: RST will improve swallow physiology, oral intake status 
and liquid/food texture tolerances. Primary Outcome: Physiologic metrics of the oropharyngeal 
swallow as measured by the Modified Barium Swallow Impairment Profile (MBSImP) 
scores,13,14,19; Secondary Outcome: Functional Oral Intake Scale (FOIS).17,18 
Specific Aim 2. Elaborate the intervention impact of RST on swallowing physiology and airway 
protection. Hypothesis: RST will improve tongue base retraction, laryngeal vestibular closure, 
pharyngeal shortening, and pharyngeal clearance. Primary Outcome Measures: MBSImP 
scores,13,14,19 Penetration-Aspiration Scale scores,20 and morphometric canonical variate 
measurements. 
 

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List of Abbreviations 
AB – Abdomen  
 
A-P – Anterior-posterior 
 
ALARA – As low as reasonably achievable 
 
ANCOVA – Analysis of covariance 
 
ANOVA – Analysis of variance 
 
BMH – Bonnie Martin-Harris 
 
CASM – Computational analysis of swallowing mechanics 
 
CBOC – Community based outpatient clinic 
 
CDE – Common Data Elements 
 
CHEMO-XRT – Combined chemotherapy and radiation treatment 
 
COPD – Chronic obstructive pulmonary disease 
 
CPRS – Computerized Patient Record System 
 
CS – Charlie Strange 
 
E-E – Expiratory-expiratory 
 
E-I – Expiratory-inspiratory 
 
FDA – Food and Drug Administration 
 
FEV1 – Forced expiratory volume in 1 second 
 
FOIS – Functional Oral Intake Scale 
 
FVC – Forced vital capacity 
 
GEE – Generalized estimating equations 
 
GOLD – Global Initiative for Obstructive Lung Disease 
 
HIPAA – Health Insurance Portability and Accountability Act 
 
HNC – Head and neck cancer 
 
HP – Home practice 
 
HPV – Human papilloma virus 

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I-E – Inspiratory-expiratory 
 
I-I – Inspiratory-inspiratory 
 
 
IRB – Internal Review Board 
 
ITT – Intention-to-treat 
 
MBSImP – Modified Barium Swallow Impairment Profile 
 
MBSS – Modified barium swallow study 
 
MDADI – M.D. Anderson Dysphagia Inventory 
 
MoCA – Montreal Cognitive Assessment 
 
NU – Northwestern University 
 
OI – Overall Impression 
 
OP – Oropharyngeal  
 
PAS – Penetration-Aspiration Scale 
 
PESO – Pharyngoesophageal segment  
 
PFT – Pulmonary function testing 
 
RC – Rib cage 
 
RIP – Respiratory inductance plethysmography 
 
RST – Respiratory-Swallow Training 
 
SD – Standard deviation 
 
SLP – Speech-Language Pathologist 
 
SPiRE – Small Projects in Rehabilitation Research 
 
SS – Swallow-by-swallow 
 
SURG-XRT – Surgical resection followed by radiation treatment 
 
TDRS – TIMS DICOM Review Software 
 
TV – Tidal volume 
 
US – United States 

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VA – Veteran Affairs 
 
VAMC – Veteran Affairs Medical Center 
 
WP – William Pearson 
 
 

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Contents 
Protocol Title:…………………………………………………………………………………………….. 8 
1.0 
 Study Personnel…………………………………………………………………………………8 
2.0 
Introduction……………………………………………………………………………………….9 
3.0 
Objectives……………………………………………………………………………………….18 
4.0 
Resources and Personnel……………………………………………………………………..19 
5.0 
Study Procedures………………………………………………………………………………20 
5.1 
Study Design…………………………………………………………………………...20 
5.2 
Recruitment Methods………………………………………………………………….33 
5.3 
Informed Consent Procedures……………………………………………………….34 
5.4 
Inclusion/Exclusion Criteria…………………………………………………………..34 
5.5 
Study Evaluations……………………………………………………………………..35 
5.6 
Data Analysis………………………………………………………………………….56 
5.7 
Withdrawal of Subjects……………………………………………………………….39 
6.0 
Reporting……………………………………………………………………………………….39 
7.0 
Privacy and Confidentiality……………………………………………………………………40 
8.0 
Communication Plan…………………………………………………………………………..40 
9.0 
References……………………………………………………………………………………...41 

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Protocol Title: Clinical Impact of Respiratory-Swallow Training on Refractory Dysphagia in OP 
HNC  
1.0       Study Personnel 
Principal Investigator/Study Chair:  
 
Bonnie Martin-Harris, PhD, CCC-SLP, BCS-S, ASHA Fellow  
Research Health Scientist, Edward Hines, Jr. VA Hospital 
Alice Gabrielle Twight Professor and Associate Dean for Faculty Affairs 
Roxelyn and Richard Pepper Department of Communication Sciences and Disorders 
School of Communication 
Northwestern University 
70 Arts Circle Drive 
Evanston, IL 60208 
Phone: 847-467-0407 
E-mail: bonnie.martinharris@northwestern.edu 
 
Co-Principal Investigator/Alternate PI: 
 
Su-Min Kim, MD 
Edward Hines, Jr. VA Hospital 
5000 South 5th Ave. 
Hines, IL 60141 
Phone: 708-202-1914 
E-mail: Su.Kim@va.gov 
 
Co-Investigators: 
 
 
Kendrea L. (Focht) Garand, PhD, CScD, CCC-SLP, BCS-S, CBIS 
Associate Professor 
Department of Communication Science and Disorders 
University of Pittsburgh 
4028 Forbes Tower 
Pittsburgh, PA 15260 
Phone: 412-383-6565 
E-mail: kgarand@pitt.edu 
 
Elizabeth G. Hill, PhD  
Vice Chair for Academic Programs 
Associate Professor of Biostatistics 
Department of Public Health Sciences 
135 Cannon Street, Suite 303 
Medical University of South Carolina 
Charleston SC  29425 
Phone: 843-876-1115 
E-mail: hille@musc.edu 
 
William G. Pearson, Jr., PhD 
Assistant Professor 

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Department of Cellular Biology and Anatomy 
R&E Building, CB1811 
1459 Laney Walker Blvd 
Augusta, GA 30912 
Phone: 706-721-3811 
E-mail: wpearson@augusta.edu 
 
Charlton B. Strange 
Professor 
Division of Pulmonary, Critical Care, and Sleep Medicine 
96 Jonathan Lucas St 
Charleston, SC 29425 
Phone: 843-792-3174 
E-mail: strangec@musc.edu  
2.0 
Introduction 
 
Swallowing Impairment in Head and Neck Cancer (HNC). Veterans are approximately twice as 
likely to incur HNC when compared to the general population and may suffer life-long inability to 
eat, drink, and swallow normally.1-4 It is hypothesized that the increased incidence of cancer in 
veterans may be related to unique risk factors, such as exposure to toxic materials during 
military service, maladaptive behaviors to manage stress (e.g., smoking and alcohol abuse), or 
an increasing number of aging veterans who are more likely to manifest the disease later in 
life.24 Comorbidities of veterans, such as chronic pulmonary disorders, may further complicate 
recovery from cancer treatment.2 
 
In a 26-year follow-up study of approximately 250,000 United States (US) Veterans that 
evaluated the risks of cigarette smoking, a strong dose-response effect between smoking and a 
large number of cancer sites was revealed, including the oropharynx.25 Worldwide, 350,000-
400,000 people are diagnosed with oropharyngeal (OP) HNC each year – nearly 10% in the US 
alone.26 Of particular relevance to the current proposal is that swallowing impairment represents 
the highest functional morbidity in Veterans with OP HNC treated either with surgical 
approaches followed by radiation or with more recent organ-preservation protocols, such as 
combined chemotherapy and radiation.28-30 Although some recent data suggest these new organ 
sparing protocols are potentially less perturbing to swallowing function than surgery followed by 
radiation, toxicity from organ preserving treatments often results in devastating swallowing 
impairments.28-50 Therefore, regardless of the cancer treatment modality, swallowing 
impairments are highly significant and are potentially long-lasting medical and functional 
concerns for HNC patients and the Veterans Health Administration. 
 
Further, unlike many cancer types, the incidence of OP HNC is moving in the wrong direction. 
OP HNC incidence has increased by 1.3% from 2007 to 2011, likely related to increases in 
tumors incited by the human papilloma virus (HPV-positive).4,51 This is particularly troubling 
since oropharyngeal tumors have high propensity to impair swallowing function because the 
tumor site and medical/surgical treatments directed toward cure or local control in the 
oropharyngeal region, include critical structures involved in airway protection and clearance of 
ingested material through the upper aerodigestive tract. Specifically, disruption of the structure 
and function of the base of tongue reduces its force-generating capacity to clear ingested 
material (bolus) from the oropharynx and its airway protection capacity that normally occurs by 

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shielding the laryngeal inlet as it retracts during swallowing.52 Restrictions in the contractility of 
the pharyngeal constrictor muscles decreases their ability to shorten and compress anteriorly 
against the base of tongue and bolus tail, contributing to incomplete pharyngeal clearance with 
large amounts of pharyngeal residue, and limitations to elevation of the larynx and closure of the 
laryngeal vestibule.10,52,53 Further, sensory end organs involved in the complex coordinative 
process of swallowing initiation and safety, including respiratory-swallow coordination, may be 
disrupted consequent to toxicities associated with the common treatments for HNC. Relevant to 
the current proposal, the mechanisms of swallowing impairment described herein are precisely 
those that were shown to improve when applying our respiratory-swallow training (RST) – the 
intervention focus in the current proposal.8 
 
Along with the increase in OP HNC occurrence, the death rates associated with the disease 
have decreased and the five-year survival has increased. Five-year survival rates have been 
reported to be as high as 66% for OP HNC, and HPV-positive HNC survivors have a 54% better 
overall survival compared to those with HPV-negative tumors.3,54,55 These promising increased 
survival rates are in part related to improved surgical and nonsurgical options for cure, and yet 
the degree of toxicity associated with these treatments options is often high and leads to 
immediate and/or delayed profound inability to swallow. These swallow impairments remain 
chronic, are often resistant to traditional swallowing therapy, and have devastating effects on 
health and well-being. Increased survival with poor health and quality-of-life associated to HNC-
related dysphagia speaks to the need for focused attention on the development of innovative 
and rapidly translatable rehabilitation methods to improve the lives of Veteran and non-Veteran 
survivors. Cancer survivorship has been described as traumatic, increasing an already high 
risk of emotional and psychological distress in the Veteran population. This likely 
contributes to the refractory nature of dysphagia following treatment, especially for those with 
continued tobacco and alcohol use and chronic symptoms.56  
 
Refinement and modification of traditional swallowing therapy paradigms are emerging at a slow 
pace but do show promise toward reversing some of the toxic effects associated with radiation 
and chemotherapy.57-61 The respiratory-swallow cross-system approach that is the focus of the 
proposed study extends beyond traditional swallowing intervention that typically targets muscles 
and structures alone, and instead, is directed toward recalibration of respiratory-swallow phase 
patterning. This approach has been shown to have a significant impact on improving the 
physiologic mechanisms that are fundamental for safe and efficient swallowing. Based on our 
previous work and exciting preliminary results, we propose that persistent swallowing 
impairment may not only be related to disordered physiological processes within the 
oropharyngeal system, but also to the coordination of the swallow with respiration.8,62 The 
nature of the swallowing impairment may predispose patients to disruptions in the otherwise 
highly stable phase relationship in respiratory-swallow coupling observed in normal, non-
dysphagic individuals.9 
 
Collectively, these data speak to the high significance of this proposal – a natural progression of 
our previous work – designed to further test a novel swallowing intervention that not only 
improves key elements of swallowing physiology, but also has shown potential for functional 
recovery. Our goal is to expand on the rigor of our preliminary trial and includes a 
randomized controlled clinical trial with cross-over that provide patients with a 
respiratory-swallow recalibration strategy to minimize the coordinative demands 
between breathing and swallowing and optimize airway protection and swallowing 
mechanics. As such, the current application matches well the objectives of the VA Merit 
funding mechanism by providing definitive clinical evidence for a new therapy that shows high 

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promise to benefit a vastly underserved, Veteran and civilian population with chronic dysphagia. 
If clinical efficacy is determined, the intervention program will be easily disseminated to the VA 
clinical community and beyond through open access publications, and face-to-face and online 
web training instruction. Lastly, the current initiative will provide detailed information regarding 
the physiologic characteristics, i.e., “active ingredients” of changes in swallowing impairment 
throughout the intervention using innovative and well-tested, reproducible measurement 
approaches. Our eventual goal is to use this information to combine our RST protocol with other 
evidence-based interventions to target underlying swallowing impairments and optimize clinical 
outcomes in patients with dysphagia in both the late and acute phases of recovery.  
 
