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Reproducibility of Transcranial Magnetic Stimulation for Mapping Swallowing Musculature in the Human Motor Cortex

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Title:
Reproducibility of Transcranial Magnetic Stimulation for Mapping Swallowing Musculature in the Human Motor Cortex
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PLOWMAN, EMILY KATE ( Author, Primary )
Copyright Date:
2008

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Brain ( jstor )
Deglutition disorders ( jstor )
Electrodes ( jstor )
Genetic mapping ( jstor )
Handedness ( jstor )
Hemispheres ( jstor )
Maps ( jstor )
Motor ability ( jstor )
Strokes ( jstor )
Swallowing ( jstor )

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University of Florida
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University of Florida
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Copyright Emily Kate Plowman. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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5/31/2010
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74819883 ( OCLC )

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REPRODUCIBILITY OF TRANSCRANI AL MAGNETIC STIMULATION FOR MAPPING SWALLOWING MUSCULATURE IN THE HUMAN MOTOR CORTEX By EMILY KATE PLOWMAN A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2005

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Copyright 2005 by Emily Kate Plowman

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For my mother, whose strength, courag e, and will to survive inspire me.

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ACKNOWLEDGMENTS A doctoral dissertation does not come from the hands of one individual. The success of all aspects of the study is intimately tied to the support and guidance of many individuals. In light of this, I am extremely grateful to all of those individuals involved in my education, research and life. I am indebted to my doctoral committee for their guidance and support. First, I would like to thank my committee chair, Dr. Jay Rosenbek. His knowledge, guidance, support and encouragement throughout the past 4 years have been astounding. Above all, this man has shown me what it means to be a truly great person. Second, I would like to thank Dr. Bill Triggs, who trained me on the inner workings of TMS and allowed me to work in his lab over the past few years. His time, patience, and generosity have been appreciated. I would also like to thank my other committee members Dr. Christine Sapienza, Dr. Andrea Behrman, and Dr. Craig Velozo. Their support and guidance were invaluable and I admire them very much. I am indebted to Dick Moss, who put in countless hours in the laboratory with me and was by my side for each session. Without his technical support, data collection would have been impossible. I also appreciate the individuals who participated in this study. Without them, there would be no study. On a personal level, I would like to thank my boyfriend Bryan for his unrelenting love, support and encouragement during this challenging time. I would also like to thank my family for their enduring love and prayers that stretch over many miles. I thank my iv

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father for being such a wonderful role model and providing me with advice about the world of academics over these last years. I praise my mother for her love and warmth and her strength to survive. I also thank my brother Michael, who has shown me what true character is all about. Finally, I would like to thank my colleagues, Charles, Neila, Lori, Harrison, and Amy for being great classmates, and above all, great friends who I will always cherish. v

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TABLE OF CONTENTS Page ACKNOWLEDGMENTS .................................................................................................iv LIST OF TABLES .............................................................................................................ix LIST OF FIGURES ...........................................................................................................xi ABSTRACT ......................................................................................................................xii CHAPTER 1 INTRODUCTION........................................................................................................1 2 LITERATURE REVIEW.............................................................................................3 Incidence and Consequences of Swallowing Impairment............................................3 Cortical Control of Swallow Function..........................................................................4 Animal and Human Pathophysiologic Evidence...................................................6 Summary of Pathophysiologic Evidence.............................................................10 Investigations of Swallow Representation in the Intact Human Brain.......................11 Functional Resonance Imaging (fMRI) and Swallowing....................................11 Positron Emission Tomography (PET) and Swallowing.....................................15 Magnetoencephalography (MEG) and Swallowing............................................16 Summary of Noninvasive Studies.......................................................................18 Limitations...........................................................................................................18 Transcranial Magnetic Stimulation.............................................................................19 Motor Map Area..................................................................................................21 Motor Map Volume.............................................................................................21 Optimal Stimulating Site Location......................................................................22 Optimal Stimulating Site Size.............................................................................22 Motor Threshold..................................................................................................22 Specific Aims..............................................................................................................28 Aim I. ...................................................................................................................28 Aim II. .................................................................................................................29 Significance of Work..................................................................................................29 Summary.....................................................................................................................30 vi

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3 METHODS.................................................................................................................32 Subjects.......................................................................................................................32 Subject Set Up............................................................................................................33 Determination of Optimal Grid Position and Motor Threshold.................................35 TMS Mapping Procedure...........................................................................................35 Data Analysis..............................................................................................................37 Motor Map Area..................................................................................................38 Motor Map Volume.............................................................................................38 Optimal Stimulating Site Location......................................................................38 Optimal Stimulating Site Size.............................................................................39 Motor Threshold..................................................................................................39 Statistical Analyses.....................................................................................................40 4 RESULTS I: TEST-RETEST RELIABILITY...........................................................42 Motor Map Area Reliability.......................................................................................42 Motor Map Volume Reliability..................................................................................42 Optimal Simulation Site Location Reliability............................................................43 Optimal Simulation Site Size Reliability....................................................................43 Motor Threshold Reliability.......................................................................................44 Summary of Reliability Results..................................................................................45 5 RESULTS II: TOPOGRAPHIC REPRESENTATION OF SWALLOW MUSCULATURE......................................................................................................46 Motor Map Area.........................................................................................................46 Motor Map Volume....................................................................................................48 Optimal Stimulation Site Location.............................................................................49 Optimal Stimulation Site MEP Size...........................................................................51 Motor Threshold.........................................................................................................53 Relationship Between Handedness and Swallow Representation..............................54 Summary of Swallow Topography Results................................................................57 6 DISCUSSION.............................................................................................................58 Summary of Results....................................................................................................58 Reliability of TMS Mapping......................................................................................59 Motor Map Area..................................................................................................59 Motor Map Volume.............................................................................................61 Optimal Stimulation Site Location......................................................................63 Optimal Simulating Site Size..............................................................................63 Motor Threshold..................................................................................................64 Strengths, Limitations, and Future Directions.....................................................64 Topographic Representation of Swallow Musculature...............................................66 Spatial Organization of Swallow Representation................................................66 Excitability of Swallow Representation..............................................................69 vii

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Lateralization to the Left Hemisphere.................................................................70 Clinical Significance...........................................................................................74 Strengths, Limitations, and Future Directions.....................................................75 Summary and Conclusions..................................................................................76 APPENDIX A EDINBURH HANDEDNESS INVENTORY............................................................78 B INFORMED CONSENT FORM................................................................................79 LIST OF REFERENCES...................................................................................................87 BIOGRAPHICAL SKETCH.............................................................................................97 viii

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LIST OF TABLES Table Page 1-1 Summary of transcranial magnetic stimulation (TMS) mapping measures.............23 3-1 Subject demographics..............................................................................................33 3-2 Summary of transcranial magnetic stimulation (TMS) outcome measures.............39 4-1 Mean motor map area for Test I and II and obtained ICC results............................42 4-2 Mean map volume for Test I and II and obtained ICC results.................................43 4-3 Optimal stimulation site location and associated ICC values..................................43 4-4 Mean optimal stimulation site size (highest obtained MEP peak-to-peak area) across testing sessions with obtained ICC results....................................................44 4-5 Mean motor threshold across testing sessions and obtained ICC index..................44 4-6 Summary of test-retest reliability results for swallow muscles across TMS measures...................................................................................................................45 5-1 Individual motor map area data................................................................................47 5-2 Mean motor map area (standard deviation) for the right and left hemisphere with associated p-value....................................................................................................48 5-3 Mean motor map volume (standard deviation) across hemispheres with associated p-value....................................................................................................49 5-4 Individual subject data for motor map volume........................................................50 5-5 Mean location (in cm from Cz) of the maximal MEP for both hemispheres...........51 5-6 Mean (standard deviation) maximal MEP peak-to-peak area across hemispheres with associated p-value............................................................................................51 5-7 Individual data for optimal stimulation site MEP size.............................................52 5-8 Individual motor threshold (%) values for the right and left hemisphere................53 ix

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5-9 Individual symmetry ratio data................................................................................55 5-10 Results from correlation analysis between handedness laterality quotient and swallow symmetry ratio...........................................................................................57 x

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LIST OF FIGURES Figure Page 3-1 Pharyngeal electrode insitu......................................................................................34 3-2 Location of the vertex (Cz), interaural and nasion-inion lines, stimulating grid, and figure-of eight coil orientation of the head........................................................36 3-3 Example of obtained MEPs for the right suprahyoid, left suprahyoid and pharynx respectively................................................................................................37 4-1 Comparison of mean optimal stimulation site location for each muscle across testing sessions.........................................................................................................44 5-1 Mean motor map area for swallow musculature across hemispheres......................48 5-2 Mean motor map volume for the right and left hemisphere.....................................49 5-3 Mean optimal stimulation site MEP peak-to-peak area for the right and left hemisphere...............................................................................................................51 5-4 Mean symmetry ratios for each muscle site.............................................................54 5-5 Swallow map for representative subject showing both spatial area of representation and relative excitability of representation.........................................56 xi

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Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy REPRODUCIBILITY OF TRANSCRANIAL MAGNETIC STIMULATION FOR MAPPING SWALLOWING MUSCULATURE IN THE HUMAN MOTOR CORTEX By Emily Kate Plowman May 2005 Chair: John C. Rosenbek Major Department: Rehabilitation Science The high incidence of dysphagia following neurologic disease, together with its impact on health, fiscal, social and quality-of-life domains, has necessitated a greater understanding of the central nervous system pathways governing swallowing function. This understanding has been assisted by the development of new technologies such as Transcranial Magnetic Stimulation (TMS). TMS represents a noninvasive means of studying swallow topography in the intact human brain. However, limited psychometric data exists to document its reliability. The aims of the present study are threefold: (1) to determine the test-retest reliability for TMS mapping of swallowing musculature; (2) to determine the topographic representation of swallowing musculature; and (3) to determine the relationship of swallow representation to handedness. Twenty healthy adults attended 2 TMS mapping sessions, approximately 2 weeks apart. Electromyographic recordings were taken from the suprahyoid complex and the xii

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pharynx. TMS measures included: map area, map volume, optimal site location, optimal site size and motor threshold. Results indicated that TMS was a stable measure of corticobulbar organization and excitation in this healthy cohort. Good test-retest reliability was observed for 4 TMS measures: motor map area, optimal site location-lateral coordinate, optimal site size and motor threshold (ICC: 0.76-0.98). Moderate test-retest reliability was observed for 2 TMS measures: motor map volume and optimal site location-anterior-posterior coordinate (ICC: 0.68-0.74). Swallow topography displayed a bilateral, yet clearly asymmetric, representation across all subjects. Though individual variation was noted, a groupwise lateralization to the left hemisphere was apparent across all TMS measures and for each swallow muscle studied. In addition, motor threshold was significantly lower in the left hemisphere. No relationship emerged for handedness and swallow representation. These results provide much needed psychometric data to validate the use of TMS as an end-point measure in intervention studies overtime. Swallow topography results support a lateralization of swallow function in a normal cohort and suggest the importance of the left hemisphere for swallow function. xiii

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CHAPTER 1 INTRODUCTION This dissertation is concerned with 2 aspects of Transcranial Magnetic Stimulation (TMS), namely the reliability of TMS mapping and the cortical organization of swallowing musculature. The high incidence of dysphagia, together with its impact on health, fiscal, social and quality of life domains, has necessitated a greater understanding of the central mechanisms governing swallow function. 2 competing hypotheses have been put forth: lateralization of function and bilateral representation of swallow function. While both physiological and pathophysiological data strongly implicate a role of the cerebral cortex in the control of swallowing, the functional organization remains unclear (Kern et al., 2001; Mosier et al., 1999). Hamdy et al. (1996) provided the seminal investigation into healthy swallow topography using TMS and reported a bilateral yet asymmetric representation of swallow musculature that was not related to handedness and inconsistent among subjects. To date, no other investigator has attempted to validate these findings. In addition, basic psychometric data on TMS mapping is critically lacking. No study has investigated the test-retest reliability of TMS to map corticobulbar musculature, casting caution on interpretation of Hamdy and colleagues’ data. The aim of the proposed investigation is to: (1) demonstrate the reproducibility of TMS mapping of oral and pharyngeal swallow musculature, and if found reliable (2) define cerebral representation of human swallowing musculature using TMS. The results of this study will provide much needed psychometric data validating the use of TMS. If the technique is found to be reliable, this study will delineate the organization of 1

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2 projections from the motor cortex to the oral and pharyngeal swallow muscles. Results will provide a better understanding of the swallow process, which may help in the development of therapeutic interventions that can drive neural plasticity and facilitate recovery of swallow function. This study is presented in 6 chapters. The next chapter outlines the salient literature relating to this study. Chapter 3 details the methodology employed. Chapters 4 and 5 present results for the test-retest reliability of TMS mapping and the topographical representation of swallowing musculature respectively. A discussion of these findings and conclusions will be provided in chapter 6.

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CHAPTER 2 LITERATURE REVIEW The previous chapter outlined the two-fold rationale of this study, namely to test the reliability of TMS mapping and delineate the topographical representation of swallowing musculature. This chapter locates the study within the salient literature and consists of 7 substantive parts. First, the incidence and consequences of swallowing impairment will be reviewed. The second section reports on the cortical control of swallowing and draws upon evidence from ablation paradigms in animal models and human lesion studies. The third section introduces 3 non-invasive techniques that have been applied to the study of swallowing in the intact human brain, together with the limitations of each technique. These techniques consist of functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and magnetoencepholograhpy (MEG). The fourth section introduces the neurophysiologic technique of transcranial magnetic stimulation (TMS), detailing its potential to study central nervous system pathways for swallowing representation and the inherent limitations that currently exist. Specific aims and hypotheses will comprise the fifth component. The final section will be by way of summary. Incidence and Consequences of Swallowing Impairment Dysphagia or swallowing impairment occurs in 64% of acute stroke patients (Mann, Hankey, & Cameron, 2000). Improperly or untreated dysphagia can result in increased pulmonary infections (Martin et al., 1994); death (Schmidt, Holas, Halvorson, & Reding, 1994); reduced functional outcomes at 6 months post-stroke (Barer, 1989); 3

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4 increased length of hospital stay with greater demands on health service resources (Odderson, Keaton, & McKenna, 1995); reduction in quality of life, self esteem and socialization (Ekberg, Hamdy, Woisard, Wuttge-Hannig, & Ortega, 2002); and increased likelihood that a person will go to a long term care facility rather than the home (Mann et al., 2000). These consequences have necessitated a better understanding of the central nervous system control of deglutition. As 75% of cases of oropharyngeal dysphagia are caused by neurological disease, a precise knowledge of the underlying neural representation and circuitry is essential for the development of novel dysphagia treatment strategies (Ertekin & Aydogdu, 2003) and to facilitate the ability to predict dysfunction following cerebral injury or disease (Mosier, Liu, Maldjian, Shah, & Modi, 1999). Cortical Control of Swallow Function Swallowing in the adult human is a highly complex motor behavior requiring the coordination of 26 muscles, 5 cranial nerves and functional coordination with mastication and respiration (Miller, 1986). Deglutition occurs through 3 consecutive phases, corresponding to the anatomical segments through which the ingested material (saliva or bolus) must pass: the oral, pharyngeal and esophageal phases. The oral phase is considered to be voluntary while the later two stages are considered involuntary (Ertekin & Aydogdu, 2003). The neural control for swallowing is multidimensional and involves peripheral afferent inputs arising from the oropharynx, an integrative medullary brainstem network, muscles innervated by various bulbar and cervical nerves (V, VII, IX, X, XII), and descending inputs from higher cortical and subcortical centers to both the brainstem network and the bulbar and cervical motor nuclei (Martin et al., 1999; Miller, 1986).

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5 Historically, swallow function was believed to be an entirely automatic, reflexive behavior, triggered and mediated exclusively at the brain stem level (Amirali, Tsai, Schrader, Weisz, & Sanders, 2001). More recently, a growing body of evidence has revealed that the cerebral cortex plays an important functional role in the initiation and regulation of swallowing (Martin & Sessle, 1993). The involvement of supratentorial regions, however, is at present not fully understood (Ertekin & Aydogdu, 2003). Reports in humans of swallowing impairment following hemispheric stroke (Daniels & Foundas, 1997; Hamdy et al., 1996; Meadows, 1973; Robbins & Levine, 1988); cortical ablation studies in animals (Larson, Byrd, Garthwaite, & Luschei, 1980; Lund & Sessle, 1974; Luschei & Goodwin, 1975; Sumi, 1972); cortical stimulation studies (Car, 1970; Hamdy et al., 1996; Miller & Bowman, 1977); neuroanatomic tracing studies (Kuypers, 1958a, 1958b); and neuronal recording studies examining the activity patterns and properties of ‘swallow-related’ cortical neurons (Martin, Murray, Kemppainen, Masuda, & Sessle, 1997; Martin & Sessle, 1993) have suggested that the lateral pericentral cortex, the anterolatereal frontal cortex, the frontal and parietal opercula, and the anterior insular mediate swallowing as well as a number of related functions such as sucking, mastication and salivation. Nevertheless, although these cortical regions have been implicated in the initiation and modulation of swallowing , it remains unclear whether the right or left cerebral hemisphere is more critical or dominant for swallowing (Daniels & Foundas, 1999). Knowledge of the cortical representation for swallow function is critical to understand fully the role of supratentorial regions in deglutition and how neurologic disease may affect swallowing (Daniels et al., 2002).