Respiratory-Swallow Coordination. A substantial body of literature, including work from our labs, 
using a variety of measurement techniques including respiratory flow, chest wall movements, 
and motion imaging of the upper aerodigestive tract has shown that there is a highly stable, 
coordinative relationship between respiration and oropharyngeal swallowing in healthy 
adults.4,12,15,16,53,62-78 Swallows have been shown to occur most frequently during a pause 
(respiratory inhibition) in the expiratory phase of the breathing cycle between middle and low, 
quiet breathing expiratory lung volumes.4,12,15,16,52,62-80 This coordinative phase relationship 
appears to serve two related functions. First, it is vital to airway protection and secondly, it 
facilitates key, advantageous swallowing mechanical functions, such as laryngeal elevation and 
closure, pharyngeal shortening and pressure generation with consequent bolus clearance, and 
pharyngoesophageal segment (PES) opening.12,15,52,68 Therefore, swallowing within this range of 
expiratory lung volumes may be a clinical marker for both the integrity of neural control 
mechanisms coordinating breathing and swallowing, and of airflow and mechanical events that 
are essential for safe and efficient swallowing.62,63 
 
Precise respiratory-swallow coordination is vital for airway protection. Respiration is inhibited 
before and during pharyngeal swallowing in all species, including human infants and 
adults.11,15,16,52,63-68,80 The exact timing of this pause or obligatory inhibition (sometimes referred 
to as deglutition apnea) differs slightly for liquid swallows, most likely due to differences in 
experimental procedures (e.g., differences in delivery of the bolus into the oral cavity for 
swallowing), measurement devices (e.g., nasal flow vs. chest wall measurements) and analysis 
procedures (e.g., looking at flow events vs. categorizing respiratory phase and volumes). 62-66,68-
71,75 Swallowing at mid-to-low expiratory volumes during the expiratory limb of the quiet 
breathing cycle (optimal phase pattern), provides important mechanical advantages. The 
diaphragm continues to be active during the early expiratory phase and this places traction of 
the trachea and larynx limiting laryngeal elevation and cricopharyngeal opening. At mid-to-low 
expiratory volumes, the diaphragm is relaxed and traction on the trachea is minimal.15,78,80    
Although we are beginning to have a clearer understanding of normal respiratory-swallow 
coordination, our understanding of the potential impact of various medical conditions on this 
synergy is far from complete. Non-optimal respiratory-swallow phase patterning (swallowing at 
high lung volume during the inspiratory phase) has been found in HNC patients with dysphagia 
and in several neurologic conditions both in the absence and presence of significant respiratory 
disease.9 Particularly relevant to the present study are our previous findings that partial surgical 
ablation of the oropharynx and/or various combinations of radiation and chemotherapy 
negatively impacted normal respiratory-swallow phase stability.9 This may be due to: 1) 
impairments within the oropharyngeal swallowing system, such as delayed pharyngeal swallow 
due to sensory loss, incomplete tongue base retraction, and impaired shortening and elevation 
of the larynx and pharynx leading to incomplete laryngeal vestibular closure and opening of the 
PES9 – all of which may impact coordination with breathing; 2) impairments within the 
respiratory system that may impact coordination with swallowing; and/or 3) disruptions in the 

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coordination of breathing and swallowing that exceed these systems and are related to neural 
control impairments. This creates, therefore, the important theoretical context for the necessity 
of examining both “within” and “across” swallow system impairment.80 Our previous study 
supports the notion that this cross-system impairment can be trained or normalized.8 Consistent 
with other areas of motor performance, we suggest that RST recalibrates the “sensory percept 
(perceived lung volume) specific to the domain of perturbation” (airway protection and 
pharyngeal clearance during swallowing performance).82 
 
Our previous research findings have established an ideal backdrop for exploring the presence 
and effect of cross-system respiratory-swallow impairments on “within” swallowing system 
impairment (Figure 1). Further, we are ideally positioned to test interventions that minimize the 
impact of cross-system impairment on swallowing function (disordered physiology and 
aspiration) in our target population –Veterans and non-Veterans with chronic dysphagia treated 
for HNC.  
 
 
PRELIMINARY STUDIES 
 
Specific Aim 1. Understanding normal versus disordered aspects of swallowing, including 
respiratory-swallow coordinative processes, has been the focus of the principal and affiliated 
investigator’s research for over 20 years. Additionally, the principal investigator (BMH) has 
extensive clinical experience and expertise in swallowing impairments consequent to HNC. Our 
team’s expertise, experiences and laboratories provide the ideal scientific and clinical 
background for the proposed clinical study that is a natural progression of our previous 
successful trial.8 We will focus our review on three areas of our previous work looking at 
respiratory-swallow coordination and discuss the impact of this work as it relates to the rationale 
for the methodology proposed in the current study.  
 
Respiratory-Swallow Coordination and Phasing – Healthy, Adults without Dysphagia. Work 
unique to the laboratories of the current investigators has led to the development of a normative 
model of temporally integrated breathing and swallowing patterns using simultaneous 
respiratory flow and kinematic data time-linked to videonasoendoscopic and videofluoroscopic 
imaging of oropharyngeal swallowing.12,52,62,68,78,83 These simultaneous recordings permit timing 
measures of a variety of key swallowing events, such as lingual and hyolaryngeal motion, 
laryngeal vestibular closure, tongue base retraction, pharyngeal contraction, and extent and 
duration of PES opening as they occur at various points along the respiratory signal (Figure 2). 
The broad objective of this line of research has been to establish normative temporal and 
respiratory phase pattern relationships between breathing and liquid swallowing in healthy, adult 
humans across the aging continuum. The significance of this work is deviations from normal 
Figure 1 Theoretical model of cross-system, respiratory-swallow impairment.  

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timing relationships may represent hazardous consequences during otherwise airway protective 
and bolus clearing mechanical swallowing events. 
 
Our early work (and that of others) has provided a clear description of respiratory-swallow 
coordination in normal, healthy individuals.11,15,16,52,63-68,80 We have found that the respiratory 
pause to accommodate swallowing was most frequently and consistently preceded and followed 
by expiratory airflow. This “optimal” phase pattern has been termed expiratory-expiratory (E-E) 
to describe the respiratory events that bracket the swallow (Figure 3), which represented 75% of 
the observed respiratory-swallow phase relationships in one of our previous study of 76 healthy 
adults across the age spectrum.8,52,77 This pattern was followed in frequency of occurrence 
when swallowing was immediately preceded by inspiratory and followed by expiratory (I-E) flow 
(20%). The two least frequently occurring patterns were when swallowing was preceded by 
expiratory activity but immediately followed by inspiratory flow (E-I) (4%), and when swallowing 
interrupted inspiratory flow (I-I) (1%). None of the healthy individuals in the few cases of the 
non-optimal pattern demonstrated swallowing impairment or aspiration. However, swallows 
immediately preceded or followed by inspiratory flow (E-I, I-E, I-I) could potentially expose the 
passing bolus during the swallow or residual bolus after the swallow to negative, inspiratory 
pressures, thus increasing risk of aspiration that could pose problems in non-healthy  
populations with swallowing disorders. 
 
 
 
 
 
 
 
Figure 2 The timeline derived from simultaneous videofluorographic and nasal airflow recordings illustrating the 
phases of respiration surrounding swallowing and the temporal relationships between the respiratory pause and 
functional groupings of swallowing events (Figure adapted).52 

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The preferential segment of the expiratory limb during which swallowing occurs has implications 
for the influence of lung volume on airway protection and swallowing function which will be 
measured and studied directly in the current project. It has been shown that the manipulation of 
lung volume under experimental conditions (i.e., inspiring to total lung capacity, or expiring to 
functional residual capacity) prior to swallow modulates the timing of the swallow.81,84 Exhaling 
to residual volume resulted in slower swallows compared to those swallows performed at 
functional residual capacity or total lung capacity.83 However, given that healthy individuals do 
not typically initiate swallows at these lung volumes11,12,15,16,51,62-67 and because it has been 
shown that single bolus swallows, regardless of bolus type, occur within a restricted range of 
mid-to-low quiet breathing lung volumes,85 the relevance of lung volume on swallow safety and 
efficiency has not been entirely clear. In the proposed study, participants will be trained to 
swallow at mid-to-low, quiet breathing lung volumes to match the airway protective benefits of 
E-E phasing with the mechanical and airway benefits of this restricted range of quiet breathing 
lung volumes. 
 
A final example of the airway protective and mechanical advantages of swallowing during mid-
to-late expiratory phase during quiet breathing, hence mid-to-low lung volume, have been 
shown from another early study that examined the glottic configuration associated with 
respiratory phasing surrounding liquid swallowing.62 The mid-to-late expiratory phase of the 
respiratory cycle was coincident with medialization (partially adducted) of the true vocal fold-
arytenoid complex. This expiratory laryngeal posture promoted an advantageous set point for 
further glottic closure that is required at the height of the swallow to aid in the prevention of 
aspiration (Figure 3).12,68 This medial glottic position was also observed during laryngeal 
descent in the late stage of the swallow and was associated with a brief expiration depicted in 
the flow and kinematic data. It has been stated that the positive pressure associated with post-
swallow expiration may be assistive to bolus clearance.52,63,68,70 
 
Respiratory-Swallow Coordination and Swallowing Impairment – Patients Treated for OP HNC. 
Against this backdrop and based on our extensive research and clinical experience with the 
target patient population, we had reason to believe that respiratory-swallow coordination as 
described above is impaired and should be considered an appropriate target of clinical 
intervention. Patients who had been treated for OP HNC presented with non-optimal and 
potentially hazardous and inefficient respiratory-swallow coordinative patterns that contributed 
to their overall swallowing impairment. Our first preliminary investigation in patients treated for 
HNC investigated whether non-optimal respiratory-swallow phase patterning was present and if 
so, what are the implications for swallowing impairment. The early investigation was the first to 
examine the potential relationship between “within system” swallowing impairments (aspiration 

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and impairment in swallowing physiology) and “cross-system” alterations, such as respiratory-
swallow phasing.9 Twenty medically stable and chronically dysphagic OP HNC patients 12 
months post-cancer treatment and traditional swallowing intervention were compared to 20 
healthy, age-matched controls. Nine of the cancer patients were treated with surgical resection 
followed by radiation treatment (SURG-XRT), and 11 were treated with combined chemotherapy 
and radiation treatment (CHEMO-XRT). 
 