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6 Two competing hypotheses of swallow topography have been proposed by Daniels and colleagues (2002): lateralization of function versus bilateral representation of swallowing. The lateralization of function hypothesis proposes that swallowing is predominantly mediated by the right or left hemisphere, although there may not be a consistent pattern of lateralization across individuals (Daniels et al., 2002). Conversely, the bilateral representation of function hypothesis suggests that there is bilateral and symmetric control of swallow function across both hemispheres (Daniels et al., 2002). Empirical studies from both animal models and the pathologic human brain have provided partial support for each of these hypotheses. These will now be explicated. Animal and Human Pathophysiologic Evidence In anaesthetized animals, electrical stimulation of either hemisphere has been reported to induce swallowing (Sumi, 1969). This might be interpreted as indicating that both hemispheres have an equal role in controlling the swallow process. Analogous neurosurgical studies of the motor cortex in man (Penfield & Boldery, 1937; Woolsey, Erickson, & Gilson, 1979) have usually been confined to 1 hemisphere, so that a direct comparison with animal data has not been possible. These human neurosurgical studies, however, have shown that the locus of cortical control for swallowing lies within and antero-caudal to the face area of the primary motor cortex (Penfield & Boldery, 1937). Despite inferential animal evidence for bilateral control, studies after brain injury tend to suggest at least in humans, 1 hemisphere may be dominant (Daniels & Foundas, 1997; Meadows, 1973; Robbins & Levine, 1988; Robbins, Levine, Maser, Rosenbek, & Kempster, 1993; Tuch & Nielson, 1941). A number of studies have confirmed that perhaps 40% or more of patients with unilateral hemispheric stroke may suffer from dysphagia (Barer, 1989; Gordon, Hewer, & Wade, 1987; Kidd, Lawson, Nesbitt, &

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7 MacMahon, 1995; Logemann et al., 1993; Martin & Sessle, 1993; Smithard, O'Neill, Parks, & Morris, 1996). While reports of dysphagia following unilateral stroke provides evidence for some degree of swallow lateralization, it remains unclear which hemisphere is most critical for deglutition. Some human lesion studies point towards the left hemisphere as being the dominant swallowing hemisphere. In a prospective study of unilateral stroke patients (n=79), Shanahan, Logemann and Colangelo (1995) identified ‘swallowing apraxia’ in a small subset of left hemisphere damaged (LHD) patients but not in any right hemisphere damaged (RHD) individuals. Another group of investigators reported that oral stage dysfunction was more evident after LHD as compared to RHD in a small group of stroke patients (Irie & Lu, 1995). In prospective studies of consecutive unilateral stroke patients, Robbins and Levine (1988) and Robbins, Levine, Maser, Rosenbek and Kempster (1993) described a subset of patients with LHD who presented with incoordination of labial, lingual and mandibular musculature during bolus transfer. Severe oral dysmotility patterns were evident in these patients who also exhibited buccofacial and speech apraxia. Robbins and colleagues (1988, 1993) suggested that the left hemisphere might significantly contribute to the oral phase of swallowing and that the observed dysfunction might be associated with buccofacial and speech apraxia, which are also left hemisphere dominant functions. Logemann et al. (1993) studied 8 patients suffering a single, small left basal ganglia/internal capsule infarction. Oropharyngeal swallowing performance in these patients was compared to age-matched normal controls. Logemann and colleagues

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8 (1993) reported significantly delayed oral transit times and reduced oropharyngeal swallow efficiency in the stroke subjects and suggested the involvement of the left hemisphere in swallow coordination and timing. Interpretation of these findings, however, is limited due to the lack of a comparison RHD group. Other pathological evidence points towards the right hemisphere for mediating swallowing function. Smithard, O’Neil, Martin and England (1997) performed a prospective study on 87 consecutive acute stroke patients admitted to a neurological service. On admission, 17 patients (19.5%) were observed via videofluoroscopy to be aspirating. At this time, the authors found no relationship between side of lesion and presence of aspiration. A follow-up assessment 1 month post stroke, however, revealed that 9 of 69 patients (13.5%) were aspirating. Seven of the 9 aspirators (78%) had RHD and this difference between lesion site was found to be statistically significant (p <0.001). These results hold even greater clinical significance when 1 considers the reported odds ratio for developing pneumonia post-stroke is 6.5 times greater for those who aspirate versus those who do not aspirate (Holas, DePippo, & Reding, 1994) and the fact that aspiration often results in prolonged hospitalization and death (Barer, 1989; Brown & Glassenberg, 1973; Hickling & Howard, 1988; Lugger, 1994; Silver, Norris, Lewis, & Hachinski, 1984). Smithard et al. (1997) concluded that chronic dysphagia and specifically continual aspiration may be related to side of cerebral lesion. In a retrospective study of 441 consecutive stroke patients admitted to a stroke rehabilitation unit, Teasell, McRae, Heitzner, Bhardwaj and Finestone (1996) reported a higher incidence of pneumonia in RHD patients. Though these authors did not report the incidence of aspiration across lesion sites, they did note that the presence of aspiration

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9 lead to a 20-fold increase in developing pneumonia, leading to the inference that these RHD patients demonstrated a higher incidence of aspiration. In a recent prospective study of consecutive acute stroke patients (n =59), Daniels, Brailey and Foundas (1999) attempted to identify patterns between lesion site and oral dysphagia. Though these authors concluded that hemisphere of stroke could not predict the occurrence of oral dysphagia, inspection of data reveals some interesting patterns favoring a right hemisphere involvement with the oral stage of swallowing. Eleven of the 59 patients (19%) in the total sample presented with lingual discoordination. Of these, 7 patients (64%) had RHD, 3 (27%) had LHD, and 1 (5%) suffered bilateral cortical lesions. Thus for lingual discoordination, the incidence of right hemisphere damage was 3fold that of the left hemisphere. Further, 3 patients (5% of the total sample) presented with moderate to severe lingual discoordination. Site of lesion in all 3 of these patients was within the right hemisphere. Thus Daniels et al’s (1999) findings suggest a critical role of the right hemisphere for lingual movements during the oral stage of swallowing. Pharyngeal stage dysfunction, aspiration and dysmotility patterns have also been reported to be more common in RHD patients than in LHD individuals by other investigators (Daniels, Foundas, Iglesia, & Sullivan, 1996; Robbins & Levine, 1988; Robbins et al., 1993). Conversely, other investigators have reported an equal incidence of dysphagia and aspiration in LHD and RHD stroke patients alike (Alberts, Horner, Gray, & Brazer, 1992; Chen, Ott, Peele, & Gelfand, 1990; Daniels, Brailey, & Foundas, 1999; Daniels & Foundas, 1999; Jacob, Kahrilas, Logemann, Shah, & Ha, 1989; Veis & Logemann, 1985).

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10 Summary of Pathophysiologic Evidence The clinical literature is divided on the issue of an association between infarct location and patterns of swallowing deficit. Whereas some studies suggest patterns of swallowing abnormalities are dependent on stroke laterality that favor a left hemisphere dominance (Irie & Lu, 1995; Logemann et al., 1993; Shanahan, Logemann, & Colangelo, 1995) or a right hemisphere dominance (Daniels et al., 1996; Daniels et al., 1999; Smithard, O'Neill, Martin, & England, 1997; Teasell, McRae, Heitzner, Bhardwaj, & Finestone, 1999); others have reported a lack of any association between swallow deficits and infarct characteristics (Alberts et al., 1992; Daniels & Foundas, 1999; Jacob et al., 1989; Veis & Logemann, 1985). Thus human pathologic evidence in dysphagia is largely equivocal. Knowledge of the lateralization of cortical representation for swallow function is critical to understanding fully the role of supratentorial regions in deglutition and how neurologic disease, in particular stroke, may affect swallowing (Daniels et al., 2002). However, based on the aforementioned studies, it remains unclear whether swallowing is lateralized and if so, whether it is hemisphere specific. Additionally, inherent limitations of ablative paradigms exist. Differences between the cortical representation of swallowing in the human and non-human primate brain, for instance, might limit the generalizability of the animal model findings discussed. Limitations of human lesion studies include variables such as differences in site, size and acuteness of disease across patients. Moreover, ablative paradigms do not tell us how the functional brain and swallow system operate but rather how they perform in compromised circumstances.

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11 The missing piece of data in these studies has been the lack of information regarding the normal pattern of cortical projections to swallowing muscles in healthy humans. The recent advent of non-invasive neuroimaging and electromagnetic techniques has permitted the investigation of motor representations in the intact healthy human brain (Siebner & Rothwell, 2003). The literature suggests that there are 4 primary techniques for investigating the organization of the motor cortex. These are outlined in the next section. Investigations of Swallow Representation in the Intact Human Brain Non-invasive neuroimaging techniques include functional resonance imaging (fMRI) and positron emission tomography (PET). These techniques measure regional blood flow or metabolic changes linked to function-related activity in neurons. fMRI and PET may be used at the regional level to visualize an entire neural network subtending a particular motor act and thereby are thought to provide a detailed relationship between function and anatomy (Rossini & Pauri, 2000). Magnetoencepholography (MEG) and transcranial magnetic stimulation (TMS) represent two non-invasive techniques that utilize electromagnetic fields and currents to explore the neurophysiologic properties of the human central nervous system. Functional Resonance Imaging (fMRI) and Swallowing With fMRI, blood oxygen level dependent (BOLD) effects are mapped in the intact brain. This method is based on the principle that a disproportionate increase in blood flow over metabolic demands yield reduced deoxyhemoglobin levels in regions of high neuronal activity. Recently, investigators have utilized fMRI to correlate brain structures with swallow function. These neuroimaging studies have consistently shown that swallowing activates multiple brain regions of the adult human cerebral cortex (Hamdy,

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12 Mikulis et al., 1999; Hamdy, Rothwell et al., 1999; Kern, Birn et al., 2001; Kern, Jaradeh, Arndorfer, & Shaker, 2001; Martin, Goodyear, Gati, & Menon, 2001; Martin et al., 2004; Mosier, Liu et al., 1999; Toogood et al., 2005; Zald & Pardo, 1999) and developing pediatric brain (Hartnick, Rudolph, Willging, & Holland, 2001). The most prominent activated foci correspond to the lateral precentral gyrus, postcentral gurus, perisylvian cortex, anterior cingulate cortex (ACC) and insula. These cortical regions have been implicated in voluntary swallowing of a water bolus (Hamdy, Mikulis et al., 1999; Hamdy, Rothwell et al., 1999; Martin, Gati, Fox, & Menon, 1997; Martin et al., 2001; Mosier, Liu et al., 1999; Zald & Pardo, 1999), voluntary swallowing of saliva (Kern, Jaradeh et al., 2001; Martin et al., 2001; Mosier, Patel et al., 1999; Zald & Pardo, 1999), and ‘autonomic’ swallowing of saliva in nave subjects (Kern, Jaradeh et al., 2001; Martin et al., 2001). The later finding suggests that cortical mechanisms may play a role in regulating swallowing, even when deglutition is not a conscious action. While some investigators have failed to report any hemispheric differences across activated cortical foci (Hartelius & Svensson, 1994; Mosier & Bereznaya, 2001; Toogood et al., 2005), the majority of neuroimaging studies have reported some degree of lateralization for swallow function. Kern, Jaradeh, Arndorfer and Shaker (2001) investigated cortical areas of activation for reflexive and volitional swallowing in 8 healthy volunteers. Though cortical activation was observed bilaterally for both reflexive and volitional swallow tasks, these authors reported laterality of cortical activation that was observed to be task-dependent. Specifically, within the primary sensory/motor cortex, reflexive swallowing was seen to elicit greater activation in the left hemisphere while for volitional swallowing, the right

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13 hemisphere showed larger activation. Differences between hemispheric activation for both tasks were statistically significant (p<0.05). Kern, Birn and colleagues (2001) performed an fMRI study investigating cortical representation during volitional swallowing and swallow-related motor tasks (jaw clenching, lip pursing, and tongue rolling). Subjects consisted of 14 adults, 1 of whom was left handed and the remainder right handed. Volitional swallowing elicited bilateral cortical activation in the premotor cortex, motor cortex and insula that was larger and more intense in the right hemisphere. Oral-motor tasks were seen to be bilaterally represented without conclusive evidence of hemispheric asymmetry. Interestingly, these authors noted that the right handed individuals all lateralized to the right hemisphere, whereas the lone left hander exhibited left hemispheric dominance for swallowing function. Hamdy et al. (2001) investigated volitional swallowing cortical representation in 10 healthy adults. These authors noted bilateral activation which was lateralized to either the right or left hemisphere for the premotor cortex and frontal opercula inconsistently among subjects. Activation for the insula, however, was noted to be predominantly lateralized to the right hemisphere. Martin et al. (2001) performed an fMRI study looking at 3 swallow paradigms: (1) nave saliva swallowing (i.e. reflexive swallowing), (2) volitional saliva swallowing and (3) volitional water bolus swallowing. These authors reported a statistically greater activation of the right insula during voluntary swallowing of saliva and suggested a functional lateralization of insula processing for swallowing. In contrast, Martin and colleagues (2001) did not find any clear functional asymmetry of swallow representation

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14 within the pericentral/premotor cortex, neither across subjects nor within individual subjects, across swallowing conditions. Mosier and colleagues (1999) examined lateralization of cortical activation of swallowing and potential relations to handedness in 8 subjects who performed 3 different swallow tasks (repeated dry swallows for 10 or 15 seconds or repeated wet swallows for 10 seconds). These authors observed activation in the primary motor and sensory cortices, motor association areas, and subcortical sites. No significant correlations were revealed for handedness and swallow representation. To assess potential hemispheric dominance, Mosier et al. (2001) specifically calculated a laterality index for each hemisphere. This index represented the relative proportion of cortical activation in a given (right or left) hemisphere. Examination of Mosier and colleagues’ (1999) data for the 3 swallow tasks individually, as well as pooled, consistently showed that 5 of 8 (63%) subjects were left hemisphere dominant. When present, however, right hemisphere dominance showed a stronger degree of lateralization (as indexed by a higher laterality index). Similar to Kern et al. (2001) lateralization within a given subject was noted to vary across swallow task. Specifically, 6 of 8 subjects were noted to display inconsistent sides of lateralization across the 3 swallow task. In addition, all subjects showed a change in degree of laterality among the tasks (i.e. the laterality index value increased or decreased in each subject over the 3 tasks). These findings suggest some sort of task-dependent laterality. Mosier et al. (1999) postulated that the observed variant hemispheric dominance within individuals may reflect a cortical organization scheme for swallowing that facilitates the diverse neuromuscular demands of different swallow tasks. Mosier et al. (1999)

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15 concluded that examination of the role of lateralization in the cortical control of swallowing and the implications for normal and abnormal swallowing was necessary. More recently, Martin and colleagues (2004) performed a neuroimaging study on 14 individuals who performed voluntary swallow tasks. These authors reported asymmetric activations of the lateral pericentral, opercula, and anterior parietal cortices that was strongly lateralized to the left hemisphere in the majority of subjects. While left hemisphere lateralization was the typical pattern for swallowing, Martin and colleagues reported substantial inter-subject variation with a minority showing strong right hemisphere lateralization. These authors concluded that the oral sensorimotor cortices within the right and left hemispheres are functionally non-equivalent. fRMI studies have contributed to our knowledge of cortical territory involved in normal swallow function. Common cortical foci reported in the aforementioned studies include: the premotor cortex, primary motor and sensory cortices, opercula cortex, and the insula. The majority of fMRI studies have reported bilateral yet asymmetric representation of swallow function and thus appear to support lateralization of swallowing function. Side of lateralization for cortical regions has been inconsistent, though the sub-cortical insula structure appears to have consistently shown greater activation in the right hemisphere. Positron Emission Tomography (PET) and Swallowing Positron emission tomography (PET) is another neuroimaging tool that has been utilized by two groups of investigators to study swallow-brain structural relations. PET uses radiotracers that circulate within the cerebral blood and diffuse into cerebral tissue to be imaged. Zald and Pardo (1999) noted strong regional cerebral blood flow (rCBF) within the inferior precentral gyrus bilaterally, the right anterior insula, and the left

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16 cerebellum. While asymmetry was noted in the later two sites, equivalent activation was seen in the precentral gyrus. Theses authors concluded that swallowing involves the recruitment of a large-scale distributed neural network which helps to explain why so many neurological conditions produce dysphagia. Hamdy and colleagues (1999) performed a PET study investigating swallow representation in 8 healthy adults. During swallowing, increased rCBF was noted within bilateral caudolateral sensorimotor cortex, right anterior insula, right orbitofrontal and temporopolar cortices and the left mesial premotor cortex. In addition, decreased rCBF was observed within bilateral posterior parietal cortex, right anterior occipital cortex, left suprerior frontal cortex, right prefrontal cortex and bilateral superiomedial temporal cortex. Thus across cortical regions, inconsistent lateralization was noted. Individual PET analysis revealed asymmetric representation within sensorimotor cortices in 6 of 8 subjects, 4 lateralizing to the right hemisphere and two to the left hemisphere. The authors concluded that volitional swallowing recruits multiple cerebral regions and displays strong degrees of interhemispheric asymmetry that is inconsistent among subject. They too made the comment that such findings might explain the variable nature of swallowing disorders after stroke and other focal lesions to the cerebral cortex. PET studies have revealed similar cortical foci that participate in swallow function. Both studies revealed inconsistent lateralization across cortical sites. Hamdy et al. (1999) but not Zald and Pardo (1999), revealed lateralized swallow representation in the sensorimotor cortex. Magnetoencephalography (MEG) and Swallowing More recently, magnetoencephalography (MEG) has been applied to the study of swallowing (Abe et al., 2003; Dziewas et al., 2003; Loose, Hamdy, & Enck, 2001;