As presented in Table 1, our preliminary data [from an early study that in part motivated our first 
training trial, revealed that only 35% of cancer patients (n = 7) used the optimal pattern (E-E) 
(65% used non-optimal) during single liquid swallows as compared to 75% (n = 15) of the 
normal controls (p = .04). The cancer patients used E-I (n = 3) and I-E (n = 10). None of the 
cancer patients in this sample produced the I-I pattern.  
 
We also explored the relationship between respiratory-swallow phase pattern and Penetration-
Aspiration Scale (PAS) scores. Of the 13 OP HNC patients (65%) presenting with the non-
optimal phase patterns, 30% (n = 4) demonstrated varying degrees of penetration (PAS = 3-5) 
and 30% (n = 4) aspirated (PAS = 6-8). Patients with non-optimal phase patterns had 
statistically significantly greater (worse) PAS scores than patients with optimal phase patterns (p 
= 0.004). There were no differences between cancer treatment groups. Given the occurrence of 
non-optimal phase patterning and the higher PAS scores in these patients, we hypothesize that 
OP HNC patients may be swallowing at less than ideal and potentially hazardous moments in 
the respiratory cycle placing this group, or at least a subgroup of these patients, at increased 
risk of aspiration and physiologic swallowing impairment.9 Further, the patients with non-optimal 
respiratory-swallow phase patterning also demonstrated higher (worse) scores relative to 
swallowing physiology. Patients with inconsistent phase patterns (some optimal, some non-
optimal) across trials had significantly higher (worse) physiologic impairment indicated by higher 
Modified Barium Swallow Impairment Profile (MBSImP™) scores when compared to patients 
who produced consistent phase pattern across trials (T1: F = 3.597, p = 0.039; T2: F = 3.427, p 
= 0.045). The findings from this preliminary data set indicate that not only does the phase 
pattern play a role in the severity of swallowing dysfunction, but the consistency or stability of 
phase pattern may also impact severity of swallowing impairment. These preliminary data lead 
us to consider that respiratory-swallow phasing issues are important factors underlying chronic 
swallowing impairments and the presence of aspiration in patients with chronic dysphagia 
following OP HNC treatments.  
 
Respiratory-Swallow Training Intervention: Preliminary Trial. In contrast to previous intervention 
approaches to swallowing rehabilitation, we designed a trial that targeted the coordinative 
relationships between respiration and swallowing directly using a recalibration approach that 
included visuallydirected, respiratory-swallow feedback. We minimized the coordinative 
requirements and trained consistent and optimal respiratory phase relationships shown to be 
ideal for airway protection and other mechanical aspects of liquid swallowing.  
 
Our primary aims were three-fold: 1) use a novel, well-established hierarchy of motor skill 
acquisition,62-64and respiratory-related feedback protocol to train optimal respiratory-swallow 
coordinative phase patterns;63-65 2) determine the effect(s) of training on respiratory-swallow 
Table 1 Respiratory-swallow patterns during single liquid swallow in OP HNC patients. 
 
Respiratory Phase Pattern 
 
E-E 
Not E-E 
Age-matched controls 
75% 
25% 
Cancer 
35% 
65% 

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phasing and physiologic swallowing measures; and 3) test the stability of the training effect one-
month post-intervention. We hypothesized that more optimal respiratory-swallow coordination 
could be learned, sustained, and have a beneficial impact on swallowing function in chronically 
dysphagic patients treated for HNC. Our current goal is to provide a context through RST that 
goes beyond improvements in swallow physiology alone and extends the clinical impact to 
achievement of increases in food and liquid options with minimized risk of laryngeal penetration 
and/or aspiration.  
 
Using visual feedback similar to our previous study, patients in our previous study were trained 
to initiate swallows during the expiratory phase of quiet breathing between mid-low lung volume 
and to continue to expire after swallowing. Patients were instructed to not use any other 
previous swallowing maneuvers or compensations, nor did they demonstrate implementation of 
such. Patient implementation of the optimal phase patterning increased significantly after the 
RST intervention (p <0.0001) regardless of bolus viscosity (Table 2). That is, all patients learned 
to recalibrate their respiratory-swallow phasing and produced the optimal pattern (E-E). 
 
Specific Aim 2. Physiologic changes to the swallowing mechanism were demonstrated using 
one metric approach (MBSImP) in our preliminary study. The investigators explored the 
physiologic changes expected to occur following RST using innovative analysis methods that 
clarified the nature of these changes.  
 
Computational Analysis of Swallowing Mechanics (CASM) is a multivariate morphometric 
analysis of coordinates mapping the functional anatomy of swallowing using modified barium 
swallow study (MBSS) imaging. As muscle groups underlie changes in coordinates, so then 
shape change characterizes swallowing mechanics (Figure 4).22,86 CASM provides statistical 
analysis and visualization of covariant swallowing mechanics including hyolaryngeal movement, 
tongue base retraction, and pharyngeal contraction and shortening associated with any 
independent variable or outcome variable of interest. 
Table 2 Optimal phase pattern rates by bolus viscosity and volume for all study patients. 
Viscosity 
Volume 
Pre-intervention 
Post-intervention 
p-value 
Thin liquid 
5ml 
53.3 
93.3 
<0.0001 
 
15ml 
18.6 
78.3 
<0.0001 
 
Cup sip 
27.1 
86.7 
<0.0001 
Nectar 
5ml 
51.7 
90.0 
0.0001 
 
15ml 
43.1 
80.0 
0.0009 
 
Cup sip 
41.7 
89.7 
<0.0001 
Honey 
5ml 
50.0 
84.7 
0.0013 
 
15ml 
53.4 
86.4 
0.0018 
 
Cup sip 
48.3 
84.5 
0.001 

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In a preliminary study using 192 pre- and post-RST swallows from 9 participants, CASM 
showed statistically significant differences in pharyngeal swallowing mechanics between pre- 
and post-RST groups (mean patient specific analysis, D = 3.33 ± 0.90, p <0.0001; aggregate 
data analysis, D = 0.80, p <0.0001). Regression analysis indicated that pharyngeal swallowing 
mechanics associated with RST was predictive of mechanics associated with laryngeal 
vestibular closure in the aggregate (R2 = 0.25, p <0.0001), whereas pharyngeal swallowing 
mechanics associated with bolus changes from a large thin liquid bolus to a small thick bolus 
(pudding) was less predictive of mechanics associated with laryngeal vestibular closure in the 
aggregate (R2 = 0.07, p <0.0001). Based on the demonstrated feasibility and outcome when 
using the morphometric analysis in this pilot study, this approach will be a primary method to 
detail physiologic change associated with RST. 
 
The Modified Barium Swallow Impairment Profile© (MBSImP™). The MBSImP, which has been 
developed and tested over the past 10 years, is a valid and reliable standardized approach for 
the training and measurement of swallowing physiology, data collection, data analysis, and 
reporting results from a MBSS.13,14,19 The objectives of the approach, including clinical validation 
of the physiologic metrics, achievement of inter-rater reliability, practicality in execution of the 
protocol and scoring, and linking to clinical action (intervention planning), have been translated 
to clinical practice throughout the US, Canada, Europe, and Asia.13 This metric was used to 
quantify observations of changes in swallowing physiology that occurred following RST in our 
preliminary study. Achievement of optimal respiratory-swallow phase pattern was found to be 
associated with improvements in three MBSImP component scores: laryngeal vestibular closure 
(p = 0.0004), tongue base retraction (p <0.0001), and pharyngeal residue (p = 0.01). Significant 
improvements were also seen in PAS scores (p <0.0001). Relative to pre-intervention values, 
patients participating in one-month follow-up had: increased optimal phase patterning (p 
<0.0001); improved laryngeal vestibular closure (p = 0.01), tongue base retraction (p = 0.003), 
and pharyngeal residue (p = 0.006) MBSImP scores; and improved PAS scores (p <0.0001). 
These results led us to conclude that improvements in respiratory-swallow phase patterns can 
be trained using a systematic training protocol, and the respiratory phase-lung volume related 
visual feedback approach has favorable effects on airway protection and bolus clearance in 
patients with chronic dysphagia following HNC treatment.  
Table 3 Pre- and post-intervention rates (respiratory-swallow phase pattern, PAS, and 
MBSImP), and average MDADI scores. 
Outcome Measure 
Pre-
intervention 
Post-
intervention 
p-value 
Figure 4 Example of landmark coordinates and automated tracker tool designed specifically for coordinate mapping of 
swallowing structures. 

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INNOVATION 
Although the previously demonstrated positive effects of RST on swallowing physiology are 
promising, the clinical efficacy remains unknown until we determine if the training results in 
physiologic changes in of the oropharyngeal swallow leading to changes in what and how the 
patient is able to drink and eat. Thus, these questions and our preliminary results motivate the 
current study that will not only test the clinical effect and durability of the training, but also serve 
to test the feasibility and added benefit of home practice using a refined approach for automated 
cueing and tracking respiratory-swallow phase and volume.  
 
As with our preliminary trial, our prediction is that these innovative intervention methods 
will not only improve swallowing physiology and quality-of-life, but will also result in 
functional improvements in every day eating and drinking in Veterans and non-Veterans 
with chronic, severe swallowing impairment that have been otherwise refractory to 
traditional swallowing interventions. The benefit of this training is that its simple, 
straightforward, and easy to learn methods facilitate patient compliance and 
maintenance of intervention effects include rationale for including or excluding certain 
populations – in particular vulnerable populations. 
 
Inclusion of Women, Minorities and/or Children. No participants will be excluded based on sex 
or race/ethnic origin. Sex, ethnic, and racial information will be collected as part of the 
demographic information. Participants will be selected based on the inclusion criteria identified 
above.  
 
Ethnicity (i.e., Hispanic/Latino, Non-Hispanic/Latino) will be recorded separately from race. All 
applicable racial categories (i.e., American Indian/Alaskan Native, Asian, Native Hawaiian or 
other Pacific Islander, Black/African American, White) will be recorded for each participant by 
study personnel. All ethnic and racial totals will be reported, including specific categories for 
those Veterans and non-Veterans who report mixed racial descent (any combinations recorded 
by study personnel).  
 
Optimal respiratory-swallow phase 
43.0 
86.0 
<0.0001 
PAS ≥3 
78.0 
38.3 
<0.0001 
Lip closure ≥2 
5.7 
9.3 
0.17 
Tongue control during bolus hold 
58.7 
53.8 
0.14 
Bolus transport/lingual motion 
37.3 
50.2 
0.07 
Oral residue ≥2 
77.3 
76.4 
0.80 
Initiation of pharyngeal swallow 
90.4 
90.8 
0.87 
Soft palate elevation 
19.8 
31.0 
0.03 
Laryngeal elevation 
76.6 
70.8 
0.43 
Anterior hyoid excursion 
94.7 
90.5 
0.10 
Epiglottic movement 
71.9 
68.3 
0.31 
Laryngeal vestibular closure 
78.2 
55.5 
0.0004 
Pharyngeal stripping wave 
59.3 
67.6 
0.27 
Pharyngoesophageal segment opening 
80.6 
80.5 
0.99 
Tongue base retraction ≥2 
96.0 
88.6 
<0.0001 
Pharyngeal residue ≥2 
96.1 
88.4 
0.01 
MDADI (mean ± SD) 
60.4 ± 14.8 
65.3 ± 16.7 
0.003 

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No outreach program to recruit minorities is planned because all individuals both within 
and outside of the VA healthcare system, regardless of race or ethnic origin, will be 
invited to participate. Every attempt will be made to recruit all racial and ethnic 
categories. No subjects will be excluded based on race or ethnicity. Though it is difficult 
to predict the sex, racial, and ethnic composition of the study sample, admission data 
reveals that there is a disproportionate composition between males and females for 
outpatient visits of Veterans and non-Veterans with OP HNC, with males have a 
substantially higher rate of outpatient visits. Historic data indicates men are twice as 
likely to have OP HNC compared to women.4 Recent studies from three countries 
(United States, United Kingdom, and Romania) suggest there is a 2:1 ratio of males to 
females diagnosed with HNC and make up 80% Caucasian, 11% Black/African 
American, 4% Hispanic, and 5% other racial/ethnic categories.122-124 It is anticipated that 
the sex, ethnic and racial mix of this study sample will roughly parallel these 
demographic data. 
 
3.0 
Objectives 
 
Our previous trial in patients with severe and resistant dysphagia after cancer treatment and 
traditional swallowing therapy showed that targeting and recalibrating respiratory-swallow phase 
patterning directly through an innovative respiratory-swallow training (RST) method significantly 
improved aspects of swallowing physiology crucial for airway protection and clearance of 
ingested materials through the pharynx.8,16 As with our preliminary trial, our prediction is that 
these innovative intervention methods will not only improve swallowing physiology and quality-
of-life but will also result in significant functional improvements in every day eating and drinking 
in Veterans and non-Veterans with chronic, severe dysphagia that has been otherwise 
refractory to traditional swallowing intervention(s). The benefit of RST training is that it is a 
simple, straightforward method for patients to easily learn. . We are also using commercially 
available and simple to use recording and analysis hardware and software that can easily be 
expanded to mobile technology for more widespread application to the many thousands of 
patients with dysphagia consequent to HNC.  
 
The goal of this current study is to extend our preliminary trial that yielded compelling 
physiologic changes with potential to improve the impact and durability of RST on clinical 
outcomes essential for eating, drinking, health, and quality-of-life.  
 
Specific Aim 1. Directly train optimal respiratory-swallow phase patterning using RST and test 
the clinical efficacy and durability of the effect measured by change in physiologic metrics of the 
oropharyngeal swallow. Hypothesis: RST will improve oral intake status and liquid/food texture 
tolerances. Primary Outcome: Physiologic metrics of the oropharyngeal swallow as measured 
by the Modified Barium Swallow Impairment Profile (MBSImP) scores,13,14,19; Secondary 
Outcome: Functional Oral Intake Scale (FOIS).17,18 
 
 
 
Specific Aim 2. Elaborate the intervention impact of RST on swallowing physiology and airway 
protection. Hypothesis: RST will improve tongue base retraction, laryngeal vestibular closure, 
pharyngeal shortening, and pharyngeal clearance. Primary Outcome Measures: MBSImP 
scores,13,14,19 Penetration-Aspiration Scale scores,20 and morphometric canonical variate 
measurements. 

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4.0 Resources and Personnel 
 
Approved study personnel, including PI, clinical and research SLPs, and the Project Coordinator 
will be responsible for recruiting subjects, and consenting subjects; thus, they will have access 
to proteced health information. Additionally, the PI and clinicial/research SLP will also be 
responsible for administering study procedures.  
 
The PI, Dr. Martin-Harris, will be responsible for and will supervise all aspects and 
coordination of all phases of the research project including the recruitment of study 
participants, completion of patient examinations, execution of the modified barium swallow 
studies (MBSSs), examination scoring, data entry, and data quality control. Furthermore, Dr. 
Martin-Harris will have primary responsibility for training study participants on the optimal 
respiratory-swallow pattern, conducting respiratory-swallow data analyses, preparation of 
manuscripts and scientific presentations, and dissemination of activities. 
 
Dr. Kim, Co-PI, will assist in subject recruitment and monitoring respiratory function and will also 
assist interpretation of all study outcomes.  
 
Research Assistant(s), will assist in participant accrual, data entry, database management, 
VA and IRB compliance and preliminary analysis. They will convert all MBSSs from TIMS 
DICOM System to .avi format for data analysis by the scoring SLPs and archive/backup 
the TIMS DICOM System study records week.  They will coordinate and disseminate the 
examinations for scoring to the scoring SLPs. They will schedule pre- and post- intervention 
MBSS, pulmonary function screenings, and treatment intervention. They will maintain and update 
all subject files. 
 
SLP Research Assistant, will assist the Research Assistants, including participant recruitment and 
scheduling, and IRB compliance, as well as SLP training and participant interventions. They will 
also assist in data analysis and interpretation. 
 
Dr. McFarland, Consultant, will assume oversight for equipment calibration and respiratory 
data analyses. 
 
VA SLPs, Anne Mary Lunkes and Rebecca Rogers, will assist in subject recruitment, 
completion of pre- and post-intervention MBSSs, and provide treatment intervention.  
 
Scoring SLPs/Research Assistants, TBD, will be trained at the PI’s lab at Northwestern 
University. Scoring SLPs will be responsible for completing all baseline and post-intervention 
scoring of swallowing physiology and respiratory patterning. 
 
There is a MOU in place between Hines VA Hospital and Northwestern University for the PI, Dr. 
Martin-Harris for her 4/8ths effort.  
 
5.0 
Study Procedures 
 
5.1       Study Design 
 
 
Specific Aim 1  – Respiratory-Swallow Training (RST) In-Clinic.  

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Patient Sample. A total of 51 participants will be enrolled with the goal of 40 recruited if they 
meet inclusion criteria. Forty participants will be randomly assigned (1:1) to either RST 
(intervention arm) or no active treatment (control arm), which is considered standard of care in 
this patient population. Participants assigned to the control arm will cross-over after 4 weeks of 
no active treatment to undergo RST. All patients will participate in a pre-RST MBSS. The 
purpose of this pre-RST MBSS is to identify their baseline pre-RST respiratory-swallow phase 
patterning by specifying the respiratory phase and volume at time of swallowing initiation, 
assess swallowing physiology (MBSImP) and assess clinical swallowing status (FOIS). 
Participants will be included in the study if they are able to swallow at least one liquid 
consistency without visible tracheal residue (PAS ≤6) and without the use of a compensatory 
strategy or swallow maneuver. Participants will be excluded if they have known allergy or 
dietary restriction for contrast materials or liquids used during the MBSS or training, currently 
drinking greater than two drinks per day, severe COPD, are unable to swallow one liquid 
consistency without the use of a compensatory strategy or swallow maneuver without 
aspiration, or history of aspiration pneumonia within the past 12 months.  
 
Clinician Examiners, Raters and Trainers. Expert speech-language pathologists (SLPs) will 
participate in this study to provide RST training, conduct the MBSSs, and perform blinded 
MBSImP and PAS scoring (i.e., without benefit of patient identifiers, randomization, clinical 
information, and performance during RST). The SLPs will not crossover study roles.  
 
Spirometry. All Veteran and non-Veteran participants will undergo PFTs using spirometry 
performed by American Thoracic Society standards to stage COPD.88 Participants will be 
characterized into Global Initiative for Obstructive Lung Disease (GOLD) spirometric groups on 
the basis of % predicted FEV1.90 Any patient with severe stage COPD will be excluded from the 
study to protect against risk since experience in our clinic and previous study showed these 
patients could not consistently perform the proposed training tasks. 
 
Modified Barium Swallowing Study (MBSS). MBSSs will be conducted in a routine 
fluoroscopy suite with a radiologist and examining SLP present. Fluoroscopy will be captured 
using a high-resolution imaging platform (TIMS 2000 SP DICOM System, Foresight Imaging, 
Chelmsford, MA). Participants will be seated upright and positioned in the lateral and anterior-
posterior viewing planes. The visualization field will include the lips anteriorly, nasal cavity 
superiorly, cervical spinal column posteriorly, and the pharyngoesophageal segment (PES) 
inferiorly.78,79,91-93 The MBSImP, a standardized, reliable, reproducible, and valid approach for 
the execution, assessment and interpretation of the MBSS, will be used to provide measures of 
swallowing physiology pre- and post-intervention. The MBSImP protocol includes 12 swallowing 
tasks via presentations of varying bolus consistencies, bolus volumes, and presentation 
methods. However, consistent with the MBSImP protocol, if a patient is unable to tolerate a 
swallow task because of safety (aspiration) concerns, that task is not included, and the 
component scores associated with the missing task are given the worst (highest) score in 
keeping with the statistical methods inherent in the tool. Standardized ready-to-use barium 
contrast (Varibar® E-Z-EM, 40% w/v, Bracco Inc.) will be presented. These swallowing tasks 
include: thin barium (two trials of 5ml via teaspoon, one cup sip, and sequential swallows from 
cup), nectar barium (one trial of 5ml via teaspoon, one cup sip, and sequential swallows from 
cup), thin-honey barium (one trial of 5ml via teaspoon), pudding barium (one trial of 5ml via 
teaspoon), a solid (one-half portion of a Lorna Doone shortbread cookie coated with 3ml 
pudding barium), and two additional tasks presented in the anterior-posterior viewing plane (one 
trial each of 5ml nectar and pudding barium). Participants will be asked to maintain a neutral 

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posture during the drinking tasks, since alteration of posture from the upright position may affect 
respiratory-swallow phasing.93  
 
Respiratory-Swallow Phase Pattern Measures.  
 
Respiratory Recording and Lung Volume Calibration. Respiratory movements of the rib cage 
(RC) and abdomen (AB) will be recorded using respiratory inductance plethysmography (RIP) 
(Inductotrace System; Ambulatory Monitoring, Inc., Ardsley, New York) coupled to a data 
acquisition system (BIPOAC Systems, Inc., Santa Barbara, CA, Model MP150).95 The RC band 
will be placed around the rib cage at midsternal level, and the AB band will be placed around 
the abdomen below the lowest rib. The method developed by Banzett et al.96 will be used to 
calibrate the summed RC and AB signals provided by the Inductotrace system to infer 
respiratory lung volume changes.96 A standard ratio (RC to AB) of 2:1 will be used to weight the 
signals (originally recorded at equal gain) prior to being summed. The summed signal (in 
voltage) will then be calibrated using a known volume excursion to provide an estimate of lung 
volume. Each participant will be instructed to breathe in and out 3 times filling and emptying a 
Spirobag with a fixed 800 ml of air in the bag.  
 
The optimal respiratory-swallow phase pattern targeted in RST is swallow initiation during the 
expiratory limb of the breathing cycle between mid-to-low quiet breathing lung volumes with 
resumption of expiration upon swallow completion. Respiratory data will be time synchronized 
with videofluoroscopic imaging data. Cycle detection and threshold algorithms programmed 
within AcqKnowledge software will be used to measure respiratory-swallow phase patterning for 
each subject during pre-intervention, post-intervention and follow-up.95 
 
Functional Swallowing Measures.  
 