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17 Watanabe, Abe, Ishikawa, Yamada, & Yamane, 2004). MEG is a technique for non-invasive recording and analysis of minute magnetic fields emanating from the brain. The instrument, which is positioned over the subject’s head, contains magnetic detection coils that are called superconducting quantum interference device (SQUID). MEG provides functional information via the magnetic fields from active neurons. Loose and colleagues (2001) provided the first investigation of swallow cortical representation using MEG. These authors reported bilaterally evoked magnetic fields for tongue movement and swallowing, however found significant artifact from tongue movement and were thus unable to detect any associated cortical activity during the tasks of tongue movement or swallowing. Abe et al. (2003) more successfully investigated voluntary swallowing using MEG. These authors reported activation in the cingulate gyrus and supplementary motor area. They did not make any references to possible differences or equivalences between cortical hemispheres at these sites. Watanabe and colleagues (2004) performed a MEG analysis on 8 subjects who performed voluntary swallow tasks. Results indicated that 6 of 8 subjects had a strong left hemisphere lateralization, with 1 subject displaying a right hemisphere dominance and another showing symmetrical activation across hemispheres. Finally, Dziewas et al. (2004) assessed cortical areas of activation associated with voluntary and reflexive swallowing as well as simple tongue movements. These authors reported that activation of the mid-lateral primary sensorimotor cortex was strongly lateralized to the left hemisphere during volitional water swallows, less strongly lateralized to the left hemisphere for reflexive water swallows, and not lateralized at all

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18 during tongue movement tasks. Activation of the left insula and frontal operculum were also observed during the preparation and execution of volitional water swallowing. Dziewas and colleagues concluded that their findings suggested a left hemisphere dominance for the cortical control of swallowing in humans. Summary of Noninvasive Studies Converging evidence from neuroimaging and electromagnetic studies in-vivo suggest that a number of spatially discrete cortical and subcortical foci may be organized within a functional neural network for swallowing. Despite methodologic differences in these non-invasive techniques, common sites of involvement include the primary sensorimotor cortex, the prefrontal cortex, the insula, and the anterior cingulate and parietooccipital regions (Dziewas et al., 2003; Hamdy, Rothwell et al., 1999; Kern, Birn et al., 2001; Martin et al., 2001; Mosier, Liu et al., 1999). Nevertheless, the specific contributions of each brain region in regulating swallowing and the relative contributions of the right and left hemisphere remain unclear. Limitations Certain limitations inherent to the aforementioned techniques should be considered when interpreting these findings. Limitations of these techniques include: limited temporal resolution; the inability to differentiate decreases from increases of neuronal firing in activated areas (i.e. excitatory or inhibitory net effects); significant movement artifact; and the requirement for a subject to perform a discrete movement (which may pose a practical problem in some patient populations). Additional limitations specific to PET include: radiation exposure, difficulty achieving an accurate region of interest placement and limited spatial resolution (Nadeau & Crosson, 1995).

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19 Further, since fMRI and PET measure hemodynamic changes, they have major limitations regarding the looseness of the relationship between blood flow and function. Moreover, these neuroimaging studies fail to define the role of a given structure for a specific behavior. Rather, they simply establish an association between activity in a given neural structure or network and performance of a task. Given these limitations, fMRI, PET and MEG may not be the most sensitive and appropriate techniques to map cortical areas of representation for swallowing function. Transcranial Magnetic Stimulation These limitations have paved the way for an emergent neurophysiologic instrument, transcranial magnetic stimulation (TMS). Introduced in 1985, TMS represents a non-invasive, quantitative means of assessing central nervous system motor pathways in humans (Thickbroom, Byrnes, & Mastaglia, 1999). TMS has the ability to ‘map’ corticomotor projections and to characterize changes in the inherent excitability of neural circuitry (Hallett, 1996). Such maps indicate the region over the scalp within which stimulation can evoke a response in a muscle of interest, and therefore is indirectly related to the origins of corticomotor projections in the underlying cortex. This technique has made it possible to study topography of corticomotor projections in human subjects in a non-invasive and painless manner. TMS uses the principles of inductance to get electrical energy across the scalp and skull. A brief high-current pulse is produced in a coil of wire, called the magnetic coil, which is placed above the scalp. A rapidly changing magnetic field is produced, oriented orthogonally to the plane of the coil that passes unimpeded through the tissues of the head. The changing magnetic field, in turn, causes a much weaker electrical current to flow in the conductive medium of the brain. If current amplitude, duration and direction

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20 are appropriate, they will depolarize cortical neurons and generate action potentials (Rothwell et al., 1999). When applied over a muscle representation in the motor cortex, TMS generates a motor evoked potential (MEP), which may be quantified by means of electromyography. Thus, magnetic fields painlessly penetrate tissues and induce electric currents, which can depolarize nerve cells and axons and generate an MEP at the muscle of interest. TMS, using a figure-of-eight coil, has a spatial resolution of 5mm and a temporal resolution in the order of a few milliseconds (Weiller, 1998). Depth of stimulation of the cerebral cortex is approximately 1.5 to 2 cm from the surface of the coil (Epstein, Schwartzberg, Davey, & Sudderth, 1990; Rudiak & Marg, 1994), translating to activation of neurons superficial to output layer V (Sanes & Donoghue, 1997). Due to the perpendicular orientation of the magnetic field to the brains surface, TMS is thought to activate intracortical axons and horizontally oriented interneurons rather than cortical output cells directly (Di Lazzaro et al., 1998; Rothwell, Thompson, Day, Boyd, & Marsden, 1991). TMS has several advantages as a neurophysiologic tool. The technique is non-invasive; does not require movement from the subject; has a high temporal and spatial resolution; and is relatively inexpensive to administer. While PET and fMRI take up to two or 3 hours to administer, a complete map of swallow representation may be performed in 1 hour using TMS. Additionally, TMS may be performed while the subject is comfortably seated in a reclined position (whereas fMRI requires the subject to be in a loud and potentially claustrophobic space). In contrast to a PET examination, TMS does not require harmful exposure to radiation. A major benefit of TMS is that it requires no

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21 movement from the subject. This benefit is especially valuable when studying stroke survivors, as the ability to move may be limited and highly variable from person to person. TMS can be used to study different parameters of motor cortex excitability. The method typically employed for mapping a muscle is to apply a standard stimulus to a grid of points distributed across the scalp and record the resulting MEPs. Plotting the average MEP amplitude evoked at each site against the site’s Cartesian coordinates generates a map of the motor representation for a target muscle (Wassermann, Cohen, & Hallet, 2000). Five different measures may be extracted from a typically TMS motor mapping exam. These include: motor map area; motor map volume; optimal stimulation site location; optimal stimulation site size; and motor threshold. Each measure reveals a different facet of the of the corticomotor representation of a specific function. The aforementioned TMS mapping variables will be briefly described in turn. A summary of TMS mapping measures is provided in Table 1.1. Motor Map Area Motor map area may be calculated and represents the number of excitable scalp positions found on the mapping grid. These excitable positions are then used to plot a representational map for the muscle of interest, providing a spatial area of cortical representation. The motor map is thought to reflect: (1) the excitability of the motor representation (Siebner & Rothwell, 2003) and (2) the precise location of the muscles representation (Wassermann et al., 1996). Motor Map Volume Motor map volume is the summation of obtained MEP peak-to-peak areas from all active positions within the representation (Mortifee, Stewart, Schulzer, & Eisen, 1994).

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22 This parameter provides information regarding the overall excitability of a motor representation. Optimal Stimulating Site Location The optimal stimulating site location is the grid position of a motor map yielding the highest MEP waveform peak-to-peak area (Thickbroom et al., 1999). The location of the optimal stimulating site is thought to reflect the cerebral location where corticomotor projections to the muscle of interest are most concentrated. Thus this measure provides a single spatial coordinate in the brain for the site of maximal representation. Optimal Stimulating Site Size The optimal stimulating site size is the MEP peak-to-peak area for the maximal MEP on the motor map. While optimal stimulating site location provides a spatial coordinate for the site where corticomotor projections to the muscle of interest are most concentrate, optimal stimulation size provides information regarding the relative strength and excitability of these projections. Motor Threshold Motor threshold may be determined and is defined as the lowest TMS intensity capable of inducing a small MEP from the target muscle (Cohen et al., 1998). Motor threshold is raised by drugs that block sodium channels, but not affected by GABAergic or antiglutamatergic drugs (Ziemann, Rothwell, & Ridding, 1996). Given these pharmacological effects, motor threshold is thought to reflect the neuronal membrane excitability (Chen, 2000). Although TMS has been used extensively to study various components of the corticospinal system, application to the corticobulbar system, and specifically the swallow system, has been limited to only 1 group of researchers. Hamdy et al., (1996)

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23 Table 1-1. Summary of transcranial magnetic stimulation (TMS) mapping measures. TMS Mapping Measure Measure Description Data Quantitation Motor Map Area Spatial area of motor representation # active stimulating sites Motor Map Volume Overall excitability of motor representation waveform peak-to-peak areas Optimal Stim. Site Location Cerebral location where corticobulbar projections to muscle of interest is most concentrated Distance (cm) from vertex (y) and intra-aural line (x) Optimal Stim. Site Size Excitablity / strength of motor representation at maximal site Peak-to-Peak area for the largerst obtained MEP site Motor Threshold Threshold of corticobulbar excitation Lowest stimulus intensity (%) largerst obtained MEP site reported the first in a series of studies utilizing TMS for the study of swallow topography in health and disease. These authors studied the topographic representation of oral, pharyngeal and esophageal musculature in the human motor cortex across 20 normal healthy volunteers. Hamdy et al.’s (1996) seminal paper reported a bilateral and asymmetric representation of swallowing musculature. Hemispheric dominance was found to be inconsistent amongst subjects and not related to handedness. The results of this influential study are 1 of the most highly referenced works regarding swallow topography. Of concern is the fact that no other group of investigators has attempted to replicate these works using TMS and validate Hamdy et al.’s preliminary findings. An additional concern with the interpretation of Hamdy and colleagues (1996) results is that the reliability of TMS mapping techniques has not, to date, been adequately established. Though TMS has been utilized in over 2,700 published studies, alarmingly only 6 papers report the reliability of TMS mapping procedures over time (Kamen, 2004; Malcolm, 2003; McDonnell, Ridding, & Miles, 2004; Mortifee et al., 1994; Uy, Ridding, & Miles, 2002; Wolf et al., 2004). This fundamental oversight is of particular concern to

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24 the recent application of TMS to map motor representations serially over time following treatment intervention as an index of activity-dependent neural plasticity. Establishing the reliability of TMS, and limits of normality within the nervous system, are essential factors that need to be determined prior to future claims of activity-dependent reorganization/plasticity. Considering the importance of obtaining reliable TMS results, it is somewhat surprising that there is relatively little data detailing the conditions required to obtain statistically reliable results. Although the 6 cited TMS reliability papers are important early studies, most of them have methodological and statistical issues that cast doubt on their validity. Mortifee and colleagues (1994) published the first paper on the reproducibility of TMS mapping in the aductor pollicis brevis (APB) and abductor digiti minimi (ADM) hand muscles. These authors reported that the map area and map volume for both intrinsic hand muscles were relatively stable across time (ICC=0.63-0.85). Although this is important seminal work with a robust method for statistical analysis, there are a number of limitations to the study. First, Mortifee et al’s results are based on the investigation of only 6 subjects. Such a small sample size casts doubt on the generalizability of the authors’ findings. Second, only 1 of the two muscles studied was reliable above the suggested significance level for replication of results (i.e. ICC index >0.75; Fleiss, 1986; Portney & Watkins, 2000). Third, these investigators used a circular coil rather than the more focal figure-of-eight coil that is the standard of practice for TMS motor mapping. Thus, the results of this study may not be applicable to most mapping studies. Fourth, the group did not average MEP responses over a set number of stimuli per site. This is now standard practice in mapping research. Fifth, only two TMS measures (map area and volume)

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25 were examined for reliability. Other TMS variables such as optimal stimulation location and size, and motor threshold could have been assessed to provide important information on the reliability of available TMS mapping variables. Finally, several technical issues were not delineated such as: How was the stimulus grid referenced from session to session? Did motor threshold change from session to session? Was stimulus intensity kept constant from session to session? Each of these issues would likely affect the motor map. In the case of the later two, transient changes in motor threshold could affect the size and shape of the motor map. With an n=6, the effect of such transient changes could not be adequately accounted for. Following Mortifee and colleagues (1994) seminal works, McMillian et al. (1998), Uy et al. (2002) and Wolf and colleagues (2004) published studies documenting good reliability for TMS mapping over time. Similar methodological limitations can be found in these works such as the use of small sample sizes (samples sizes were 7, 8 and 9 respectively). The most fundamental flaw in these 3 studies however, is that these authors did not use an adequate statistical analysis to determine reliability. Specifically a repeated measures ANOVA was used to determine significant differences between testing sessions. Only if a significant difference was found between testing session, was the technique thought to be unreliable. With alpha set at 0.05, the chance that the two testing sessions could be different (and deemed unreliable) was only 5%. This design heavily favors an outcome of so called ‘good reliability’. This limitation is quite apparent in Uy and colleagues’ (2002) work who reported for map area an F score of 2.4, with a corresponding probably value equal to 0.09. These results indicated to the authors that there was no statistically significant difference between testing sessions and they

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26 therefore concluded that TMS mapping was stable over time (although the low probability value approached significance suggesting that there might have been a trend for a difference). More recently, Kamen (2004) investigated the test-retest reliability for the biceps and first dorsal interosseous (FDI) muscles using the ICC. Kamen studied the reproducibility of these arm muscles at 3 different stimulation intensities (100%, 85% and 70%) and at the biceps site, reliability was assessed for two different conditions, in a relaxed state (muscle resting) and an active state (muscle contracted). With a sample size of 14, these works stand as the largest reliability study to date. Kamen (2004) reported moderate to good reproducibility for the biceps (relaxed: 0.95-0.99; active: 0.68-0.79) and FDI (relaxed: 0.60-0.81) muscles with reliability index observed to differ across stimulation intensity levels. Kamens’ work revealed 3 interesting findings: (1) reliability was higher for the biceps than the FDI muscle site across all measures and intensities in analogous states, (2) for the biceps, the resting condition was found to be more reproducible than the active condition, and (3) reliability was observed to vary dependent upon the stimulation intensity employed. These findings unveil influential parameters that might affect the stability of TMS mapping over time. First, level of reproducibility may not be consistent across different muscle sites. Second, different muscle states (resting vs. active) might influence the degree of reliability. Finally, different stimulation intensities might influence obtained motor map stability. Though this eloquent study provides much needed reliability data for TMS mapping, two limitations exist. First, Kamen assessed the reliability of only 1 TMS outcome measure, namely the motor evoked potential

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27 (MEP) amplitude. Mapping studies typically provide data for map area and volume, as well as motor thresholds and site of maximal response. A more informative study would have incorporated these parameters into the analysis. Second, similar to Mortifee et al (1998), Kamen utilized a circular coil rather than the focal figure-of-eight coil. As previously explained, the figure-of-eight coil is the instrument of standard practice in mapping studies. It is therefore hard to gauge the applicability of Kamens’ results for TMS mapping studies. In addition, Kamen only assessed 1 TMS parameter, the obtained MEP amplitude. In a recent dissertation, Malcolm (2003) studied the test-retest reliability of TMS mapping of the first dorsal interosseous (FDI), adductor pollicis brevis (APB), extensor digitorum communis (EDC) and flexor carpi radialis (FCR) muscles. Malcom reported moderate to good reliability, with better reproducibility in the forearm muscle representation as compared to the intrinsic hand muscles. He used rigorous statistical analyses to obtain these findings and unlike any of study, assessed a number of mapping variables (map area, map volume, center of gravity and motor threshold). In addition, Malcom employed an N of 20, making his study the largest to date. A closer look at the 6 TMS mapping reliability studies reveal that all of these studies have investigated corticospinal musculature and specifically hand and arm muscles. To date, no study has documented the reproducibility of TMS mapping for corticobulbar musculature. While the corticospinal system is largely controlled via contralateral pathways, the corticobular system is made up of bilateral and parallel pathways. Kamens’ finding of differential levels of reliability across muscle sites further underscores the necessity to investigate TMS mapping reliability across all corticomotor

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28 systems and muscle sites. Though Hamdy and colleagues have already used this device as an outcome measure over time to track ‘cortical changes’ following therapeutic interventions, no study has yet looked at the reproducibility of TMS motor mapping for the swallow system. Clearly, studies assessing the intra-subject variability across time are critical to assess the potential utility of TMS end points in studies of plasticity. The implementation of any novel procedure requires an understanding of the conditions under which stable and reliable measures can be obtained (Kamen, 2004). As is indicated in this review, reliability of TMS mapping has not yet been established. The present study seeks to remedy this neglect. Specific Aims The proposed study will focus on two specific aims: reliability of TMS cortical mapping procedures and determination of the neural representation of swallowing musculature in the healthy human motor cortex. Aim I To demonstrate the reproducibility of TMS mapping of suprahyoid and pharyngeal constrictor muscles in healthy adults. Specifically: To determine the test-retest reliability of motor map area. To determine the test-retest reliability of motor map volume. To determine the test-retest reliability of the optimal site location. To determine the test-retest reliability of the optimal site size. To determine the test-retest reliability of motor threshold. Hypothesis: Aim I The following physiological characteristics of the cortex, as measured by TMS, will demonstrate good test re-test reliability when assessed over two testing sessions in