Functional Oral Intake Scale (FOIS). The FOIS, a 7-point ordinal scale shown to associate with 
dysphagia severity, will be completed by the examining SLP to rate functional oral intake.17 
Level 1 implicates nothing by mouth, while a Level 7 indicates total oral diet without restrictions. 
Initial psychometric testing revealed high inter-rater reliability, validity, and sensitivity to change 
in oral intake status.17 A clinical meaningful improvement on the FOIS has been defined as an 
improvement of ≥2 levels.18   
 
Penetration-Aspiration Scale (PAS). The PAS is a widely used, standardized, valid, and reliable 
rating scale used to capture the presence and degree of penetration and aspiration during the 
MBSS exam.20,97 The PAS is a multidimensional, 8-point ordinal scale. A score of 1 represents 
absence of aspiration or penetration, and a score of 8 represents the most severe degree of 
aspiration with no attempt made by the patient to react to or expectorate the aspirated material. 
A PAS score will be recorded by the scoring SLP for each swallowing task presented in the 
lateral viewing plane. 
 
M.D. Anderson Dysphagia Inventory (MDADI). The MDADI is a self-administered questionnaire 
designed to evaluate the impact of dysphagia on the quality-of-life of patients with HNC.98 The 
tool consists of 20 items across 4 subscales (global, emotional, functional, and physical). Each 
item is scored on a 5-point Likert scale. Two summary scores (global and composite) can be 
obtained. The composite score summarizes overall performing on 19 items as a weighted 
average of the subscales. Summary and subscale scores are normalized to range from 20 
(extremely low-functioning) to 100 (high-functioning). A 10-point difference has been identified 
as a clinically meaningful difference in swallowing function.99 

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Performance Status Scale for Head & Neck Cancer Patients (PSS-HN). The PSS-HN is a scale 
administered by health professionals ( e.g. physicians, speech-language pathologists, nurses, 
nutritionists) or other data managers (e.g. clerks, data managers) designed to evaluate the 
dysfunction and quality of life in patients with HNC.131 Three subscales, (Normalcy of diet, Public 
Eating and Speech Intelligibility) each with 100 point rating scales and arranged in a 
hierarchically order from total incapacitation to normal functioning, are used to evaluate relevant 
parameters of functional status specifically for the HNC patient. 
 
Respiratory-Swallow Training (RST). We will encourage optimal respiratory-swallow phase 
pattern in Veteran and non-Veteran participants using a protocol well supported by principles of 
motor learning and neural plasticity.100-102 Participants will be given the option to complete RST 
at the Hines VA or Northwestern University. 
 
Respiratory Tracking and Swallow Initiation Feedback. During the feedback portions of the 
training and using each participant’s lung volume signals as described above, we will track and 
signal the appropriate moment of swallowing initiation using cycle detection and threshold 
algorithms programmed within AcqKnowledge software – an interactive software that allows for 
complex data acquisition, including simulation of model respiratory waveforms, respiratory cycle 
and threshold detection.95 Respiration has a high degree of periodicity with relatively sharp-
sloped waves and narrow peaks. During initial recordings with each participant, we will record at 
least two minutes of stable quiet breathing in the absence of experimental manipulation or other 
instrumentation. A peak detection algorithm steps through the respiratory waveforms (the 
cyclical changes in lung volume provided by the summed and calibrated Inductotrace signals) to 
find positive and negative peaks in a cycle and, from this, determines an average lung volume 
excursion from peak inspiration to peak expiration of each subject’s quiet breathing lung volume 
change. From this, a threshold will be automatically determined as 50% of the expiratory lung 
volume change. During the training sessions in real time, the threshold detection algorithm will 
detect positive peaks in the respiratory volume change marking the end of inspiration and the 
beginning of expiration and will emit a visual and auditory feedback signal when 50% of the 
negative going lung volume change (expiration) has been reached. In this way, participants will 
be cued to produce their swallows beginning in the optimal range of lung volumes. These 
customizable programs to each participant’s quiet breathing waveforms will track performance 
during RST. In this way, we can evaluate the achievement of criteria and performance for each 
of our training modules. In the RST modules, a visual and audio signal will be provided when 
the participant’s tracked lung volume is within the optimal range and this feedback will 
eventually be removed as they move to the mastery module of training. A contact microphone 
(BIPOAC Systems, Inc., Santa Barbara, CA, Model TSD108) will be connected to the MP150 
(in-clinic) units. The microphone signal will be used as a reliable indicator of the presence of 
swallows. The percentage of trials that each participant swallows within the target mid-to-low 
quiet breathing expiratory lung volume will be used to advance participants to subsequent 
modules of training. 
 
 
AcqKnowledge software used during in-clinic RST is accessible via the desktop upon logging in 
to the computer. Templates are pre-programmed and once opened, the software only requires 
the participant to select the appropriate template and click “start” for data collection to begin. In 
addition to remote assistance by the treating speech-language pathologist (SLP), written and 
video, step-by-step tutorials will be provided to the participant for at home set-up, calibration, 
and training. Calibration is defined as 2 minutes of at-rest breathing and will be part of the step-

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by-step guides provided to the participant. The participant must demonstrate independence in 
set-up and use of equipment and software within clinic under the supervision of the treating SLP 
prior to use at home. All signals acquired during RST sessions will be recorded on the laptop 
and analyzed offline. 
 
Based 
on a 
well-
established hierarchy of motor skill acquisition and consistent with our preliminary study,100-102 
the RST training protocol will be divided into 3 learning modules for a total of 21 goals: 
identification, acquisition (performance), and mastery (Figure 5). For each goal within the 
identification and acquisition modules, a minimum of 8 of 10 trials will be required for the goal to 
be met. A minimum of 9 of 10 trials will be required during the mastery module. If the participant 
does not meet the goal, reinstruction will be provided. Liquids will be standardized for all 
patients, but participants will be trained only on liquid consistencies with PAS scores ≤6 
identified on the pre-RST MBSS.  
 
During the Identification Module, samples from recordings of each participant’s quite breathing 
cycle will be printed onto 8½” x 11” cards and used to train participants to accurately identify 
inspiratory and expiratory phases of the respiratory cycle. Their up-going trace will represent 
inspiration and down-going trace will represent expiration. Participants will be instructed to 
identify the mid-to-late portion of the expiratory phase of the respiratory cycle (latter ½ of the 
expiratory phase) (Figure 5).  
 
 
 
 
 
 
 
 
 
 
 

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  Figure 6. Cue cards for training participants on lung volume and phase 
 
Once participants can identify the phases of respiration during rest breathing and the target 
respiratory-swallow phase pattern (swallow initiation during expiration at mid-to-low lung volume 
with resumption of respiration in the expiratory limb) on the printed tracings, they will learn to 
identify these targets during actual breathing using the Inductotrace/MP150 system (described 
above). Participants will progress from demonstrating the optimal phase pattern during 
respiratory-swallow recording with visually assisted feedback to independently producing the 
targeted respiratory-swallow phase pattern. The training SLP will monitor the participant’s 
respiratory-swallow phase patterns on the visual monitor, but the participant will not be 
permitted to view their performance in these later stages of training. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Each RST session lasts approximately one hour, with two sessions completed weekly. Based 
on previous clinical trial that demonstrated an average of six RST sessions to reach mastery.8 
Figure 6 Depiction of goals for each training module and intervention timeline. 

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Thus, it is expected for participants to complete all goals and reach mastery within 4 weeks of 
RST (see Figure 6). 
During the in-clinic RST training sessions, the computer videorecorder will be taking front-facing 
video of each patient’s training sessions. These recordings will be compared to the physiologic 
signals received via the BIOPAC to better understand/learn/become informed about how the 
patients learn during intervention training sessions. These recordings will also be used for 
teaching purposes for study staff.  
At the completion of RST, the participants will be asked to complete the NASA Workload Index, 
a 7-point scale which estimates the participant’s perceived effort in completing the training. 
 
Data Management, Analysis, and Reporting System Overview. Study related data are 
stored on VA approved computers and the VA research shared drive (S:), including de-identified 
study-related data (videofluoroscopic images, respiratory traces). Identifiable data (VASA), 
including demographic data, questionnaire responses, and treatment results are stored on the 
VA REDCap behind the VA firewall. De-identified videofluoroscopic images and respiratory 
tracings will be transported via VA issued encrypted external hard drives for analysis by 
specially trained analytic experts to the PI’s lab at Northwestern University, and then stored on 
and analyzed from a password protected, dedicated server. This server is managed by 
Northwestern Information Technology and accessible to only approved study personnel. We will 
update the data transfer and storage operations as we are provided additional guidance and 
requirements from the ORO, Office of Research Oversight. 
 
Power and Sample Size Justification. A total of 40 subjects will be randomized 1:1 using 
stratified block randomization to either Respiratory-Swallow Training (RST, intervention arm) or 
no control arm, where the participants serve as their own control and then cross over into the 
intervention group. Strata will be defined by treatment type. Data obtained will be used to 
evaluate clinical efficacy and durability. The primary outcome measure will be MBSImP 
physiologic function metrics of the oropharyngeal swallow. Our previous preliminary trial that 
tested the safety and efficacy of the behavioral swallowing intervention in a small sample of 
Veteran and non-Veteran patient with head and neck cancer showed a positive change in the 
physiologic outcomes. Assuming a similar treatment effect in the current trial, 20 patients in 
each arm provides 95% power to detect a change in MBSImP physiologic function in at least 
one of three MBSImP components (laryngeal vestibular closure, tongue base retraction, and 
pharyngeal residue) based on a Cochran-Mantel-Haenszel test with two-sided α = 0.025. 
Although dropouts have been rare in our prior studies, we nonetheless inflated our sample size 
by 10% to adjust for unanticipated attrition, and plan to recruit 20 participants per arm for a total 
sample size of 40 subjects to guarantee at least 80% power. Thus, our final sample size will be 
a total of 40 participants. 
 
Analysis Populations. Participants in the intervention arm who withdraw consent prior to 
completing their first training session will be replaced. Those who have completed at least one 
RST session will contribute to the intent-to-treat (ITT) population. Participants in the control arm 
who withdraw consent prior to visit 1 will be replaced. All others in the control arm will contribute 
to the ITT population. The per-protocol population will be composed of participants who 
complete both visit 0 and visit 1 evaluations (both arms), and who complete all required training 
sessions (intervention arm). Efficacy will be evaluated based on the ITT population. Participants 
in the ITT population who withdraw prior to endpoint evaluation at 6-weeks will be treated as 
failures (no improvement) in the ITT analysis. The safety population is defined as all participants 

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who partake in any component of the proposed study and will be based on the intervention 
actually received. 
 
 
 
 
Specific Aim 2 Design and Methods – Intervention Impact of RST on Swallowing 
Physiology. We will elaborate the treatment impact of RST by detailing the physiological, 
airway protective and morphometric changes that occur from the intervention. We will use 
MBSImP, PAS (described for Aim 1), and CASM. 
 