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29 healthy individuals: (1) motor map area; (2) motor map volume; (3) optimal site location; (4) optimal site size; and (5) motor threshold. Aim II To define cerebral representation of human swallowing musculature using TMS. Specifically: To determine the topographic representation of suprahyoid and pharyngeal constrictor musculature To determine the relationship of swallow representation to handedness Hypothesis: Aim II Based on the lateralization of function theory, pathological evidence of dysphagia following unilateral stroke and in-vivo human studies, swallowing musculature is hypothesized to display inter-hemispheric asymmetry/functional lateralization in the healthy human cortex. It is hypothesized that cortical representation of swallow musculature will be independent of handedness. Significance of Work Although TMS has been used for two decades, psychometric data concerning the reliability of this neurophysiologic technique has been neglected. This study provides the first piece of data documenting the reliability of TMS for mapping corticobulbar musculature in healthy adults. In addition, as compared to published data, this study stands as the largest TMS reliability study documented to date. This data is crucial to validate the use of TMS in studies of cortical representation and as an endpoint in treatment/plasticity studies. The central neural control mechanism of swallowing is not completely understood (Daniels et al., 2002). The incidence of dysphagia together with the serious

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30 consequences across all domains of health has necessitated a greater understanding of normal swallow physiology. With proven reliability across the two testing sessions, these works provide information concerning the cerebral representation of swallowing musculature in healthy adults. These add to the literature concerning hemispheric lateralization in the intact human brain. Summary The incidence of dysphagia, coupled with its impact on health, fiscal, social and quality of life domains have necessitated a greater understanding of the central mechanisms governing swallow function. Two competing hypotheses have been put forth: lateralization of function vs. bilateral representation of swallow function. While both physiological and pathophysiological data strongly implicate a role of the cerebral cortex in the control of swallowing, the functional organization remains unclear (Kern et al., 2001; Mosier et al., 1999). Hamdy et al. (1996) provided the seminal investigation into healthy swallow topography using TMS and reported a bilateral yet asymmetric representation of swallow musculature that was not related to handedness and inconsistent among subjects. To date, no other investigator has attempted to validate these findings. In addition, basic psychometric data on TMS mapping is critically lacking. No study has investigated the test-retest reliability of TMS to map corticobulbar musculature, casting caution on interpretation of Hamdy and colleagues data. The aim of the proposed investigation is to: (1) demonstrate the reproducibility of TMS mapping of oral and pharyngeal swallow musculature, and if found reliable (2) define cerebral representation of human swallowing musculature using TMS. The results of this study will provide much needed psychometric data validating the use of TMS. If this technique is found to be reliable, this study will delineate the organization of

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31 projections from the motor cortex to the oral and pharyngeal swallow muscles. Results will provide a better understanding of the swallow process, which may help in the development of therapeutic interventions that can drive neural plasticity and facilitate recovery of swallow function.

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CHAPTER 3 METHODS The previous chapter introduced the purpose of this study as well as the relevant literature touching upon the two areas of investigation. This chapter presents an outline of the methodology employed and has 6 substantive sections. The next section provides details of the subjects who participated in the study. Section two outlines the subject set up and preparation employed. Section 3 describes how determination of the optimal grid stimulation position was achieved. The TMS mapping procedure used is outlined in Section 4, while sections 5 and 6 detail data and statistical analyses respectively. Subjects A total of 20 healthy adult volunteers (12 female, 8 male) aged between 21 and 55 years (mean=30.45, sd=8.23) participated in this study. Four subjects reported being left handed and sixteen right handed. Scores on the Edinburgh Handedness Inventory (Appendices A) ranged between (-20) and (+100) with a mean handedness laterality quotient of +58.75 (sd=52.99). Individual subject demographic data are provided in Table 3.1. Subjects were recruited from a convenience sample and met the following inclusion and exclusion criteria: (1) 18-90 years of age; (2) no history of swallowing problems nor medical conditions that would contribute to dysphagia; (3) normal cognition; (4) no history of neurological damage or disease; (5) no history of psychiatric disease; (6) no history of seizures or epilepsy; (7) no implanted 32

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33 pacemakers or other metal implants in the body or skull; and (8) negative pregnancy test (for females of child bearing potential). Table 3-1. Subject demographics. Subject Age Gender* Handedness Edinburgh Handedness Quotient^ 1 36 M Right +100 2 28 F Right +100 3 27 F Right +90 4 30 F Right +100 5 26 F Right +85 6 26 F Right +75 7 27 F Right +75 8 21 M Left -55 9 42 F Left -20 10 37 M Right +100 11 28 F Right +90 12 41 F Left -30 13 29 F Right +100 14 28 M Right +85 15 22 M Left -50 16 28 M Right +40 17 21 F Right +80 18 27 M Right +60 19 30 M Right +45 20 55 F Right +100 * For gender, M=male and F=female ^ Edinburgh Handedness Inventory Laterality quotient (Oldfield, 1971). The protocol was approved by the University of Florida’s Institutional Review Board and each participant signed a written informed consent prior to his or her participation. Each subject was assessed on two occasions separated by approximately 2 weeks. The exact same procedure was followed in each session. Subject Set Up Subjects were seated in a modified dental chair in the Human Motor Physiology laboratory at Shands Hospital. A pair of passive bipolar surface electrodes (Nicolet Biomedical, Maddison, WI) were prepared with conductive gel and carefully placed on the right and left suprahyoid muscle complex, each 1cm lateral to the midline. Correct

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34 placement was verified by asking the subject to maximally contract the muscles of interest (by performing a tongue press against the hard palate) while the investigator monitored online suprahyoid electromyographic (EMG) activity. A bipolar electrode built into a 3mm diameter intraluminal catheter (Medical Measurements Inc., NJ) was passed trans-orally a standard length (15cm). This position approximated the vertebral level C2-C4 and measured pharyngeal constrictor muscle activity (see Figure 3-1). A ground electrode was prepared with conductive gel and placed on the posterior neck. EMG signals were filtered with a bandpass set at 2-10 kHz, rectified, and amplified with a Viking II Electromyograph (Nicolet Biomedical, Madison, WI). Audio feedback from electromyography was routinely monitored to ensure muscle relation during the testing session. In preparation for marking stimulation coordinates to the scalp, a latex cap was placed on the participant’s head. The vertex (Cz) was marked as the intersection of the nasion-inion and interaural lines. Measurement of these lines (in cm) was recorded to ensure consistent location of the Cz across testing sessions. All TMS stimulation points were recorded in reference to Cz (see Figure 3-2). Figure 3-1. Pharyngeal electrode insitu.

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35 Determination of Optimal Grid Position and Motor Threshold Stimulation was delivered with a Magstim Rapid magnetic stimulator (Magstim Company Limited, UK) through a 5cm mean loop diameter figure-of-eight shaped magnetic coil. The technique for stimulation was performed as described by Wassermann et al. (1992). The coil handle was oriented sagitally, with the handle pointing posteriorly and the figure-of-eight coil situated tangential to the skull (Figure 3-2). With the stimulator set at 75% of the maximum output, and the subject relaxed, the ‘optimal position’ for stimulation was identified and this location recorded in relation to the Cz. The optimal position is defined as the stimulation point that elicits the largest peak-to-peak motor evoked potential (MEP). Once the optimal spot was determined, motor threshold was assessed in a step-wise fashion. Motor threshold is defined as the lowest stimulation intensity that elicits discernable MEPs in at least 5 of 10 consecutive stimulations using an oscilloscope gain of 50V per cm (Thickbroom, Byrnes, & Mastaglia, 1999). TMS Mapping Procedure A 7cm X 7cm grid was marked on the latex cap and centered around the optimal position (49 points, separated by 1cm; see Figure 3-2). The stimulator was set at 115% of the motor threshold and 5 stimuli were delivered to each grid site at a frequency of 0.9Hz. The EMG responses from the 5 stimuli/grid point were rectified and averaged online using Viking II nerve conduction software (Nicolet Biomeidcal, Madison, WI). Each of the 49 grid points were randomly stimulated in accordance to an aproiri randomization schedule to minimize possible stimulation order effects or cross contamination from adjacent neurons. Hemisphere stimulation order (right or left) was counterbalanced across subjects to minimize any possible hemisphere stimulation order

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36 effects. For an individual subject, however, the exact same stimulation order was maintained across testing sessions. In considering the test-retest reliability of mapping motor representations with TMS, we recognized that changes in motor threshold between testing sessions could occur and might influence the mapping results. Therefore, the same intensity of stimulation (115% of motor threshold determined in testing session 1) for both testing sessions was used. Figure 3-2. Location of the vertex (Cz), interaural and nasion-inion lines, stimulating grid, and figure-of eight coil orientation of the head (adapted from Malcolm, 2003).

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37 Data Analysis MEP peak-to-peak area was determined by visual inspection of rectified waveforms using the Viking III software and specific latency and appearance criteria. Onset of MEP waveform was defined as the first upward deflection leading into a MEP waveform. To be considered a cortical response, latency needed to be >8 milliseconds (earlier waveforms were excluded and considered non-cortical). Offshoot of the MEP waveform was marked, using visual inspection, at the first point where the waveform returned to the resting baseline level. An example of MEP waveforms from a single site is provided in Figure 3-3. Figure 3-3. Example of obtained MEPs for the right suprahyoid, left suprahyoid and pharynx respectively.

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38 Five TMS outcome measures (motor map area, motor map volume, optimal stimulation site location & size, and motor threshold) were calculated for the suprahyoid and pharyngeal swallow musculature and used to assess the test-retest reliability of TMS mapping. Motor Map Area Motor Map Representational Area was quantified as the number of stimulus sites producing MEPs > 10% of the maximal peak-to-peak MEP area. Obtained excitable grid positions provided a spatial area of cortical representation for the suprahyoid and pharyngeal constrictor muscles. The motor map is thought to reflect: (1) the excitability of the motor representation (Siebner & Rothwell, 2003) and (2) the precise location of the muscles representation (Wassermann et al., 1996). Motor Map Volume Motor map volume represented the sum of all peak-to-peak MEP areas in a given hemisphere. This parameter provided information regarding the overall excitability of a given motor representation. Optimal Stimulating Site Location The optimal stimulating site location constituted the scalp position producing the largest peak-to-peak MEP area and was identified separately for suprahyoid and pharyngeal swallow musculature. This cortical location was indexed in relation to the Cz and designated by a medial-lateral and anterior-posterior coordinate (in cm). The optimal stimulating site is thought to reflect the cerebral location where corticomotor projections to the muscle of interest are most concentrated. Thus this measure provided the spatial coordinates in the brain for the site of maximal suprahyoid and pharyngeal representation.

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39 Optimal Stimulating Site Size The optimal stimulating site size constituted the value of the largest peak-to-peak MEP area on the scalp grid for each muscle of interest. While optimal stimulating site location provided a spatial coordinate for the site where corticomotor projections to the swallow musculature was most concentrated, optimal stimulation size provided information regarding the relative strength and excitability of these corticobulbar projections. Motor Threshold Motor threshold was quantified as the lowest stimulation intensity (%) that elicited discernable MEP’s in at least 5 of 10 consecutive stimulations (>50V). Motor threshold was determined only for the suprahyoid muscle complex only. Motor threshold is raised by drugs that block sodium channels, but not affected by GABAergic or antiglutamatergic drugs (Ziemann, Rothwell, & Ridding, 1996). Given these pharmacological effects, motor threshold is thought to reflect the neuronal membrane excitability (Chen, 2000). A description of each TMS outcome measure is summarized in Table 3-2. Table 3-2. Summary of transcranial magnetic stimulation (TMS) outcome measures. TMS Mapping Measure Measure Description Data Quantitation Motor Map Area Spatial area of motor representation # active stimulating sites Motor Map Volume Overall excitability of motor representation waveform peak-to-peak areas Optimal Stim. Site Location Cerebral location where corticobulbar projections to muscle of interest is most concentrated Distance (cm) from vertex (y) and intra-aural line (x) Optimal Stim. Site Size Excitablity / strength of motor representation at maximal site Peak-to-Peak area for the largerst obtained MEP site Motor Threshold Threshold of corticobulbar excitation Lowest stimulus intensity (%) to produce a discernable MEP

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40 Statistical Analyses To assess TMS mapping test-retest reliability (Aim I) an intraclass correlation coefficient (ICC) analysis was performed on TMS measures of motor map area, motor map volume, optimal stimulating site location, optimal stimulating site size, and motor threshold. The ICC statistic is the preferred index of reliability, as it reflects both the degree of association and agreement between the two test session findings (Portney & Watkins, 2000). The two-way mixed model (3,1) using absolute agreement was utilized. An ICC > 0.75 is generally considered high, while those below 0.75 are indicative of moderate to poor reliability (Fleiss, 1986; Portney & Watkins, 2000) To investigate the cerebral representation of oral and pharyngeal swallow musculature (Aim II), mapping data for each subject from Test I was used. To explore evidence of hemispheric asymmetry (Aim II: Part 1), mean differences between right and left hemisphere activations were tested for statistical significance for each TMS measure (map area, map volume, optimal stimulating site location, optimal stimulating site size, and motor threshold) using a t-test across with alpha set at 0.05. In addition, a symmetry ratio (%) (Hamdy et al., 1996) was calculated for each muscle of interest whereby hemisphere activation was expressed as a ratio of the activation within 1 hemisphere to the total bilateral activation. The symmetry ratio was quantified as the difference between sum peak-to-peak MEP areas (i.e. motor map volumes) for the right and left hemispheres divided by the total (right + left hemisphere) cerebral MEP area. Thus, the symmetry ratio represents the relative muscle motor excitation in a given hemisphere. This formula is provided in Equation 3-1.

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41 areapeak -to-peak Totalareapeak -to-peak hem.Right areapeak -to-peak hem.Left RatioSymmetry Equation 3-1. Formula for the Symmetry Ratio The range of possible scores for the symmetry ratio ranges between (-100) and (+100). A positive score indicates left hemisphere dominance, while a negative score indicates right hemisphere dominance. The further the score is away form zero, the stronger the lateralization for a given hemisphere. Ratios at or close to zero are thought to represent an indeterminate / non-equivalent dominance. To assess the relationship between handedness and inter-hemispheric swallow asymmetry (Aim II: part 2), a Spearman’s correlation analysis was performed between the Edinburgh handedness inventory (Oldfield, 1971) laterality quotient and obtained swallow symmetry ratios.

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CHAPTER 4 RESULTS I: TEST-RETEST RELIABILITY The previous chapter outlined the methodology of the present study. The current chapter details the test-retest reliability results for TMS mapping of swallow representation (Aim I). This chapter consists of 6 substantive parts. The first 5 parts present reliability results for the motor map area, motor map volume, hot spot location, hot spot size, and motor threshold respectively. This chapter will end by way of summary and conclusion. Motor Map Area Reliability Motor map area was assessed as an indicator of swallow spatial representation stability across testing sessions. The mean number of MEP sites and associated intraclass correlation coefficient indices are shown in Table 4-1. Overall motor map area was found to show good stability over the two testing sessions for both suprahyoid (ICC=0.91) and pharyngeal (ICC=0.76) muscle sites. Table 4-1. Mean motor map area for Test I and II and obtained ICC results. Muscle Mean Area (SD) Test I Mean Area (SD) Test II ICC Suprahyoids 15.78 (7.64) 17.64 ( 9.08) 0.91 Pharynx 15.00 (7.66) 17.28 (12.55) 0.76 Motor Map Volume Reliability Motor map volume was assessed as an indicator of the total MEP size across sessions. The mean sum peak-to-peak MEP areas and corresponding ICC indices are presented in Table 4-2. Test-retest reliability was observed to be moderate for the suprahyoid (ICC=0.70) and pharyngeal muscle site (ICC=0.68). 42

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43 Table 4-2. Mean map volume for Test I and II and obtained ICC results. Muscle Mean Area (SD) Test I Mean Area (SD) Test II ICC Suprahyoids 28.22 (25.93) 36.03 (53.18) 0.70 Pharynx 15.53 (16.69) 19.82 (41.53) 0.68 Optimal Simulation Site Location Reliability Optimal stimulation site location was assessed as an indicator of stability of the maximal MEP cortical location. The lateral (y, distance from Cz) and anterior-posterior ( + x, distance from interaural line) coordinates of the optimal site of each motor map were analyzed separately for the test-retest reliability. The lateral distance (y) of the hotspot displayed good test-retest reliability for both suprahyoid (ICC=0.97) and pharyngeal (ICC=0.98) sites. The anterior-posterior optimal site coordinate demonstrated moderate stability across testing sessions with ICC indices of 0.68 and 0.74 for the suprahyoid and pharyngeal sites respectively. Thus the lateral coordinate was observed to be the more stable coordinate across testing sessions. Mean optimal stimulation site location coordinates for each muscle of interest are displayed in Figure 4-1. Obtained ICC results are shown in Table 4-3. Table 4-3. Optimal stimulation site location and associated ICC values. Muscle Ant-Post Coord. ICC Lateral Coord. ICC Suprahyoids 0.68 0.97 Pharynx 0.74 0.96 Optimal Simulation Site Size Reliability The optimal stimulation site size (highest obtained MEP peak-to-peak area) was assessed as an indicator of stability of maximal MEP size/excitation across testing sessions. As is indicated in Table 4-4, both swallow muscle groups displayed good MEP peak-to-peak area reproducibility at the site of maximal response across testing sessions.