MBSImP Scores. The MBSImP scores will provide a primary outcome measure of swallowing 
impairment. The MBSImP is a validated and reliable scoring system for the quantification of 
swallowing impairment from MBSS recordings.13,14,19 This tool has an ordinal scoring schema 
that permits quantification of oral, pharyngeal, and esophageal components of swallowing 
physiology. The operational definitions for the component scores represent a unique and 
unambiguous observation of structural movement and bolus flow. Seventeen physiologic 
components will be scored on a previously validated, rank order scale from least to most 
impaired. The scale for components ranges from 0-2 to 0-4 for each physiologic component.14 
Years of field testing shows scores of 0 or 1 for the physiologic components of lip closure, oral 
residue, pharyngeal residue, and tongue base retraction are considered to be within normal 
limits.112 For all other components, scores greater than 0 represent some level of impairment. 
Two methods will be used for MBSImP scoring: swallow-by-swallow (SS) and overall impression 
(OI). SS scoring assigns an MBSImP score for all applicable physiologic components for each 
of the 12 swallowing tasks given during the protocol. SS cores will be recorded for each 
participant. The highest (worst) score will be given during SS scoring when the participant’s 
condition or performance on a previous swallowing task results in the withholding of a 
subsequent swallowing task for safety concerns.9,52 Additionally, missing data in SS 
interpretation will result if a participant refuses a swallowing task.52 As such, we will only include 
scores for swallowing tasks that are actually presented.  
 
Computational Analysis of Swallowing Mechanics (CASM). Annotators who meet reliability 
criterion109 will use a MATLAB (version R2015a, 8.5.0.197613, 64-bit) semi-automated tracker 
tool designed specifically for coordinate mapping of swallowing structures.113,114 Coordinates are 
annotated in all frames during oral transit and pharyngeal swallowing. The tracker tool produces 
an .mp4 video file of annotated landmarks for review and a .csv file of coordinates with a unique 
identifier assigned to each row of coordinates. Once video files are reviewed by an expert head 
and neck anatomist (Co-Investigator, WP), coordinates for all swallows are concatenated and a 
second file of variables that match unique identifiers is compiled to include group (pre-
intervention vs. post-intervention), swallowing domain (oral vs. pharyngeal), bolus volume (large 
[cup] vs. small [5ml]), bolus viscosity (thin vs. thick), sex (male vs. female), penetration-
aspiration status (within functional limits [PAS = 1,2] vs. penetration-aspiration PAS = 3-8]), and 
MBSImP component scores. These files are uploaded into MorphoJ integrated software for 
analysis.115 
 
Statistical Considerations. The primary endpoints for Specific Aim 2 are MBSImP scores, PAS 
scores, and morphometric canonical variate scores for participants enrolled in the clinical trial 
(Specific Aim 1). MBSImP component scores and PAS will be dichotomized as impaired versus 
not-impaired as previously described.8 [Analyses of impairment rates, MBSImP composite (oral 
and pharyngeal total) scores, and time course data will be conducted using ANACOVA, GEEs 

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and Rao-Scott Chi-square tests as described in Specific Aim 1. To evaluate rater reliability for 
MBSImP and PAS measures, 20% of MBSSs will be re-scored by each rater. Intra-class 
correlations coefficients will be calculated to measure inter- and intra-rater reliability. 
 
CASM will be applied to pre- and post-RST MBSSs to determine and visualize improvements in 
covariant swallowing mechanics resulting from RST and determine which of these treatments is 
predictive of swallowing improvement as measured by MBSImP and PAS scores. Following a 
Procrustes fit of coordinates to control for differences in size and image rotation, a canonical 
variate analysis with post hoc discriminant function analyses21,22 will be performed to determine 
statistical differences in pre- and post-RST swallowing mechanics by phase of swallowing for 
each subject and the aggregate. Eigenvectors will be used to visualize differences in covariant 
swallowing associated with treatment effect. Morphometric regression analysis will be used to 
evaluate respiratory-swallow training as a predictor of improved swallowing outcomes as 
measured by MBSImP and PAS scores. 
 
 
Potential Risks 
 
Radiation Exposure. The MBSS is a videofluoroscopic examination that includes minimal 
exposure to radiation. Data collected during the study will be used solely for research. The 
amount of radiation is minimized because fluoroscopy requires no film and radiation is kept to a 
minimum by tight coning of the x-ray beam to include only the superior structures of the upper 
aerodigestive tract. A lead apron will be used to protect reproductive organs from radiation 
scatter in all participants. Involvement of a trained radiologist and use of dedicated fluoroscopy 
equipment are likely to minimize radiation exposure. The radiation of a swallow study is 
approximately 40 mrem of radiation for approximately 5 minutes of exposure, which is 0.8% of 
the annual maximum amount permitted by the Food and Drug Administration (FDA) for 
radioactive drug research.125 A fluoroscopy timer will alert the examiners if and when the 5-
minute time limit is met, and the study will be subsequently stopped at this point. The average 
duration for each participant during the MBSS, including set-up and positioning, is 
approximately 30 minutes. Published data from Dr. Martin-Harris’ lab demonstrated the 
standardized MBSImP protocol increases efficiency and speed for MBSS completion.125 It takes 
an average of 2.89 minutes of fluoroscopy exposure (95% confidence interval (CI) of 2.80 to 
2.97 minutes), which is well under the reported 3-5 minutes encountered in an upper 
gastrointestinal series.125 Interpolating from the relationship Moro et al. (2006) published, the 
mean of 170 seconds relates to an effective dose of approximately 0.44 mSv, while the mean in 
the literature of 240 seconds relates to an effective dose of approximately 0.67 mSv.125,126 On 
average, the use of a standardized protocol decreased effective dose by 0.23 mSv.125 
 
Aspiration. Aspiration occurs when ingested materials enter the airway below the level of the 
vocal folds. Because these participants have known dysphagia, there is a risk of aspiration 
occurring during the MBSS.127 If the barium is aspirated, it is not expected to cause severe lung 
injury due to its relatively non-irritant matter. However, acute inflammation, and even death, has 
been reported, despite whether it was attributed to either high or low-density preparations of 
barium. Participation in this investigation will not increase the risk of aspiration. If a swallowing 
impairment is observed during the examination, a referral to the participant’s attending physician 
will be made.   
 
The risk of aspiration will be clearly stated on the informed consent and during the consenting 
process. Despite this potential, our collaborative speech pathology and medical teams plan to 
institute measures that optimize the participant’s safety. These include: 1) inclusion of 

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participants with no history of aspiration pneumonia during the past 12 months; and 2) liquid 
consistencies that result in PAS scores of ≥7 during the baseline MBSS will not be given during 
intervention portion of the study.  
 
Participants are not required to have participated in previous traditional swallowing therapy. If 
they have participated in traditional swallow therapy, they must be 6 months post last treatment 
session and still have swallow disorders.127 Consistent with our past trial that showed no 
adverse events, participants will be encouraged to swallow naturally without employing any 
previously instructed maneuvers or strategies. If the participant cannot swallow without a 
maneuver or strategy and meet inclusion criteria, he/she will be excluded from the study.    
  
Respiratory Monitoring and Training. Respiratory monitoring and phase training will be 
accomplished using Inductotrace (Ambulatory Monitoring, Inc.) data.128 There are no known 
risks associated with the placement of loose elastic bands (Inductobands, Ambulatory 
Monitoring, Inc.)128 around participants’ chests and abdomens while data are collected on a data 
acquisition system (BIPOAC Systems, Inc., Santa Barbara, CA, Model MP150). There is the 
unlikely potential, though inconsistent with our preliminary observations, that manipulation of 
respiratory phase surrounding the swallow may make the participant’s swallowing worse, either 
during the intervention or the post-intervention MBSS. If there is any clinical indication that the 
participant is experiencing coughing or discomfort with the task, the task will be discontinued, 
and the participant will be excluded from further treatment. No alternative procedures or 
treatments are available. 
 
Patient Perceived Effort Associated with Training. All patients will be asked to complete the 
NASA Task Load Index survey. This survey contains 6 task load domains and asks the 
participant to indicate the mental, physical and temporal demand, performance success, effort 
and frustrations levels associated with the training using a visual analog rating scale.  
 
Adequacy of Protection from Risk 
 
Recruitment and Informed Consent 
 
Designated approved study personnel will obtain informed consent, including PI, Study 
Coordinator, Research SLP (speech-language pathology), and clinical SLPs. All potential 
participants (volunteers) will be explained the study procedures, potential risks and benefits by 
the consenting study personnel. All eligible participants, regardless of race, ethnic origin, or sex, 
will be asked to participate as long as authorization and informed consent can be obtained. Any 
participant may withdraw from the study at any time without penalty or prejudice for treatment.   
 
Protection against Risk 
 
Recruitment and Informed Consent. Potential participant volunteers will be identified by the 
following methods of participant recruitment, all approved by the VA Institutional Review Board 
(IRB): 1) follow-up medical visits, such as the otolaryngology-head and neck clinics at the Hines 
VAMC, Loyola University Medical Center; 2) announcement of the study in the VA patient 
bulletins and monitors; 3) community based outpatient clinics (CBOCs); 4) review of patient 
medical charts (CPRS) at HVA to find patients that match the diagnosis of oropharyngeal 
cancer and dysphagia diagnoses and mailing informational letters to these potential patients; 
and 5) posting of recruitment flyers at Jesse Brown VA, Loyola University Medical Center, 
Northwestern Memorial Hospital, and Northwestern Medicine Healthcare Partners. 

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All potential eligible participant will sign a study consent form approved by the VA’s IRB. The 
potential risks as described above will be clearly stated on the informed consent and during the 
consenting process (see above in Potential Risks). Veterans and non-Veterans who express 
interest in participating will be explained the study protocol, presented with a consent form to 
sign and date, and be given an opportunity to have any questions regarding the procedure or 
the research study addressed and answered to their satisfaction. Additionally, non-Veteran 
participants will sign a Notice of Privacy Practices (NoPP) form which will be sent to the 
appropriate privacy officer. 
 
The study investigators will not treat the socially/economically disadvantaged participant 
volunteers differently from other participants in the study. This includes all study personnel 
ensuring there are no coercive behaviors undertaken during the study period. For this study, 
study personnel will not be obtaining data regarding the veterans’ social and/or economic 
status. Therefore, study-related complications are not anticipated, and all participants will be 
treated identically and equally. 
 
Radiation. This research study involves exposure to a small amount of radiation. As part of 
everyday living, everyone is exposed to naturally occurring background radiation and receives a 
dose of about 3.0 mSv each year.125 The effective does from this study is about 0.44 mSv, 
which is estimated from a 3-minute exposure during a videofluoroscopic study.125 This is equal 
to the average radiation all Americans receive in two months from natural background radiation, 
such as naturally occurring radioactivity in the soil.126 Any risk from this small amount of 
radiation is too small to be measured directly and is small when compared to other every day 
risks. 
 
Care should be taken to reduce the influence of all possible factors not related to improved 
diagnostic yield according to the as low as reasonably achievable (ALARA) principle.125 This 
means that the radiation exposures resulting from the practice must be reduced to the lowest 
level possible considering the cost of such a reduction in dose. The amount of radiation each 
participant will be exposed to is relatively small since the X-ray machine is only turned on while 
he/she swallows. Although such doses of radiation may be potentially harmful, the risks are so 
small that they are difficult to measure. The potential long-term risk from the radiation doses is 
uncertain, but the risk to each participant is estimated to be slight. The barium that allows the 
liquid and food to show up on X-ray is not harmful and will stay in the body only for a relatively 
short period of time.  
 
Examining SLPs will wear lead-lined, radiation shielding aprons around their chest and torso. 
SLPs will also wear lead-lined thyroid shields. A radiation dosimeter will also be worn to 
measure exposure levels that are monitored by the facility. A lead apron skirt will be provided to 
each participant to protect his/her reproductive organs from radiation scatter.  
  