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44 3 Figure 4-1. Comparison of mean optimal stimulation site location for each muscle across testing sessions. Table 4-4. Mean optimal stimulation site size (highest obtained MEP peak-to-peak area) across testing sessions with obtained ICC results. Muscle Mean Area (SD) Test I Mean Area (SD) Test II ICC Suprahyoids 4.01 (2.88) 4.28 (3.32) 0.78 Pharynx 2.28 (2.12) 2.38 (3.36) 0.76 Motor Threshold Reliability Motor threshold was assessed as an indicator of stability for corticobulbar excitation. Motor threshold displayed excellent stability over testing sessions as indexed by an ICC of 0.98. Mean motor threshold data for both hemispheres are shown in Table 4-5. Table 4-5 . Mean motor threshold across testing sessions and obtained ICC index. Muscle Mean Area (SD) Test I Mean Area (SD) Test II ICC Suprahyoids 61.14 (9.87) 59.32 (9.42) 0.98 1 1.5 2 2. 5 9 9.5 10 10.5 11 lateral distance from Cz (cm) R. Suprahyoid R. Suprahyoid Test I Test II L. Suprahyoid L. Suprahyoid Pharynx Pharynx Ant-Post distance from Cz (cm)

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45 Summary of Reliability Results This chapter provides test-retest reliability results for TMS mapping of swallow musculature. In general, results of the present study support the hypothesis that TMS mapping will be stable over time. TMS mapping measures were seen to demonstrate moderate – excellent reliability with ICC indices ranging from 0.68 – 0.98, dependent upon measure. Motor map area, hot spot location: lateral coordinate, hot spot size and motor threshold measures exceeded the ICC threshold value ( > 0.75) for significant replication of results (Portney and Watkins, 2000). Map volume and hot spot location: anterior coordinate measures did not pass this threshold, however demonstrated moderate reproducibility over testing sessions. A summary table of obtained ICC indices for each measure across muscle sites is provided in Table 4-6. The next chapter presents topographic data for the motor representation of swallowing musculature (Aim II). Table 4-6. Summary of test-retest reliability results for swallow muscles across TMS measures. Muscle Map Area Map Volume Optimal Site Location Anterior Lateral Optimal Site Size Motor Threshold Suprahyoids 0.91* good 0.70 moderate 0.68 moderate 0.97* good 0.78* good Pharynx 0.76* good 0.68 moderate 0.74 moderate 0.98* good 0.76* good 0.98* good *Met or exceeded the threshold value for a significant replication of results of ICC > 0.75. Qualitative scores are based on the following scale of ICC values: > 0.75=good, 0.50-0.74= moderate, <0.50 = poor reliability (Portney & Watkins, 2000).

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CHAPTER 5 RESULTS II: TOPOGRAPHIC REPRESENTATION OF SWALLOW MUSCULATURE The previous chapter presented test-retest reliability results (Aim I). As these results revealed an acceptable level of reliability, topographic details of swallow representation will be detailed in the current chapter. Chapter 5 consists of 8 substantive parts. Parts 1-6 detail topographic results for motor map area, motor map volume, hot spot location, hot spot size, motor threshold, and symmetry ratios respectively (Aim II: Part I). The seventh section provides results concerning the relationship between handedness and swallow representation (Aim II: Part II). This chapter will end by way of summary and conclusion. Motor Map Area Individual subject motor map area data are presented in Table 5-1. All individuals displayed a bilateral, yet asymmetric swallow motor map area. Inter-hemispheric asymmetry was present in all subjects and across all muscle sites. Side of lateralization varied across subjects, with some subjects lateralizing to the left hemisphere and others to the right hemisphere. The majority of subjects (number provided in parentheses) lateralized to the left hemisphere for the pharynx (14/20), right suprahyoid (13/20) and left suprahyoid (11/20) suprahyoid muscle sites. Group data revealed, on average, a larger motor map area in the left hemisphere across all swallow muscles of interest (Table 5-2, Figure 5-2). A t-test of right vs. left motor map area revealed a statistically significant difference between hemisphere motor 46

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47 map area for the right suprahyoid muscle site [t(19)= -2.59, p=0.02]. Mean motor map area for each hemisphere and obtained t-test results are provided in Table 5-2. Table 5-1. Individual motor map area data. Subject Hem. Map Area R. Suprahoid Map Area L. Suprahyoid Map Area Pharynx Right 14 18 22 1 Left 8 8 14 Right 27 28 22 2 Left 25 17 26 Right 21 23 3 3 Left 24 26 5 Right 8 14 12 4 Left 18 8 4 Right 19 18 10 5 Left 18 23 30 Right 24 19 3 6 Left 33 33 19 Right 14 15 19 7 Left 24 20 25 Right 1 1 6 8 Left 6 10 19 Right 22 25 25 9 Left 21 15 23 Right 21 29 32 10 Left 22 24 10 Right 2 2 7 11 Left 12 11 17 Right 2 1 4 12 Left 8 9 3 Right 18 14 12 13 Left 22 32 19 Right 35 39 43 14 Left 28 19 21 Right 22 21 21 15 Left 16 17 29 Right 21 28 18 16 Left 22 14 17 Right 4 11 30 17 Left 23 22 34 Right 10 11 5 18 Left 20 20 15 Right 1 1 9 19 Left 6 1 16 Right 15 14 35 20 Left 17 15 43

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48 Table 5-2. Mean motor map area (standard deviation) for the right and left hemisphere with associated p-value. Muscle Right Hem. Mean (SD) Left Hem. Mean (SD) p-value R. Suprahyoid 15.05 ( 9.69) 18.60 ( 7.42) .03* L. Suprahyoid 16.60 (10.47) 17.20 ( 8.20) .80 Pharynx 16.90 (11.74) 19.45 (10.10) .31 * Statistically significant at = 0.05 25 20 Mean number of MEP sites. 15 Right Hem. Left Hem. 10 5 0 R. Suprahyoid Pharynx L. Suprahyoid Muscle of Interest Figure 5-1. Mean motor map area for swallow musculature across hemispheres. Motor Map Volume Individual motor map volume data are presented in Table 5-4. Swallow map volume inter-hemispheric asymmetry was present in all subjects and across all muscle sites. Inter-individual differences for side of lateralization were again noted. The majority of subjects lateralized to the left hemisphere for the pharynx (17/20), right suprahyoid (14/20) and the left suprahyoid (11/20) muscle sites. Group data revealed, on average, higher motor map volumes (i.e.-more excitable motor representations) in the left hemisphere across all swallow muscles of interest.

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49 Statistical analysis revealed this difference was statistically significant a the pharyngeal site [t(19)= -2.14, p=0.04]. Mean group data are presented in Table 5-3 and Figure 5-2. Table 5-3. Mean motor map volume (standard deviation) across hemispheres with associated p-value. Muscle Right Hem. Mean (SD) Left Hem. Mean (SD) p-value R. Suprahyoid 16.66 (16.42) 25.42 (28.05) .13 L. Suprahyoid 21.33 (23.88) 30.89 (49.14) .40 Pharynx 17.39 (21.41) 26.86 (36.25) .04* Statistically significant at = 0.05. 05101520253035R. SuprahyoidL. SuprahyoidPharynxMuscle of InterestMotor Map Volume Right Hem. Left Hem. F igure 5-2. Mean motor map volume for the right and left hemisphere Optimal Stimulation Site Location Mean optimal stimulation site location coordinates (lateral and anterior-posterior distance in cm from Cz) are presented in Table 5-5. Group data revealed a tight, overlapping and non-distinct maximal MEP location for each swallow muscle of interest. Due to the size of the raw data for this particular outcome measure (12 data points per subject), only group data are presented here.

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50 Table 5-4. Individual subject data for motor map volume. Subject Hem. Map Area R. Suprahoid Map Area L. Suprahyoid Map Area Pharynx Right 8.1 13.1 36.5 1 Left 8.0 4.9 53.6 Right 51.7 51.6 88.2 2 Left 63.9 49.7 165.7 Right 7.1 11.3 .4 3 Left 6.0 6.4 .5 Right 2.1 16.1 7.6 4 Left 18.8 6.5 1.0 Right 27.4 76.6 5.3 5 Left 122.8 60.15 12.7 Right 17.2 27.2 .4 6 Left 19.7 223.6 3.8 Right 23.8 23.5 12.7 7 Left 49.7 46.4 52.5 Right .3 .5 1.9 8 Left 1.3 2.8 5.7 Right 13.4 18.1 20.6 9 Left 28.5 15.9 24.4 Right 34.7 14.8 7.2 10 Left 22.1 18.0 10.8 Right .5 .5 11.1 11 Left 15.3 12.3 14.4 Right .9 1.1 .7 12 Left 2.7 3 12.5 Right 5.1 9.7 8.8 13 Left 24.2 16.1 19.0 Right 6 7.3 13.8 14 Left 29.2 26.1 19.6 Right 35.6 17.2 30.8 15 Left 16.3 14.4 35.5 Right 49.2 87.9 49.8 16 Left 18.4 6.9 28.5 Right 3.7 17.6 21.3 17 Left 15.9 22.4 39.5 Right 29 13.9 .7 18 Left 39.2 61.2 2.8 Right .8 .8 24.8 19 Left 1.4 .1 21.6 Right 16.7 17.1 5.2 20 Left 5.10 20.9 13.1

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51 Table 5-5. Mean location (in cm from Cz) of the maximal MEP for both hemispheres. Muscle of Interest: Right Hemisphere (lat, ant-post coord.) Left Hemisphere (lat, ant-post coord.) R. Suprahyoid 9.3, 1.2 9.6, 0.9 L. Suprahyoid 9.3, 1.2 9.8, 1.2 Pharynx 9.5, 2.7 9.7, 1.5 Optimal Stimulation Site MEP Size Individual data for optimal stimulation site MEP size are provided in Table 5-7. Similar to other TMS map measures, hot spot size demonstrated hemispheric asymmetry that was inconsistent across subjects. Group data revealed the largest MEP peak-to-peak area was, on average, found to in the left hemisphere for all swallow muscles. Group data are displayed in Figure 5-3 and Table 5-6. Statistical analysis of right vs. left hot spot MEP size revealed a significant difference for the pharynx [t(19)= -2.01, p=0.05]. Table 5-6. Mean (standard deviation) maximal MEP peak-to-peak area across hemispheres with associated p-value. Muscle Right Hem. Mean (SD) Left Hem. Mean (SD) p-value R. Suprahyoid 1.99 (1.73) 2.44 (1.62) .30 L. Suprahyoid 2.23 (1.62) 3.01 (2.93) .27 Pharynx 2.21 (2.04) 3.37 (3.14) .05* 00.511.522.533.54R. SuprahyoidL. SuprahyoidPharynxMuscle of InterestHot Spot MEP Size Right Hem. Left Hem. Figure 5-3. Mean optimal stimulation site MEP peak-to-peak area for the right and left hemisphere.

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52 Table 5-7. Individual data for optimal stimulation site MEP size. Subject Hem. Hot Spot Size R. Suprahyoid Hot Spot Size L. Suprahyoid Hot Spot Size Pharynx Right 1.4 1.9 3.9 1 Left 3.2 1.2 7.5 Right 4.2 3.8 6.8 2 Left 5.9 5.6 12.7 Right .6 1.1 .2 3 Left .9 .6 .1 Right .5 2.6 1.2 4 Left 3.5 2.2 .3 Right .7 3.9 .8 5 Left 5.7 3.2 .7 Right 2 2.8 .2 6 Left 1.2 13.2 .4 Right 3.6 3.1 1.5 7 Left 4.4 5.1 5.7 Right .3 .6 .7 8 Left .4 .5 1 Right 1.5 2.3 2.4 9 Left 2.5 2.6 2.9 Right 4.3 1.2 .7 10 Left 2.5 1.9 3.1 Right .4 .3 4.7 11 Left 2.5 2.3 2.6 Right .4 .9 .3 12 Left .5 .7 7.3 Right 1.2 1.9 1.7 13 Left 2.2 1.4 3.8 Right .5 .6 3 14 Left 2.5 5 3.1 Right 3 2.5 3.5 15 Left 2.8 2.4 5.5 Right 5.1 7.4 6.2 16 Left 2.1 1.2 3 Right 1.3 2.9 .9 17 Left 1.6 2.8 3.5 Right 5.8 1.7 .3 18 Left 3.5 5.6 .6 Right .8 .8 4.2 19 Left .3 .1 2.9 Right 2.2 2.4 1 20 Left .7 2.7 .7

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53 Motor Threshold Individual motor threshold data (Table 5-8) revealed that 13/20 subjects (65%) displayed lower motor thresholds in the left hemisphere. The remaining 7 subjects displayed equivalent motor thresholds across hemispheres. Mean motor threshold was lower for the left hemisphere (mean=57.25, sd=10.32) than the right hemisphere (mean=66.00, sd=10.95). A t-test reveled this difference to be statistically significant [t(19)= 4.21, p<0.001]. Table 5-8. Individual motor threshold (%) values for the right and left hemisphere. Subject Motor Threshold Right Hemisphere Motor Threshold Left Hemisphere 1 55 55 2 55 55 3 55 50 4 55 55 5 60 60 6 55 45 7 60 50 8 60 40 9 75 65 10 75 75 11 75 50 12 70 40 13 75 55 14 60 55 15 65 65 16 90 75 17 90 75 18 60 60 19 65 60 20 65 60 Symmetry Ratio Individual symmetry ratio data are provided in Table 5-9. As with other TMS mapping measures, inter-individual variation was present. Group data revealed asymmetric swallow motor representations. The left hemisphere emerged as the dominant hemisphere across all muscle sites, though the degree of lateralization varied

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54 dependent on muscle site. On average, the pharynx displayed the greatest degree of asymmetry (mean symmetry ratio =64%, followed by the right suprahyoid site (mean symmetry ratio = 63%) and finally the left suprahyoid site (mean symmetry ratio = 55%). Group data are presented in Figure 5-4. 70 60 64 63 55 1020304050Mean Symmetry Ratio (%) 45 Right Hemisphere 37 Left Hemisphere 36 0 R. Suprahyoid L. Suprahyoid Pharynx Muscle of Interest Figure 5-4. Mean symmetry ratios for each muscle site. A representative subject’s cortical map displaying the spatial map area, map volume, hot spot location and relative inter-hemispheric asymmetry is provided in Figure 5-5. Relationship Between Handedness and Swallow Representation No relations were found between handedness and swallow motor representation. A Spearmans correlation analysis between the Edinburgh handedness laterality quotient and obtained swallow muscle symmetry ratios revealed no significant correlations. Results are provided in Table 5-10.

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55 Table 5-9. Individual symmetry ratio data. Subject Hem. Symmetry Ratio R. Suprahyoid Symmetry Ratio L. Suprahyoid Symmetry Ratio Pharynx Right 50 73 40 1 Left 50 27 60 Right 45 51 35 2 Left 55 49 65 Right 54 64 44 3 Left 46 36 56 Right 10 71 88 4 Left 90 29 12 Right 18 56 29 5 Left 82 44 71 Right 46 11 10 6 Left 54 89 90 Right 32 34 19 7 Left 68 66 81 Right 19 15 25 8 Left 81 85 75 Right 32 53 46 9 Left 68 47 54 Right 61 45 40 10 Left 39 55 60 Right 3 4 43 11 Left 97 96 57 Right 25 27 5 12 Left 75 73 95 Right 21 38 18 13 Left 79 62 82 Right 17 22 41 14 Left 83 78 59 Right 69 54 46 15 Left 31 46 54 Right 73 93 64 16 Left 27 7 36 Right 19 44 20 17 Left 81 56 80 Right 42 18 20 18 Left 58 82 80 Right 36 89 53 19 Left 64 11 47 Right 78 45 28 20 Left 22 55 72

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56 Left Hemisphere Right Hemisphere Pharynx 1.5cm a nt 1cm ant Right Suprahyoid 0cm ant 1cm post Left Suprahyoid Figure 5-5. Swallow map for representative subject showing both spatial area of representation (presence/absence of grid shading) and relative excitability of representation (relative color of grid white-grey-black shading scale). The maximal elicited MEP (optimal stimulation site) is shaded black and all other site MEPs are depicted as a percentage of this maximal site on a white-gray-black scale. 0.5cm ant 3cm a nt

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57 Table 5-10. Results from correlation analysis between handedness laterality quotient and swallow symmetry ratio. Muscle Spearmans r s value p-value R. Suprahyoid -.38 .09 L. Suprahyoid -.27 .24 Pharynx .07 .77 Summary of Swallow Topography Results The results of the present study support the lateralization of swallow function hypothesis. Swallow motor representation was found to display a bilateral yet clearly asymmetric representation. While side of lateralization demonstrated inter-individual variation, the left hemisphere emerged as the dominant hemisphere for the majority of subjects. On average, the pharynx and right and left suprahyoid muscle sites displayed larger motor map areas, motor map volumes, hot spot sizes and symmetry ratios in the left hemisphere. Further, mean motor threshold (corticobulbar excitation threshold) was significantly lower in the left hemisphere.

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CHAPTER 6 DISCUSSION The previous two chapters presented data regarding the test-retest reliability of TMS mapping techniques and the topographic organization of swallowing musculature respectively. This chapter provides a discussion of these results and consists of 4 substantive sections. First, a summary of obtained results will be provided. A discourse of obtained TMS reliability results for each measure will follow with strengths, limitations and suggested future directions provided. The third section will explicate swallow topography findings across all TMS measures and discuss strengths, limitations and suggested future directions. This chapter will end by way of summary and conclusion. Summary of Results The results of the present study demonstrate that TMS measures of motor representation size, organization and excitability are reliable across multiple testing sessions for both oral and pharyngeal muscle sites. Map area, optimal site location: lateral coordinate, optimal site size and motor threshold all displayed good stability for the suprahyoid and pharyngeal muscles. Map volume and optimal site location: anterior-posterior coordinate displayed moderate reproducibility across the two testing sessions for both muscles. Swallow topography displayed a bilateral yet asymmetric representation across all subjects. Though individual variation were noted, on average; map area, map volume, optimal site location and optimal site location size were larger in the left hemisphere. In addition, mean motor threshold (i.e. corticobulbar threshold) was 58

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59 significantly lower in the left hemisphere. No relationship emerged for handedness and swallow representation. The following sections provide an in-depth discussion on the study findings for each TMS measure employed for test-retest reliability and swallow topography respectively. Reliability of TMS Mapping Motor Map Area We found test-retest reliability for motor map area to be good for both swallow muscle sites. This implies that the spatial area of swallow representation was stable over the two testing sessions. The reproducibility of map area in this investigation was similar (Malcolm, 2003) or better (Mortifee et al., 1994; Uy et al., 2002) than reported in previous studies. Though both muscle sites surpassed the criteria level for significant replication of results (i.e. > 0.75, Portney & Watkins, 2000), the suprahyoid site was observed to demonstrate a greater degree of reproducibility (ICC=0.91) than the pharyngeal site (ICC=0.76). This finding of different degrees of stability across specific muscle sites is consistent with previous investigations. While Mortifee and colleagues (1994) reported good reliability for the hypothenar muscle (ICC=0.85), they observed moderate consistency in the thenar muscle (ICC=0.63) with an ICC index difference of 0.22. Similarly, Malcom (2003) reported superior reliability in forearm muscles (ICC: 0.86-0.85) than in intrinsic hand muscles (ICC: 0.60-0.68). Finally, Kamen (2003) reported disparity across muscle site reproducibility for MEP amplitudes. Specifically, the biceps displayed superior stability (mean ICC= 0.97) than the FDI muscle site (mean ICC=0.70) with an ICC index difference of 0.27.

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60 There are several potential factors, both methodological and anatomical, that may have contributed to the observed discrepant map area reliability across muscle sites. First, EMG-related issues may have affected motor map area. The suprahyoid electrodes were clearly visible and we could ensure correct placement and adequate electrode contact to the target muscle. Though the pharyngeal electrode was passed a consistent length through the oral cavity across sessions, we could not actually visualize where the electrode was sitting in the pharynx. It is possible, for instance, that the electrode may have rested on the right pharyngeal wall on 1 testing session and the left pharyngeal wall or posterior pharyngeal wall for the second testing session. Although the depth of electrode placement was consistent across testing sessions, the exact placement at this depth was not. Such subtle changes may have affected the overall stability of the motor map area. Second, in addition to electrode placement, the actual electrodes measuring electromyographic activity for the suprahyoid muscle complex and pharyngeal constrictor muscles differed. While circular surface electrodes were applied to the suprahyoid site, an intraluminal electrode built into a 3mm catheter, recorded electromyographic activity in the pharynx. Third, motor threshold was only recorded for the suprahyoid site. This measure was not obtained for the pharynx as it would have required the subject to have the pharyngeal electrode in place for almost double the testing time and caused considerable subject discomfort and drop outs. It is well documented that changes in motor threshold can significantly alter the obtained motor map area (Thickbroom, Sammut, & Mastaglia, 1998). While we where able to test changes in motor threshold for the suprahyoid muscle

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61 site and attest that this measure was very stable over time (and hence not a potential confounder for map area), we cannot be sure this is true for the pharyngeal site. Any subtle changes in the pharyngeal motor threshold may have contributed to the relatively lower stability of pharyngeal map area across testing sessions. Finally, inherent anatomical and physiological differences exist between the two muscle sites that might contribute to the observed differences in reliability. The suprahyoid and pharyngeal constrictor muscles are innervated by different cranial nerves (V and X respectively) that follow different pathways from the peripheral muscles through the brainstem and to higher cortical regions. In addition, at the periphery, these muscles are located in different regions of the body, with muscle fibers aligned in different orientations and are of different relative size. It is possible, that these inherent anatomical and physiological differences may have contributed to different degrees of stability across testing sessions. Overall, however, both swallow muscle sites displayed good test-retest reliability and demonstrated that motor map area could be a valid measure to capture changes in spatial reorganization in the brain. Motor Map Volume Motor map volume was assessed as the sum of all MEP peak-to-peak areas. In this investigation, map volume displayed moderate test-retest reliability for the suprahyoid (ICC=0.70) and pharyngeal (0.68) sites. Unlike map area, map volume showed consistent degrees of stability across muscle sites. The current reliability findings are lower than those reported by Malcom (2003) and Mortifee (1994) who obtained ICC indices of 0.85 and 0.89 respectively for map volume. When comparing these results, however, it is important to note that these earlier studies mapped intrinsic hand and

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62 forearm muscles while the current investigated oral and pharyngeal musculature. As already described, mapping reproducibility has been noted to differ across muscle sites, providing 1 potential explanation for the noted discrepancy. Several variables may have affected the stability of the swallow representation excitability. First, fluctuations in levels of alertness and anxiety have all been noted to affect MEP amplitudes (Miranda, de Carvalho, Conceicao, Luis, & Ducla-Soares, 1997). Anecdotally, it was noted that many subjects displayed higher levels of anxiety on their first visit when the test procedures were somewhat ‘unknown’ to them. Altered levels of anxiety across testing sessions may have affected the stability of map volume. Other potential variables known to influence the central nervous system include consumption of caffeine and amount of sleep. These factors were not controlled for and may have influenced stability of motor map volume. Variations in coil orientation have also been noted to affect the size of MEPs and concurrently the volume of a map (Pascual-Leone, Cohen, Brasil-Neto, & Hallett, 1994) (Miranda et al., 1997). While every effort was made by the investigator to maintain the same coil position across sites and sessions, minute variations may have occurred that might have influenced the results. Future investigation, which attempt to use changes in map volume as a marker of plasticity, should consider that alterations in these maps may occur secondary to spontaneous fluctuation in the cortico-motoneuronal output. Multiple assessments would account for such variability prior to the introduction of a controlled behavioral intervention and are recommended.

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63 Optimal Stimulation Site Location Optimal site location represented the scalp position where the largest MEP was obtained. The medial-lateral coordinate displayed excellent test-retest reliability for the suprahyoid (ICC=0.97) and pharynx (ICC=0.98) over mapping sessions. In contrast, the anterior-posterior coordinate showed moderate stability for the suprahyoid (ICC=0.68) and pharynx (ICC=0.74). The results of this investigation concur with Malcom (2003) who also found greater stability of the optimal site location along the medial-lateral plane (ICC’s: 0.82-0.86) compared with the anterior-posterior plane (ICC’s: 0.38-0.70). The observed disparity between stability of medial-lateral and anterior-posterior planes of reference both in the current and in Malcoms’ (2003) study may be explained, in part, by a technical issue related to coil positioning and current spread. In normal subjects, map shape often mirrors the pattern of induced current flow and is elongated along the axis of the coil (Wilson, Day, Thickbroom, & Mastaglia, 1996). As a result, there is a larger area over which the optimal stimulating site may fall in the anterior-posterior direction when the coil handle is oriental parallel to the midsagital, thus increasing the room for variation in this measure across sessions. Future investigations should consider the effect of coil orientation on the distribution of optimal stimulating site locations. Optimal Simulating Site Size Optimal stimulating site size was indexed as the largest MEP peak-to-peak area obtained in the grid. This measure showed good reproducibility for both the suprahyoid (ICC=0.78) and pharynx (ICC=0.76), with a consistent degree of reliability across muscle sites.

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64 This study represents the first to explicitly assess optimal stimulation site MEP size. Our results reveal that though the total, overall level of excitability in the swallow representation displayed only a moderate degree of reliability, corticobulbar excitation at the optimal site demonstrates good reproducibility across sessions. Future studies should confirm these findings. Motor Threshold Motor threshold, or the smallest intensity level to produce a discernable MEP, demonstrated excellent stability across testing sessions (ICC=0.98). The current results concur with Malcom (2003) who also reported excellent reproducibility for motor threshold in a hand muscle (ICC=0.97). These findings indicate that the threshold for excitation of the corticobulbar system remains relatively constant across multiple testing sessions in normal subjects. The current results demonstrate stability of both the TMS mapping procedure itself and the muscle motor representations overtime. Mapping procedures and muscle motor representations are two distinct entities of study. The earlier represents general TMS procedural reliability and the later reproducibility of specific corticobulbar muscle motor representations over time. While previous reports suggest stability of corticospinal motor representations over time, the current works provide the first piece of evidence to specifically demonstrate reliability of corticobulbar musculature. Thus muscle specific and procedural specific reliability were demonstrated in this study. Strengths, Limitations, and Future Directions Upon review of the literature, only 5 published studies (Kamen, 2004; McMillan et al., 1998; Mortifee et al., 1994; Uy et al., 2002; Wolf et al., 2004) and a recent doctoral dissertation (Malcolm, 2003) have explicitly examined the reliability of TMS mapping

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65 procedures. As previously highlighted, numerous methodological issues exist in these previous works. Most notably these include: small sample sizes, single TMS measures, inappropriate statistical analysis and restriction of study to the corticospinal system. The present study attempted to address some of these issues by testing a comprehensive set of TMS measures using a more rigorous statistical analysis. It represents the first to assess motor mapping reliability in the corticobulbar system and specifically swallowing musculature using a relatively large N. When reviewing these test-retest reliability findings, however, several limitations must be highlighted. First, EMG-related issues that may have affected reliability results were present. Though McMillian et al. (1998) used inappropriate statistics to assess reliability, they highlight an important influential variable on mapping stability. These authors reported increased reliability for map area when electrodes were kept in place between testing sessions. When the electrodes were removed, map area was significantly different between testing runs. For the suprahyoid site, we maintained a constant inter-electrode distance of 1cm. Similarly, for the pharynx, depth of insertion of the transluminal catheter was to a standard length (15cm). Despite our attention to inter-electrode distance and depth of pharyngeal electrode insertion, we found the electrode placement was difficult to replicate precisely across testing sessions separated by two weeks. Between-session electrode placement differences may have resulted in higher variability of motor maps across testing sessions. Future studies might be able to place a mark on the subjects’ skin to identify the exact position for the electrode to be reapplied, though the feasibility of this method is questionable (for example, marks may wear off skin and be an embarrassment to the subject).

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66 A second limitation encountered in this study was subjects’ aversion and/or inability to swallow the pharyngeal electrode. Eleven subjects were excluded from this protocol due to the inability to pass and keep in place this electrode. The feasibility and practicality of the pharyngeal electrodes role in future studies needs to therefore be considered. Another method of insertion might be a trans-nasal approach which might minimize contact with the sensitive posterior pharyngeal wall behind the faucal arches. Other limitations specifically related to the test-retest reliability outcomes of this study include fluctuations in a given subject’s alertness and anxiety across session, as well as technical issues such as minute changes in coil orientation during stimulation. Topographic Representation of Swallow Musculature The results of the present study support the lateralization of swallowing function hypothesis (Daniels, Ballo, Mahoney, & Foundas, 2000). All subjects demonstrated a bilateral but clearly asymmetric representation for the suprahyoid and pharyngeal muscle sites. This pattern was observed in every subject and across all TMS measures. Group data revealed that the dominant hemisphere for swallowing musculature was the left hemisphere, though individual variation was observed. The general finding of a bilateral, yet asymmetric, swallow representation confirm Hamdy et al’s (1996) findings in 20 subjects using TMS. The emergence of a dominant groupwise hemisphere, however, was not revealed in Hamdy et al’s (1996) study. Rather, these authors reported inconsistent lateralization across subjects with largely equivocal findings for left vs. right hemisphere dominance. Spatial Organization of Swallow Representation The spatial area of swallow organization (motor map area) displayed a bilateral yet asymmetric organization. This is consistent with the findings of Hamdy et al. (1996).

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67 Though inter-individual variation was observed, on average, motor maps were larger in the left hemisphere across all muscle sites with the right suprahyoid muscle displaying a significantly larger motor map area in the left hemisphere. Spatial area of representation was observed to be similar for both the right and left suprahyoid muscles, but was slightly larger for the pharynx. A comparison between the current and Hamdy et al. (1996) studies reveal similar motor map areas. For the pharynx, average motor map area was 17.4 sites for Hamdy et al. and 19.4 for the present study. Hamdy et al’s mylohyoid 1 motor map areas were 18.75 and 19.2 for left and right muscles respectively. In the current study, suprahyoid motor maps were 16.6 and 17.2 for the left and right muscle sites respectively. Taken together these studies suggest that a relatively large spatial area of representation exists for swallowing musculature. Our results revealed a largely overlapping and shared area of motor representation for the pharyngeal and suprahyoid muscles. This was most apparent when comparing the optimal stimulating site location for each muscle. In the medial-lateral plane, only a 1mm difference (1/10th of a grid point) emerged between muscle sites for both hemispheres. The anterior-posterior plane showed the most distinction between muscle groups. However, this distinction was marginal, with the pharynx differing from the suprahyoids by 5mm (1/2 grid point) in the right hemisphere and 3mm (3/10th of a grid point) in the left hemsphere. Optimal simulation locations appeared just lateral and anterior to the hand area of the primary motor cortex, consistent with the somatotopic 1 Though the oral site electrode placement was similar across both studies, different terminology was used. Hamdy et al. (1996) called this site the ‘mylohyoid’ site whereas we termed this site the ‘suprahyoid complex’ given he fact that many, over lapping floor of mouth muscles exist in this region and the fact that surface EMG may not specifically target the mylohyoid muscle itself.

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68 arrangement of the motor cortex. In contrast, Hamdy et al. (1996) reported distinct topographic differences for each muscle group studied. The observed discrepancy between the current and Hamdy’s findings may be related to a few methodological issues. First, Hamdy and colleagues (1996) compared representations of the mylohyoid, pharynx and esophageal musculature. In the present study we did not investigate esophageal representation which may have been spatially distinct from our other two swallow muscles of interest. Second, Hamdy et al. (1996) used a 12cm by 9cm grid with 70 points while we used a smaller, 7cm by 7cm 49 point grid. With 21 extra grid points, perhaps Hadmy et al’s findings of distinct topography across muscle sites was an artifact of a larger grid, with more room for variation. We performed extensive preliminary works to determine the optimal grid size that would not place a subject under long stimulation testing sessions but that would adequately capture the spatial representation. Upon looking closely at Hamdy and colleagues’ map area, we noted that though they used a 70 point grid, the number of elicited MEPs in this grid ranged from 1-38 sites, with a mean map area of 18.5 sites. Thus, the use of a 70-point grid appeared unfounded. The subject discomfort associated with having the pharyngeal electrode in place further necessitated the use of a grid that did not extend the testing sessions. Our preliminary works determined that a 7cm by 7cm grid was the optimal grid size that adequately captured swallow representation and that displayed clear negative margins (i.e. did not elicit MEP on all 4 borders). A final methodological difference between these two works is that Hamdy and colleagues (1996) used the averaged response of 3 stimulations to each grid site while the

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69 present investigation used the average of 5 stimulations. Such differences in methods may have impacted on the results. Excitability of Swallow Representation Excitability of the corticobulbar swallow representation showed a bilateral but asymmetric representation. On average, the left hemisphere displayed higher levels of corticobulbar excitation across each muscle site, providing further support for the lateralization of swallowing theory. Though individual variation persisted for motor map volume, 85% of subjects lateralized to the left hemisphere for the pharynx and 70% for the right suprahyoid muscle. The difference between mean map volumes across hemispheres was statistically significant for the pharynx. The relative size (i.e.corticobulbar excitation) at the optimal stimulation site also displayed larger MEP peak-to-peak areas in the left hemispheres for each muscle. For the pharynx, again, the level of excitation was significantly higher. Thus, both over the entire spatial map and at the site of maximal representation (as indexed by total map volume and optimal stimulation site size respectively) corticobulbar excitation were higher in the left hemisphere for each muscle site. Motor threshold was measured as the lowest stimulus intensity to produce a discernable MEP and thus reflects the threshold for corticobulbar excitation. Mean motor threshold was significantly lower for the left hemisphere. Specifically, 65% of subjects displayed a lower motor threshold in the left hemisphere while 35% showed equivalent motor thresholds across right and left hemispheres. Interestingly, no subjects revealed a lower threshold in the right hemisphere.