Female participants will not be allowed to participate if they are pregnant or if there is any 
possibility of being pregnant.  
 
Based on the inclusion/exclusion criteria described above, potential Veteran and non-Veteran 
volunteers will be asked to participate in the study only after informed consent is obtained. 
 
 

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Termination. If a participant does not meet a single target goal following 3 sessions, the RST 
intervention will cease, and data will contribute to the intention-to-treat analysis as outlined in 
the research plan. 
 
Non-participation. Each participant has the alternative to not participate in the study. If the 
participant chooses not to participate, it will not affect their current and/or future medical care or 
any benefits to which they are entitled.  
 
 
Human Subjects Involvement and Characteristics 
 
A total of 51 Veteran and non-Veteran volunteers will be recruited.  
 
Inclusion of Women, Minorities and/or Children. No participants will be excluded based on sex 
or race/ethnic origin. Sex, ethnic, and racial information will be collected as part of the 
demographic information. Participants will be selected based on the inclusion criteria identified 
above.  
 
Ethnicity (i.e., Hispanic/Latino, Non-Hispanic/Latino) will be recorded separately from race. All 
applicable racial categories (i.e., American Indian/Alaskan Native, Asian, Native Hawaiian or 
other Pacific Islander, Black/African American, White) will be recorded for each participant by 
study personnel. All ethnic and racial totals will be reported, including specific categories for 
those participants who report mixed racial descent (any combinations recorded by study 
personnel). No outreach program to recruit minorities is planned because all eligible individuals, 
regardless of race or ethnic origin, will be invited to participate. Historic data indicates men are 
twice as likely to have OP HNC compared to women.4 Recent studies from three countries 
(United States, United Kingdom, and Romania) suggest there is a 2:1 ratio of males to females 
diagnosed with HNC and make up 80% Caucasian, 11% Black/African American, 4% Hispanic, 
and 5% other racial/ethnic categories.122-124 It is anticipated that the sex, ethnic and racial mix of 
this study sample will roughly parallel these demographic data.  
 
ANTICIPATED TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex 
Females 
Males 
Total 
Hispanic or Latino 
0 
3 
3 
Not Hispanic or Latino 
2 
35 
37 
Ethnic Category: Total of All Subjects * 
2 
38 
40 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
0 
6 
6 

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White 
2 
32 
34 
Racial Categories: Total of All Subjects * 
2 
38 
40 
 
Children will not be eligible for enrollment in this project. Children do not commonly present 
with HNC. Further, respiratory-swallow phase patterns and training have not been 
systematically studied in dysphagic children. This supports their exclusion from this project that 
is based on preliminary data acquired in adults. 
 
5.2      Recruitment Methods 
 
 
A total of 51 Veteran and non-Veteran volunteers will be enrolled with the goal of 40 meeting 
inclusion criteria. Potential participant volunteers will be identified by the following methods of 
participant recruitment, all approved by the VA Institutional Review Board (IRB): 1) follow-up 
medical visits, particularly the otolaryngology-head and neck clinics; 2) announcement of the 
study in the VA patient bulletins and monitors (Appendix); 3) community-based outpatient clinics 
(CBOCs); and 4) review of patient medical charts (CPRS) at Hines VA to find patients that 
match the diagnosis of oropharyngeal cancer and dysphagia diagnoses (letters will be mailed to 
these potential patients with information in regards to the study. Also included will be a brief 
survey, along with a postage paid return envelope, which allows the patients to indicate if 
interested in participating or not); 5) posting of recruitment flyers at Jesse Brown VA, Loyola 
University Medical Center, Northwestern Memorial Hospital, University of Chicago Medical 
Center, and Northwestern Medicine Healthcare Partners. 
 
Participants will be compensated for their participation in the study to assist support of their time 
and travel. Participants will receive $40 for each MBSS and $30 for each RST session. For 
participants randomized to immediately undergo the intervention, they have the potential 
maximum of earning $440. The participants randomized to the control group will undergo one 
additional MBSS procedure immediately prior to their cross-over to the intervention arm, for a 
potential maximum of $480. Participant payment will be made according to the current local 
fiscal office guidance and processes. Planned payments will be approved by appropriate study 
personnel for disbursement according to this schedule:  
• 
Payment 1: after first study visit to determine eligibility for intervention (which includes 
first MBSS) 
• 
Payment 2: after week 1 of intervention 
• 
Payment 3: after week 2 of intervention 
• 
Payment 4: after week 3 of intervention 
• 
Payment 5: after week 4 (final) of intervention 
• 
Payment 6: after post-intervention study procedures 
• 
Payment 7: after 1-month follow-up study procedures 
• 
Payment 8: after 3-months follow-up study procedures 
• 
Payment 9: after 6-months follow-up study procedures 
• 
One additional payment will be made to those participants assigned to the control arm. 
This payment will be dispersed immediately after the MBSS procedure immediately prior 
to starting RST treatment. 
 
5.3      Informed Consent Procedures 
 

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Informed consent will be otained by all trained study personnel, including PI, Study Coordinator 
and SLP, using a VA IRB approved informed consent form. All participants will be explained the 
study procedures, potential risks, and benefits by consenting personnel.  
 
5.4      Inclusion/Exclusion Criteria 
 
Inclusion and Exclusion Criteria. Entry inclusion criteria: 1) ≥21 years of age; 2) signed 
informed consent; 3) at least 6 months post head and neck cancer treatment for oral cancer, 
oropharyngeal cancer, laryngeal cancer, or hypopharyngeal cancer; 4) consumes 2 alcoholic 
drinks daily and 5) English speaking. Entry exclusion criteria: 1) known allergy or dietary 
restriction for materials used during the exam; 2) severe chronic obstructive pulmonary disease 
(COPD); and 3) recent history of aspiration pneumonia (past 12 months). Intervention 
inclusion criteria: 1) pass Montreal Cognitive Assessment (MoCA) (≥26)87. Intervention 
exclusion criteria: 1) fails MoCA (<26); and 2) inability to tolerate at least one liquid 
consistency (PAS ≥7). Women of child-bearing age will be screened via questionnaire in 
accordance with VA Medical Center policy precautions. Women who are pregnant will be 
excluded from this trial given that five MBSSs are required and the risk of any radiation to the 
fetus exceeds the potential benefit of this study. Men will also be counseled regarding the risks 
of radiation exposure to their reproductive organs. Hospital policy precautions for radiation 
safety will be applied. Informed consent will be obtained by the examining speech-language 
pathologist (SLP). The study procedures, potential risks, and benefits will be explained to all 
participants, and caregivers when appropriate, by the examining SLP. It will be explained that 
participation in the study will not have any impact on the quality of his/her present and/or future 
care as a patient. Further, if a participant chooses not to participate or drops out of the study at 
any time, there will be no consequences of this action. There will be no additional study sites 
involved with this research. 
 
Cognitive Criteria. There exists the possibility that study volunteers may experience co-existing 
cognitive problems that preclude the learning of a new motor task. Participants will be screened 
immediately following consent (prior to the baseline modified barium swallow study, MBSS) for 
cognitive impairment using the MoCA87 – a cognitive screening test designed to assist health 
professionals for detection of mild cognitive impairment. The standardized procedure covers the 
following cognitive domains: visuospatial/executive, naming, memory, attention, language, 
abstraction, delayed recall, and orientation. Scores for each domain are summed and a total 
score is obtained that can be adjusted for educational level. MoCA scores <26 suggest 
cognitive impairment. Thus, participants with a total MoCA score of 25 or less will be excluded 
from further participation.  
 
Pulmonary Criteria. There is some evidence indicating that pulmonary function status may 
impact respiratory-swallow phasing and swallowing impairment,116-119 and many patients with 
HNC present with varying degrees of disordered pulmonary function. An important covariate of 
upper airway function is lower airway disease. Since smoking is a risk factor for both HNC and 
COPD, a number of patients have both diagnoses. Although we did not find an association 
between pulmonary function and the ability to train in our preliminary study, it remains unclear 
whether expiratory airflow obstruction changes expiratory time constants and potentially impacts 
swallowing timing or physiology. Consequently, all participants will be screened for the presence 
of pulmonary disease if they meet the cognitive screening criteria prior to the baseline MBSS. 
Pulmonary screening will include spirometry performed by a licensed pulmonary function 
technician and reviewed for compliance with the American Thoracic Society standards.117,118 
These data will permit further study of the impact of pulmonary function on respiratory-swallow 

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phasing and the outcome variables in the proposed trial. The best single objective measurement 
of COPD severity is the forced expiratory volume in 1 second (FEV1).120,121 FEV1 will be 
analyzed as a covariate in analyses. Patients with severe COPD (FEV1<50% predicted) will be 
excluded from further study and will not receive the baseline MBSS. 
 
5.5      Study Evaluations 
 
All potential participants will be screened for eligibilty as described above for inclusion/exclusion 
criteria using medical charts and collection of general history information related to cancer 
diagnosis, treatment, dysphagia treatment, and current swallowing problems. Once deemed 
eligible, the participants will then undergo evaluation to determine eligibility for RST that 
includes an MBSS with simultaneous respiratory recordings, completion of cognitive screen 
(MoCA) (Appendix), and questionnaire (MDADI) (Appendix).  
 
If participants meet eligibilityty criteria to participate in RST as outlined above, each participant 
will undergo in-clinic RST sessions with an SLP. After the RST is completed, participants will 
undergo an MBSS with simultaneous recordings, completion of MDADI, and information about 
oral intake/diet tolerance (FOIS) (Appendix) for post-treatment measurements. Further, the 
participant will undergo these same procedures at 1-month, 3-months, and 6-months after 
experimental portion is completed.  
 
5.6      Data Analysis 
 
 
Statistical Considerations. Specific Aim 1: Trial design. The primary objective of Specific 
Aim 1 is to demonstrate the clinical efficacy and durability of RST in participants with dysphagia 
with a history of OP HNC. A total of 88 participants will be [recruited and randomly assigned 
1:1to either RST (intervention arm) or control arm, given the crossover design of the study.. We 
will use a stratified permuted block randomization scheme with random block sizes of 2 or 4 to 
balance important prognostic variables across the two trial arms. There will be 5 strata defined 
by treatment modality (radiation therapy alone, surgery alone, chemo-radiation therapy, surgery 
+ post-operative radiation therapy, surgery + post-operative radiation therapy + adjuvant 
chemotherapy). The study statistician will maintain randomization lists and be responsible for 
randomizing consented participants. The study schema is depicted in Figure 8. The control arm 
will cross over to RST after visit 1 following data collection for evaluation of clinical efficacy. 
 
Endpoint Definitions and Analysis Plans. The primary efficacy endpoint for Aim 1 is 
oropharyngeal swallowing physiologic metrics (MBSImP) and evaluated at: visit 0, defined as 
pre-RST for intervention subjects, and baseline for control subjects; and visit 1, defined as post-
RST for intervention subjects or 4 weeks post-baseline evaluation for control subjects. We will 
compare changes in MBSImP physiologic function metrics in patients randomized to 
intervention versus control. Change in MBSImP physiologic function metrics will be compared 
using one-way analysis of covariance (ANACOVA), with trial arm as the main effect and 
adjustment for stratification variable of treatment type. If approximate normality is not satisfied, 
we will use generalized estimating equations (GEEs) with an identity link function and robust 
standard error estimator. Furthermore, the regression framework of GEEs will accommodate 
adjustment for stratification factor. Durability of response will be evaluated using ANACOVA or 
GEEs as described by comparing post-RST MBSImP physiologic function metrics to those 
obtained at 1-,3-, and 6-month follow-up visits. We will further evaluate the modifying and 
confounding effects of sex, age, smoking status, COPD status, and pulmonary function. 
 