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70 Comparison of the aforementioned excitability variables with Hamdy and colleagues’ previous works is not possible as these authors only reported spatial areas of swallow representation. Lateralization to the Left Hemisphere Our results support the lateralization of swallow function theory. On average, spatial organization and excitation of the swallow representations lateralized to the left hemisphere for the suprahyoid and pharyngeal muscle sites. The emergence of swallowing left hemisphere dominance confirms other reports in normal subjects using fMRI (Martin et al., 2004; Mosier, Liu et al., 1999) and MEG (Dziewas et al., 2003; Watanabe et al., 2004), as well as lesion localization studies of dysphagia following unilateral left hemispheric stroke (Irie & Lu, 1995; Robbins & Levine, 1988; Robbins et al., 1993; Shanahan et al., 1995). The finding that swallow motor representation size, organization and excitation lateralized, on average, to the left hemisphere might be explained by a number of anatomical and functional characteristics of the left hemisphere. These will now be discussed. Anatomical asymmetry has been noted between the left and right hemispheres Specifically, it has been shown that the planum temporale (superior temporal cortex behind Hechl’s gyrus), the parietal operculum, and the lateral frontal cortex are larger in the left hemisphere (Geschwind & Levitsky, 1968; Habib, Robichon, Levrier, Khalil, & Salamon, 1995; Harasty, Seldon, Chan, Halliday, & Harding, 2003; Pujol et al., 2002). This noted anatomical difference in gross size and shape has been suggested to provide structural support for lateralization of various cognitive and motor functions (Harasty et al., 2003). At a microanatomic level, asymmetries have also been noted to favor left

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71 hemisphere functioning. Specifically, pyramidal cells have been noted to display longer dendritic trees, increased branching, and more dendritic spines in the left hemisphere (Buxhoeveden, Switala, Litaker, Roy, & Casanova, 2001; Buxhoeveden, Switala, Roy, Litaker, & Casanova, 2001; Seldon, 1981a, 1981b, 1982). Thus, macroscopic and microscopic cytoartitecture of the left hemisphere might provide structural grounds for lateralization of motor functions to the left hemisphere. Our findings of lateralization to the left hemisphere may also be explained, in part, by other functionally related processes that appear to be mediated predominantly by the left hemisphere. These included planning and programming of complex motor actions and speech programming and execution. These will briefly be outlined. It has been noted that general motor planning and programming is a preeminent left hemisphere function (Heilman, 2000). In normal subjects, the left hemisphere has shown dominance for the programming of complex motor tasks (Haaland, Elsinger, Mayer, Durgerian, & Rao, 2004; Keane, 1999; Treffner & Peter, 2002; Verstynen, Diedrichsen, Albert, Aparicio, & Ivry, 2004). In human lesion models, neurologists have long noted that left hemisphere lesions are more likely to be associated with limb apraxia (Heilman, 200; Verstyen et al., 2004). Swallowing is a complex motor action requiring the coordination of over 26 muscles and 5 different cranial nerves. The aforementioned findings of left hemisphere dominance in the control of complex general motor and speech motor actions, may provide grounds for the tendency for subjects to display stronger motor representations in this hemisphere. Specifically related to motor planning and programming of corticobulbar musculature, lesion localization studies have reported a higher incidence of speech

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72 apraxia following left hemisphere stroke (Donnan, Darby, & Saling, 1997; Dronkers, 1996; Nestor et al., 2003; Shuren, 1993). Dronkers (1997) reported that the left hemisphere appeared to be specialized for the motor planning of speech. In addition a higher incidence of ‘swallow apraixia’ and bucofacial apraxia, have been noted in left hemisphere damaged individuals (Robbins & Levine, 1988; Robbins et al., 1993; Shanahan et al., 1995; Tuch & Nielson, 1941). Thus, it appears that motor planning and programming of complex general motor and speech/swallowing functions are predominantly mediated in the left hemisphere. Other disorders of corticobulbar function have also been noted. Specifically, a higher incidence of dysarthria has been observed following left hemisphere damage (Takahashi, Satoh, Takahashi, Chiba, & Tohgi, 1995; Tohgi, Takahashi, Takahashi, Tamura, & Yonezawa, 1996; Urban et al., 2003). Thus, the noted contribution of the left hemisphere for general motor planning and programming of complex motor actions, for speech programming and planning, and for the execution of speech may provided a basis for the noted lateralization to the left hemisphere. An unexpected finding in the present study was the larger cortical excitation and spatial area of representation in the ispsilateral hemisphere for the left suprahyoid muscle. This finding is contrary to the traditional conceptualization of the innervations and largely contralateral pathway of the mandibular division of the facial nerve (V3) innervating this site. While this muscle typically displayed the least amount of lateralization to the left hemisphere (as indexed by a symmetry ratio of 55% in the left

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73 hemisphere) the finding that many subjects showed a mild ipsilateral lateralization for this muscle is surprising. Unexpected ipsilateral lateralization has also been noted by several other authors for muscles with presumed contralateral innervations. Haaland, Elsinger, Mayer, Durgerian, and Rao (2004) investigated cortical areas of activation for simple and complex finger sequences via fMRI in normal subjects. Unexpectantly, these authors found greater ispsilateral activation for the left hand (but not for the right). In another fMRI study, Verstyen et al. (2004) also noted strong ipsilateral activation for the performance of finger movements that was less pronounced for the right hand. Other investigators have noted similar engagement of ipsilateral motor areas that is particularly strong during left-hand movements (Cramer, Finklestein, Schaechter, Bush, & Rosen, 1999; Kawashima et al., 1993; Kim et al., 1993; Li, Yetkin, Cox, & Haughton, 1996; Singh et al., 1998). These unexpected findings of predominant ipsilateral cortical representation in the current and previous hand studies might be explained, in part, by the already detailed role of the left hemisphere for motor programming and planning. While this is certainly a plausible explanation for the aforementioned hand studies that investigated actual movement patterns, this explanation may not be as applicable to the current TMS study that looked at the swallow musculature at rest (and thus presumably not engaged in any motor planning or programming). Though we cannot completely explain this finding, another possibility is that this motor representation was a functional one, linked to swallowing and the aforementioned speech dominance in the left hemisphere.

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74 No relations emerged for handedness and swallow representations for any of the muscle sites. This finding is in agreement with studies that have specifically investigated handedness and swallow relations (Hamdy et al., 1996; Mosier, Liu et al., 1999). Clinical Significance As previously mentioned, 75% of dysphagic cases have a neurologic etiology. The incidence of dysphagia coupled with its impact on health, fiscal, social and quality of life domains has necessitated a greater understanding of the central mechanisms governing swallowing function. The present study has contributed to the body of literature regarding corticofugal pathways to swallowing musculature. These findings hold great applications for the development of neuro-potentiating dysphagia interventions. The fact that swallow representation displayed a bilateral yet asymmetric representation arms rehabilitationists with the knowledge that they have extra neural circuitry/territory to work with. Specifically, because swallow representation is not entirely lateralized to one hemisphere such as other corticospinal musculature, following a unilateral stroke (a common cause of dyspahagia), one might want to strengthen the existent corticobulbar network and tracts in the undamaged hemisphere. This could be targeted at either the peripheral level through intensive behavioral treatments, or at the central level through the use of such devises as repetitive transcranial magnetic stimulation. At certain frequencies such stimulation techniques can excite/promote neural structures and networks. This is a luxury that not all motor systems afford. Thus, these findings arm rehabilitationists with the knowledge that they have the neural potential to facilitate functional recovery in swallow function. The observed expansive swallow representation and inherent variation across individuals may

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75 also help explain the variant neurologic etiology of dysphagia following stroke across a number of different cortical sites. Strengths, Limitations , and Future Directions The present report provides much needed validation of Hamdy et al’s seminal work using TMS. We are only the second group of investigators to apply the neurophysiologic technique of TMS to measure normal swallow pathways. While many lesion localization studies support the lateralization of swallow function theory, the present work confirms this theory in a healthy cohort. There are, however, a number of limitations that will now be explicated. First, surface electrodes were utilized to measure suprahyoid muscle activity. Electromyographic signals recorded from surface electrodes may suffer from contaminated artifact because the signal must travel through layers of skin and adipose tissue. Future studies might wish to employ fine needle EMG which is not contaminated by the aforementioned variables and which would more specifically target the muscles of interest. Although these electrodes offer greater precision, there invasiveness and potential to cause subject discomfort should also be considered. A practical issue in the current investigation was the level of discomfort and failure for many subjects to insert and keep in position the pharyngeal electrode. A total of 31 individuals were recruited and screened for participation in this study to reach the total N of 20. What remained, could potentially be a biased cohort whereby only those who could either suppress or overcome their gag reflex were able to participate. It is unknown whether or not these individuals’ motor maps would be different to those who could not ‘turn off’ or suppress their gag reflex. Future studies might consider using a trans-nasal approach for the pharyngeal electrode in individuals that experience difficulties with

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76 trans-oral pharyngeal electrode insertion. The fact that 35% of recruited subjects could not pass the electrode also brings into question its future feasibility. Summary and Conclusions The results of this study confirmed all 3 hypotheses. First, TMS was seen to be a stable measure of corticobulbar organization and excitation in this healthy cohort. Map area, optimal site location: lateral coordinate, optimal site size, and motor threshold all displayed good stability for the suprahyoid and pharyngeal muscles. Map volume and optimal site location: anterior-posterior coordinate displayed moderate reproducibility across the 2 testing sessions for both muscles. The current results suggest that TMS may be a useful tool to study the organization, excitability and plasticity of the human motor cortex for swallowing. As this is the first study to investigate reliability of swallow representation, future investigations should confirm these preliminary findings. Attainment of multiple baselines prior to initiation of intervention in treatment outcome studies is also suggested to establish limits of normality and reliability within a specific cohort. The second hypothesis under study related to the topographic organization of swallowing musculature. In this study swallow organization, excitation and size displayed a bilateral yet clearly asymmetric representation. These findings supported the hypothesized lateralization of swallow theory. On average, map area, map volume, optimal site location and optimal site location size were all larger in the left hemisphere. In addition, mean motor threshold was lower for the left hemisphere, demonstrating lower corticobulbar threshold for this side. Thus, a groupwise lateralization emerged for the left hemisphere. As hypothesized, no relationship emerged for handedness and swallow representation.

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77 Future works might investigate the representation of these swallowing muscles in active/contracted muscle states or during swallow tasks as the current study examined these muscles at rest. This might provide a more functional view of the swallow system. The observed widely distributed swallow representations that varied across subjects may explain the occurrence of dysphagia following different neurologic insult. Armed with this knowledge of a bilateral yet asymmetric swallow representation, rehabilitations should devise interventions, either at the periphery (i.e. muscle) or in the central nervous system (i.e. cortex), to strengthen the remaining intact neural circuitry and recovery of swallow function in patients suffering unilateral lesions. To conclude, TMS represents a valid neurophysiologic technique to study corticobulbar pathways of swallowing musculature. Due to the paucity of TMS reliability data, future studies should validate these findings and multiple baselines should be obtained prior to any interventions in treatment outcome studies. Swallow topography was seen to be lateralized in the left hemisphere for the majority of subjects. Future works should examine this circuitry across a number of swallow and swallow-related tasks to obtain a more functional view of the swallow system topography.

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APPENDIX A EDINBURH HANDEDNESS INVENTORY Instructions: Please indicate your preferences in the use of your hands for the following ten activities. Quantify your hand preference by placing a tick () under the appropriate column using the following guide. STRONG preference = MODERATE preference= NONE = in final column Activity LEFT RIGHT Either Writing Drawing Throwing Using Scissors Using a Toothbrush Using a Knife (without fork) Using a Spoon Using a Broom (upper hand) Striking a Match Opening a box (lid) Total Scores 78

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APPENDIX B INFORMED CONSENT FORM Informed Consent to Participate in Research and Authorization for Collection, Use, and Disclosure of Protected Health Information You are being asked to take part in a research study. This form provides you with information about the study and seeks your authorization for the collection, use and disclosure of your protected health information necessary for the study. The Principal Investigator (the person in charge of this research) or a representative of the Principal Investigator will also describe this study to you and answer all of your questions. Before you decide whether or not to take part, read the information below and ask questions about anything you do not understand. Your participation is entirely voluntary. 1. Name of Participant ("Study Subject") ____________________________________________________________________ 2. Title of Research Study Topographical representation of swallowing musculature. 3. Principal Investigator and Telephone Number(s) Emily K. Plowman: Phone: 352-273-6550 Department of Communicative Disorders Pager: 727-4754 William J. Triggs Phone: 352-392-3491 Department of Neurology 79

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80 4. Source of Funding or Other Material Support Department of Neurology University of Florida Department of Communicative Disorders University of Florida 5. What is the purpose of this research study? The purpose of this study is to better understand (1) the contribution of different parts of the brain during swallowing in healthy adults and (2) test the accuracy and reproducibility of a technique for measuring changes in brain activation during swallowing (transcranial magnetic stimulation). 6. What will be done if you take part in this research study? If you decide to take part in this investigation you will be required to attend 2 60-minute sessions that will be scheduled approximately 2 weeks apart. A technique called transcranial magnetic stimulation (TMS) will be used to study the parts of your brain that control swallowing. TRANSCRANIAL MAGNETIC STIMULATION PROCEDURE: TMS will be used to study areas of brain involvement for swallowing. TMS is a non-painful method that may be used to stimulate your brain to cause a brief activation of the muscles in your mouth and throat. During the TMS procdure: You will be seated comfortably in a modified dental chair A swimming cap will be place on your head. This will allow the Principle Investigator to make marks on the cap, rather than on your scalp. Surface electrodes will be placed on your chin. Additionally, a specially designed 3mm wide catheter containing an inbuilt electrode will be placed into your mouth and guided back to the level of your throat. These electrodes are designed to monitor activity in the muscles of your mouth and throat involved with the swallowing process and DO NOT provide an electric shock. The electrodes will be connected to a computer, which will record muscle activity responses. A magnetic coil shaped like a “figure of eight” will be positioned on your scalp. The coil will be used to locate the best spot for stimulation of swallowing muscles and to create a map for part of your brain. During the stimulation, the electrodes and computer will record muscle responses in your mouth and throat. The principle investigator will stimulate 81 specific spots on each side of your brain. You should NOT experience any discomfort or pain during this process.

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81 7. What are the possible discomforts and risks? Transcranial magnetic stimulation (TMS) has been used since 1980 in Europe, and many investigators, including the Principle Investigators of this research project, have been stimulated using TMS thousands of times over the past several years. Many normal subjects have been tested, as well as hundreds of patients with a variety of neurologic conditions. There are no reports of serious harm or discomfort, or any other side effects, nor are there any likely theoretical hazards. In fact, the United States Food and Drug Administration (FDA) as recently changed the status of the magnetic stimulator to that of non-significant risk device since adverse effects have not been observed in more than 20 years of testing this device. However, magnetic stimulation of the brain is an experimental procedure, and there could be short or long-term risks associated with this technique that are not presently known or suspected. The stimulation itself may be associated with some transient discomfort in the scalp, however typically the described sensation is that of a mild to moderate tap. There are reports from Germany of 2 patients with large strokes who each developed seizure from magnetic stimulation. This may represent coincidence, since some 10% of stroke patients develop seizures anyway. It is theoretically possible that a seizure may occur as a result of this type of stimulation. Even so, this test would have a similar risk of associated seizure to a routine electric brain tracing (EEG) test, in which stimulation with a flashing light causes a seizure to 1 in 5000 patients. Furthermore, the test has even been used in patients with epilepsy without increasing seizures. The FDA has concluded that magnetic stimulation at the low rates used in this investigation is not associated with a significant risk of seizure. In order to make TMS procedures as safe and effective as possible, we will exclude individuals with certain medical conditions. To protect your safety in this study, we ask that you review the following list of medical conditions. If you think that any of these conditions apply to you, we ask that you notify the principle investigator obtaining the consent before beginning the TMS procedures . The names and phone numbers of all investigators involved in this study are listed on the front page of this form. IMPORTANT WARNINGS : 1. Persons with any history of neurological illness, including epilepsy or seizures, brain tumors, any neurological disease, any history of head injury with loss of consciousness of any length should not receive TMS. 2. Persons with implanted heart pacemakers, deep brain stimulators or medication pumps, intravenous lines, metal plates in the skull, or metal objects in the eyes or skull should not receive TMS. 3. Patients with a history of schizophrenia, manic-depression, or alcohol or drug abuse within the past year should not receive TMS.

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82 There are no other anticipated discomforts or risks associated with this study. Throughout this study, the researchers will notify you of new information that may become available and might affect your decision to remain in the study. If you wish to discuss the information above or any discomforts you may experience, you may ask questions now or call the Principal Investigator or contact person listed on the front page of this form. 8a. What are the possible benefits to you? Taking part in this study is not expected to provide any direct health benefit to you. 8b. What are the possible benefits to others? Your participation in this study will enable the researchers to learn more about the functioning of the brain in relation to swallowing and aid in the development of tools to measure brain activity. 9. If you choose to take part in this research study, will it cost you anything? No. 10. Will you receive compensation for taking part in this research study? You will be reimbursed for your parking expenses ($3.00). 11. What if you are injured because of the study? If you experience an injury that is directly caused by this study, only professional medical care that you receive at the University of Florida Health Science Center will be provided without charge. However, hospital expenses will have to be paid by you or your insurance providerNo other compensation is offered. 12. What other options or treatments are available if you do not want to be in this study? Participation in this study is entirely voluntary. You are free to refuse to be in this study. Your refusal will not influence or prevent the usual standard of care you would receive from this institution.