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Further, response durability will be evaluated using FOIS measures obtained at 1-, 3- and 6-
months post-RST. Because control subjects cross over to RST at visit 1, FOIS measures 
collected at visit 1 for control subjects additionally will serve as their pre-RST FOIS measures 
(Figure 7). Clinical efficacy will be evaluated by comparing change in FOIS (ΔFOIS = FOISvisit1 – 
FOISvisit0) in patients randomized to intervention versus control. ΔFOIS comparisons will be 
conducted using one-way analysis of covariance (ANACOVA), with trial arm as the main effect 
and adjustment for stratification variables. If approximate normality is not satisfied, we will use 
generalized estimating equations (GEEs) with an identity link function and robust standard error 
estimator, which accommodates valid inference in the presence of misspecification.103,104 
Furthermore, the regression framework of GEEs will accommodate adjustment for stratification 
factors. Durability of response will be evaluated using ANACOVA or GEEs as described by 
comparing post-RST FOIS measurements to those obtained at the 1-, 3- and 6-months follow-
up visits. In addition, we will model longitudinally collected FOIS scores as a function of time 
(measured as a categorical variable) using GEEs, with additional independent variables for 
stratification factors and pre-RST FOIS included in all models. Comparisons at individual time 
points will be performed using model-based linear contrasts with inference based on associated 
two-sided generalized score tests. We will further evaluate the modifying and confounding 
effects of sex, age, smoking status, COPD status, and pulmonary function. Secondary 
endpoints include MDADI summary scores, and respiratory-swallow phase patterns (binary 
measure classified as optimal versus non-optimal) collected at all time points. Analysis of 
MDADI scores will follow the approach used to analyze FOIS scores. Comparisons between 
visits 0 and 1 respiratory-swallow phase patterns will be performed using a Rao-Scott chi-
square test, an approach that accommodates comparisons of proportions from paired data with 
Mantel-Haenszel-type adjustments for stratification factors.105 GEE models of respiratory-
swallow phase patterns will be similar to those described for FOIS measures but using instead a 
Figure 7 Study schema for current proposal. 

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logit or probit link function as appropriate for binary endpoints. Results for all endpoints will be 
summarized separately for males and females to assess differences by patient sex. 
  
 
 
Statistical Considerations: Specific Aim 2 Design and Methods – Intervention Impact of 
RST on Swallowing Physiology. We will elaborate the treatment impact of RST by detailing 
the physiological, airway protective and morphometric changes that occur from the intervention. 
We will use MBSImP, PAS (described for Aim 1), and CASM. 
 
MBSImP Scores. The MBSImP scores will provide a primary outcome measure of swallowing 
impairment. The MBSImP is a validated and reliable scoring system for the quantification of 
swallowing impairment from MBSS recordings.13,14,19 This tool has an ordinal scoring schema 
that permits quantification of oral, pharyngeal, and esophageal components of swallowing 
physiology. The operational definitions for the component scores represent a unique and 
unambiguous observation of structural movement and bolus flow. Seventeen physiologic 
components will be scored on a previously validated, rank order scale from least to most 
impaired. The scale for components ranges from 0-2 to 0-4 for each physiologic component.14 
Years of field testing shows scores of 0 or 1 for the physiologic components of lip closure, oral 
residue, pharyngeal residue, and tongue base retraction are considered to be within normal 
limits.112 For all other components, scores greater than 0 represent some level of impairment. 
Two methods will be used for MBSImP scoring: swallow-by-swallow (SS) and overall impression 
(OI). SS scoring assigns an MBSImP score for all applicable physiologic components for each 
of the 12 swallowing tasks given during the protocol. SS cores will be recorded for each 
participant. The highest (worst) score will be given during SS scoring when the participant’s 
condition or performance on a previous swallowing task results in the withholding of a 
subsequent swallowing task for safety concerns.9,52 Additionally, missing data in SS 
interpretation will result if a participant refuses a swallowing task.52 As such, we will only include 
scores for swallowing tasks that are actually presented.  
 
Computational Analysis of Swallowing Mechanics (CASM). Annotators who meet reliability 
criterion109 will use a MATLAB (version R2015a, 8.5.0.197613, 64-bit) semi-automated tracker 
tool designed specifically for coordinate mapping of swallowing structures.113,114 Coordinates are 
annotated in all frames during oral transit and pharyngeal swallowing. The tracker tool produces 
an .mp4 video file of annotated landmarks for review and a .csv file of coordinates with a unique 
identifier assigned to each row of coordinates. Once video files are reviewed by an expert head 
and neck anatomist (Co-Investigator, WP), coordinates for all swallows are concatenated and a 
second file of variables that match unique identifiers is compiled to include group (pre-
intervention vs. post-intervention), swallowing domain (oral vs. pharyngeal), bolus volume (large 
[cup] vs. small [5ml]), bolus viscosity (thin vs. thick), sex (male vs. female), penetration-
aspiration status (within functional limits [PAS = 1,2] vs. penetration-aspiration PAS = 3-8]), and 
MBSImP component scores. These files are uploaded into MorphoJ integrated software for 
analysis.115 
 
Statistical Considerations. The primary endpoints for Specific Aim 2 are MBSImP scores, PAS 
scores, and morphometric canonical variate scores for participants enrolled in the clinical trial 
(Specific Aim 1). MBSImP component scores and PAS will be dichotomized as impaired versus 
not-impaired as previously described.8 Analyses of impairment rates, MBSImP composite (oral 
and pharyngeal total) scores, and time course data will be conducted using ANACOVA, GEEs 
and Rao-Scott Chi-square tests as described in Specific Aim 1. To evaluate rater reliability for 

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MBSImP and PAS measures, 20% of MBSSs will be re-scored by each rater. Intra-class 
correlations coefficients will be calculated to measure inter- and intra-rater reliability. 
 
CASM will be applied to pre- and post-RST MBSSs to determine and visualize improvements in 
covariant swallowing mechanics resulting from RST and determine which of these treatments is 
predictive of swallowing improvement as measured by MBSImP and PAS scores. Following a 
Procrustes fit of coordinates to control for differences in size and image rotation, a canonical 
variate analysis with post hoc discriminant function analyses21,22 are performed to determine 
statistical differences in pre- and post-RST swallowing mechanics by phase of swallowing for 
each subject and the aggregate. Eigenvectors will be used to visualize differences in covariant 
swallowing associated with treatment effect. Morphometric regression analysis will be used to 
evaluate respiratory-swallow training as a predictor of improved swallowing outcomes as 
measured by MBSImP and PAS scores. 
 
5.7     Withdrawal of Subjects 
 
Participation is voluntary and the participant can withdraw from the study at anytime 
without penatly, consequences or loss of rights to which they are entitled. If the 
participant wishes to withdraw, they can contact study personnel at anytime. They will 
still receive compensation based on tasks completed as outlined previously. The 
investigator may withdrawal the participant from the study if they are unwilling or unable 
to follow study procedures or have worsening breathing problems, lung disease, or 
pneumonia.   
 
6.0 
Reporting 
 
The PI (BMH) will be responsible for ensuring participant safety on a daily basis. An internal 
Data and Safety Monitoring Board (DSMB) - comprised of a radiation oncologist, medical 
oncologist, head and neck surgeon, pulmonologist, biostatistician, information technology 
specialist, and a speech-language pathologist - will act in an advisory capacity to monitor 
participant safety, evaluate the progress of the study, and to review procedures for maintaining 
the confidentiality of data, the quality of data collection, management, and analyses. The PI will 
be informed of serious adverse events as soon as they occur and will notify the IRB, DSMB, VA 
RR&D within 24 hours of notification. The DSMB will meet twice annually, either in-person or by 
teleconference call, to review study progress, data quality, and participant safety.  
 
Safety reports will be sent to the PI twice a year and will include a detailed analysis of study 
progress, data and safety issues. DSMB members will have no direct involvement with the study 
investigators or intervention. Each DSMB member will sign a Conflict of Interest Statement 
regarding any relationship that could be perceived as a conflict of interest related to the study 
and/or associated with commercial interests pertinent to study objectives. Data will be presented 
in a blinded manner during the open sessions of the DSMB or in safety reports. Data and 
discussion will remain confidential during DSMB meetings and in safety reports. Participant 
identities will not be known to the DSMB members. 
 
Any unanticipated problem, SAE, and/or protocol deviations will be immediately reported to the 
PI. All the SAE will be reported within Five working days of the Investigators Knowledge of the 
event to the Hines VA IRB. In the event when the PI is not able to continue to conduct the study, 
Dr. Kim (ENT) will take over the responsibilities as a PI. 
 

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7.0 
Privacy and Confidentiality 
 
This study will use subjects’ Protected Health Information (PHI). Extensive efforts will be made 
by all study personnel to keep personal information and research records private and 
confidential. Each participant will be assigned an alphanumeric identifier (XX1, etc.), which will 
be used in lieu of other identifying information. All research related materials will be secure in a 
locked file cabinet at the Hines VA Hospital in Rm D326. Personal information will be given out 
as required by law. Only approved study personnel will be provided access, which requires 
appropriate VA and CITI training for research-related duties. A Certificate of Confidentiality will 
not be used for this study.   
 
Study related data are stored on VA approved computers and the VA research shared drive 
(S:), including de-identified study-related data (videofluoroscopic images, respiratory traces). 
Identifiable data (VASA), including demographic data, questionnaire responses, and treatment 
results are stored on the VA REDCap behind the VA firewall. De-identified videofluoroscopic 
images and respiratory tracings will be transported via VA issued encrypted external hard drives 
for analysis by specially trained analytic experts to the PI’s lab at Northwestern University, and 
then stored on and analyzed from a password protected, dedicated server. This server is 
managed by Northwestern Information Technology and accessible to only approved study 
personnel. We will update the data transfer and storage operations as we are provided 
additional guidance and requirements from the ORO, Office of Research Oversight. 
 
Per VA regulations, research records, including identifiers will be destroyed 6 years after cutoff 
(at the end of the fiscal year) after completion of the research project, but may be retained 
longer if required by other federal regulations or sponsor archive requirement. Once a VA study 
personnel member leaves, his/her access to all data related to the study will be terminated. 
Prior to destruction of any research-related records, the PI will contact Records Management 
Officer for current policy. 
 
8.0 
Communication Plan 
 
• 
Bi-monthly summary e-mail from Study Coordinator to review study progress and 
any items that need action. 
• 
Routine monthly meetings via in person or via telephone conference call 
amongst all study personnel to discuss study progress and interpretation of study 
outcomes, as well as to identify and solve any barriers to study completion.  
• 
Weekly bi-monthly meetings between Study Coordinator, Research SLP and PI, 
to discuss study progress and interpretation of study outcomes, with particular 
focus on study accrual, as well as to identify and solve any barriers to study 
completion.   
• 
If there is a protocol deviation, serious adverse event, and/or unanticipated 
problem, the PI and IRB will be immediately notified. Additionally a summary of 
the event and solution with a plan to prevent future problems will also be 
communciated with all study personnel. 
• 
Study Coordinator will routinely check for issues related to completion of IRB-
approved study protocol, data collection and ensure the regulatory binder is up-
to-date.  

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