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83 13a. Can you withdraw from this research study? You are free to withdraw your consent and to stop participating in this research study at any time. If you do withdraw your consent, there will be no penalty, and you will not lose any benefits you are entitled to. If you decide to withdraw your consent to participate in this research study for any reason, you should contact Emily Plowman at (352) 273-6550 or pager 727-4754 . If you have any questions regarding your rights as a research subject, you may phone the Institutional Review Board (IRB) office at (352) 846-1494. 13b. If you withdraw, can information about you still be used and/or collected? Only information that is obtained after your consent to participate and before your decision to withdraw will be used. No further information will be collected if you choose to withdraw from the study. 13c. Can the Principal Investigator withdraw you from this research study? You may be withdrawn from the study without your consent if it is deemed that you are unsafe to continue in the protocol. 14. How will your privacy and the confidentiality of your protected health information be protected? If you participate in this research, your protected health information will be collected, used, and disclosed under the terms specified in sections 15 – 24 below. 15. If you agree to participate in this research study, what protected health information about you may be collected, used and disclosed to others? To determine your eligibility for the study and as part of your participation in the study, your protected health information that is obtained from you, from review of your past, current or future health records, from procedures such as physical examinations, x-rays, blood or urine tests or other procedures, from your response to any study treatments you receive, from your study visits and phone calls, and any other study related health information, may be collected, used and disclosed to others. More specifically, the following information may be collected, used, and disclosed to others: Your age Date of birth Gender

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84 Handedness (if you are right or left handed) Information regarding responses from your muscles following magnetic stimulation 16. For what study-related purposes will your protected health information be collected, used and disclosed to others? Your protected health information may be collected, used and disclosed to others to find out your eligibility for, to carry out, and to evaluate the results of the research study. More specifically, your protected health information may be collected, used and disclosed for the following study-related purpose(s): To identify areas of your brain that contribute to swallowing To determine the reliability or reproducibility of a device (transcranial magnetic stimulation) in measuring brain activity 17. Who will be authorized to collect, use and disclose to others your protected health information? Your protected health information may be collected, used, and disclosed to others by the study Principal Investigator ( Emily K. Plowman ) and her staff other professionals at the University of Florida or Shands Hospital that provide study-related treatment or procedures ( Dr. William Triggs and Dr. John Rosenbek) the University of Florida Institutional Review Board 18. Once collected or used, who may your protected health information be disclosed to? Your protected health information may be given to: United States and foreign governmental agencies who are responsible for overseeing research, such as the Food and Drug Administration, the Department of Health and Human Services, and the Office of Human Research Protections Government agencies who are responsible for overseeing public health concerns such as the Centers for Disease Control and Federal, State and local health departments Malcolm Randall VA Medical center (Gainesville)

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85 19. If you agree to participate in this research, how long will your protected health information be collected, used and disclosed? Up to the year 2013 20. Why are you being asked to authorize the collection, use and disclosure to others of your protected health information? Under a new Federal Law, researchers cannot collect, use or disclose any of your protected health information for research unless you allow them to by signing this consent and authorization. 21. Are you required to sign this consent and authorization and allow the researchers to collect, use and disclose (give) to others of your protected health information? No, and your refusal to sign will not affect your treatment, payment, enrollment, or eligibility for any benefits outside this research study. However, you cannot participate in this research unless you allow the collection, use and disclosure of your protected health information by signing this consent/authorization. 22. Can you review or copy your protected health information collected, used or disclosed under this authorization? You have the right to review and copy your protected health information. However, you will not be allowed to do so until after the study is finished. 23. Is there a risk that your protected health information could be given to others beyond your authorization? Yes. There is a risk that information received by authorized persons could be given to others beyond your authorization and not covered by the law. 24. Can you revoke (cancel) your authorization for collection, use and disclosure of your protected health information? Yes. You can revoke your authorization at any time before, during or after your participation in the research. If you revoke, no new information will be collected about you. However, information that was already collected may be still be used and disclosed to others if the researchers have relied on it to complete and protect the validity of the research. You can revoke by giving a written request with your signature on it to the Principal Investigator.

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86 25. How will the researcher(s) benefit from your being in this study? In general, presenting research results helps the career of a scientist. Therefore, the Principal Investigator may benefit if the results of this study are presented at scientific meetings or in scientific journals. 26. Signatures As a representative of this study, I have explained to the participant the purpose, the procedures, the possible benefits, and the risks of this research study; the alternatives to being in the study; and how the participant’s protected health information will be collected used and disclosed: _______________________________________ _____________________ Signature of Person Obtaining Consent and Authorization Date You have been informed about this study’s purpose, procedures, possible benefits, and risks; the alternatives to being in the study; and how your protected health information will be collected, used and disclosed. You have received a copy of this Form. You have been given the opportunity to ask questions before you sign, and you have been told that you can ask other questions at any time. You voluntarily agree to participate in this study. You hereby authorize the collection, use and disclosure of your protected health information as described in sections 14-24 above. By signing this form, you are not waiving any of your legal rights. ________________________________________ _____________________ Signature of Person Consenting and Authorizing Date

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88 Cramer, S. C., Finklestein, S. P., Schaechter, J. D., Bush, G., & Rosen, B. R. (1999). Activation of distinct motor cortex regions during ipsilateral and contralateral finger movements. J Neurophysiol, 81(1), 383-387. Daniels, S., Foundas, A. L., Iglesia, G., & Sullivan, M. (1996). Lesion site in unilteral stroke patients with dysphagia. J Stroke Cerebrovasc Dis, 6, 30-34. Daniels, S. K., Ballo, L. A., Mahoney, M. C., & Foundas, A. L. (2000). Clinical predictors of dysphagia and aspiration risk: outcome measures in acute stroke patients. Arch Phys Med Rehabil, 81(8), 1030-1033. Daniels, S. K., Brailey, K., & Foundas, A. L. (1999). Lingual discoordination and dysphagia following acute stroke: analyses of lesion localization. Dysphagia, 14(2), 85-92. Daniels, S. K., Corey, D. M., Barnes, C. L., Faucheaux, N. M., Priestly, D. H., & Foundas, A. L. (2002). Cortical representation of swallowing: a modified dual task paradigm. Percept Mot Skills, 94(3 Pt 1), 1029-1040. Daniels, S. K., & Foundas, A. L. (1997). The role of the insular cortex in dysphagia. Dysphagia, 12(3), 146-156. Daniels, S. K., & Foundas, A. L. (1999). Lesion localization in acute stroke patients with risk of aspiration. J Neuroimaging, 9(2), 91-98. Di Lazzaro, V., Oliviero, A., Profice, P., Saturno, E., Pilato, F., Insola, A., et al. (1998). Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans. Electroencephalogr Clin Neurophysiol, 109(5), 397-401. Donnan, G. A., Darby, D. G., & Saling, M. M. (1997). Identification of brain region for coordinating speech articulation. Lancet, 349(9047), 221-222. Dronkers, N. F. (1996). A new brain region for coordinating speech articulation. Nature, 384(6605), 159-161. Dziewas, R., Soros, P., Ishii, R., Chau, W., Henningsen, H., Ringelstein, E. B., et al. (2003). Neuroimaging evidence for cortical involvement in the preparation and in the act of swallowing. Neuroimage, 20(1), 135-144. Ekberg, O., Hamdy, S., Woisard, V., Wuttge-Hannig, A., & Ortega, P. (2002). Social and psychological burden of dysphagia: Is impact on diagnosis and treatment. Dysphagia, 17, 139-146. Epstein, C. M., Schwartzberg, D. G., Davey, K. R., & Sudderth, D. B. (1990). Localizing the site of magnetic brain stimulation in humans. Neurology, 40(4), 666-670.

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89 Ertekin, C., & Aydogdu, I. (2003). Neurophysiology of swallowing. Clin Neurophysiol, 114(12), 2226-2244. Fleiss, J. R. (1986). The Design and Analysis of Clinical Experiments. New York: Whiley. Geschwind, N., & Levitsky, W. (1968). Human Brain: Left-right asymmetries in temporal speech region. Science, 161, 186-187. Gordon, C., Hewer, R. L., & Wade, D. T. (1987). Dysphagia in acute stroke. Br Med J (Clin Res Ed), 295(6595), 411-414. Haaland, K. Y., Elsinger, C. L., Mayer, A. R., Durgerian, S., & Rao, S. M. (2004). Motor sequence complexity and performing hand produce differential patterns of hemispheric lateralization. J Cogn Neurosci, 16(4), 621-636. Habib, M., Robichon, F., Levrier, O., Khalil, R., & Salamon, G. (1995). Diverging asymmetries of temporo-parietal cortical areas: a reappraisal of Geschwind/Galaburda theory. Brain Lang, 48(2), 238-258. Hallett, M. (1996). Transcranial magnetic stimulation: a tool for mapping the central nervous system. Electroencephalogr Clin Neurophysiol Suppl, 46, 43-51. Hamdy, S., Aziz, Q., Rothwell, J. C., Singh, K. D., Barlow, J., Hughes, D. G., et al. (1996). The cortical topography of human swallowing musculature in health and disease. Nat Med, 2(11), 1217-1224. Hamdy, S., Mikulis, D. J., Crawley, A., Xue, S., Lau, H., Henry, S., et al. (1999a). Cortical activation during human volitional swallowing: an event-related fMRI study. Am J Physiol, 277(1 Pt 1), G219-225. Hamdy, S., Rothwell, J. C., Brooks, D. J., Bailey, D., Aziz, Q., & Thompson, D. G. (1999b). Identification of the cerebral loci processing human swallowing with H2(15)O PET activation. J Neurophysiol, 81(4), 1917-1926. Harasty, J., Seldon, H. L., Chan, P., Halliday, G., & Harding, A. (2003). The left human speech-processing cortex is thinner but longer than the right. Laterality, 8(3), 247-260. Hartelius, L., & Svensson, P. (1994). Speech and swallowing symptoms associated with Parkinson's disease and multiple sclerosis: a survey. Folia Phoniatr Logop, 46(1), 9-17. Hartnick, C. J., Rudolph, C., Willging, J. P., & Holland, S. K. (2001). Functional magnetic resonance imaging of the pediatric swallow: imaging the cortex and the brainstem. Laryngoscope, 111(7), 1183-1191.

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90 Heilman, K. M. (2000). Limb apraxias: Higher-order disorders of sensorimotor integration. Brain, 123, 860-879. Hickling, K. G., & Howard, R. (1988). A retrospective survey of treatment and mortality in aspiration pneumonia. Intensive Care Med, 14(6), 617-622. Holas, M. A., DePippo, K. L., & Reding, M. J. (1994). Aspiration and relative risk of medical complications following stroke. Arch Neurol, 51(10), 1051-1053. Irie, H., & Lu, C. (1995). Dynamic evaluation of swallowing patterns in patients with cerebrovascular accident. Clin Imaging, 19, 240-243. Jacob, P., Kahrilas, P. J., Logemann, J. A., Shah, V., & Ha, T. (1989). Upper esophageal sphincter opening and modulation during swallowing. Gastroenterology, 97(6), 1469-1478. Kamen, G. (2004). Reliability of motor-evoked potentials during resting and active contraction conditions. Med Sci Sports Exerc, 36(9), 1574-1579. Kawashima, R., Yamada, K., Kinomura, S., Yamaguchi, T., Matsui, H., Yoshioka, S., et al. (1993). Regional cerebral blood flow changes of cortical motor areas and prefrontal areas in humans related to ipsilateral and contralateral hand movement. Brain Res, 623(1), 33-40. Keane, A. M. (1999). Cerebral organization of motor programming and verbal processing as a function of degree of hand preference and familial sinistrality. Brain Cogn, 40(3), 500-515. Kern, M. K., Birn, R., Jaradeh, S., Jesmanowicz, A., Cox, R., Hyde, J., et al. (2001). Swallow-related cerebral cortical activity maps are not specific to deglutition. Am J Physiol Gastrointest Liver Physiol, 280(4), G531-538. Kern, M. K., Jaradeh, S., Arndorfer, R. C., & Shaker, R. (2001). Cerebral cortical representation of reflexive and volitional swallowing in humans. Am J Physiol Gastrointest Liver Physiol, 280(3), G354-360. Kidd, D., Lawson, J., Nesbitt, R., & MacMahon, J. (1995). The natural history and clinical consequences of aspiration in acute stroke. QJM, 88(6), 409-413. Kim, S. G., Ashe, J., Hendrich, K., Ellermann, J. M., Merkle, H., Ugurbil, K., et al. (1993). Functional magnetic resonance imaging of motor cortex: hemispheric asymmetry and handedness. Science, 261(5121), 615-617. Kuypers, H. G. (1958a). Corticobular connexions to the pons and lower brain-stem in man: an anatomical study. Brain, 81(3), 364-388. Kuypers, H. G. (1958b). Some projections from the peri-central cortex to the pons and lower brain stem in monkey and chimpanzee. J Comp Neurol, 110(2), 221-255.

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91 Larson, C. R., Byrd, K. E., Garthwaite, C. R., & Luschei, E. S. (1980). Alterations in the pattern of mastication after ablations of the lateral precentral cortex in rhesus macaques. Exp Neurol, 70(3), 638-651. Li, A., Yetkin, F. Z., Cox, R., & Haughton, V. M. (1996). Ipsilateral hemisphere activation during motor and sensory tasks. AJNR, 17(4), 651-655. Logemann, J. A., Shanahan, T., Rademaker, A. W., Kahrilas, P. J., Lazar, R., & Halper, A. (1993). Oropharyngeal swallowing after stroke in the left basal ganglion/internal capsule. Dysphagia, 8(3), 230-234. Loose, R., Hamdy, S., & Enck, P. (2001). Magnetoencephalographic response characteristics associated with tongue movement. Dysphagia, 16(3), 183-185. Lugger, K. E. (1994). Dysphagia in the elderly stroke patient. J Neurosci Nurs, 26(2), 78-84. Lund, J. P., & Sessle, B. J. (1974). Oral-facial and jaw muscle afferent projections to neurons in cat frontal cortex. Exp Neurol, 45(2), 314-331. Luschei, E. S., & Goodwin, G. M. (1975). Role of monkey precentral cortex in control of voluntary jaw movements. J Neurophysiol, 38(1), 146-157. Malcolm, M. P. (2003). The reliability and utility of Transcranial Magnetic Stimulation to assess activity-dependent plasticity in human stroke. Univeristy of Florida, Gainesville. Mann, G., Hankey, G. J., & Cameron, D. (2000). Swallowing disorders following acute stroke: prevalence and diagnostic accuracy. Cerebrovasc Dis, 10(5), 380-386. Martin, B. J., Corlew, M. M., Wood, H., Olson, D., Golopol, L. A., Wingo, M., et al. (1994). The association of swallowing dysfunction and aspiration pneumonia. Dysphagia, 9(1), 1-6. Martin, R. E., Gati, J., Fox, A., & Menon, R. (1997a). Cortical activation associated with human swallowing: a fMRI study. Soc Neurosci Abstr, 23, 1275. Martin, R. E., Goodyear, B. G., Gati, J. S., & Menon, R. S. (2001). Cerebral cortical representation of automatic and volitional swallowing in humans. J Neurophysiol, 85(2), 938-950. Martin, R. E., Kemppainen, P., Masuda, Y., Yao, D., Murray, G. M., & Sessle, B. J. (1999). Features of cortically evoked swallowing in the awake primate (Macaca fascicularis). J Neurophysiol, 82(3), 1529-1541.

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92 Martin, R. E., MacIntosh, B. J., Smith, R. C., Barr, A. M., Stevens, T. K., Gati, J. S., et al. (2004). Cerebral areas processing swallowing and tongue movement are overlapping but distinct: a functional magnetic resonance imaging study. J Neurophysiol, 92(4), 2428-2443. Martin, R. E., Murray, G. M., Kemppainen, P., Masuda, Y., & Sessle, B. J. (1997b). Functional properties of neurons in the primate tongue primary motor cortex during swallowing. J Neurophysiol, 78(3), 1516-1530. Martin, R. E., & Sessle, B. J. (1993). The role of the cerebral cortex in swallowing. Dysphagia, 8(3), 195-202. McDonnell, M. N., Ridding, M. C., & Miles, T. S. (2004). Do alternate methods of analysing motor evoked potentials give comparable results? J Neurosci Methods, 136(1), 63-67. McMillan, A. S., Watson, C., & Walshaw, D. (1998). Transcranial magnetic-stimulation mapping of the cortical topography of the human masseter muscle. Arch Oral Biol, 43(12), 925-931. Meadows, J. C. (1973). Dysphagia in unilateral cerebral lesions. J Neurol Neurosurg Psychiatry, 36(5), 853-860. Miller, A. (1986). Neurophysiological basis of swallowing. Dysphagia, 1, 91-100. Miller, A. J., & Bowman, J. P. (1977). Precentral cortical modulation of mastication and swallowing. J Dent Res, 56(10), 1154. Miranda, P. C., de Carvalho, M., Conceicao, I., Luis, M. L., & Ducla-Soares, E. (1997). A new method for reproducible coil positioning in transcranial magnetic stimulation mapping. Electroencephalogr Clin Neurophysiol, 105(2), 116-123. Mortifee, P., Stewart, H., Schulzer, M., & Eisen, A. (1994). Reliability of transcranial magnetic stimulation for mapping the human motor cortex. Electroencephalogr Clin Neurophysiol, 93(2), 131-137. Mosier, K., & Bereznaya, I. (2001). Parallel cortical networks for volitional control of swallowing in humans. Exp Brain Res, 140(3), 280-289. Mosier, K., Patel, R., Liu, W. C., Kalnin, A., Maldjian, J., & Baredes, S. (1999a). Cortical representation of swallowing in normal adults: functional implications. Laryngoscope, 109(9), 1417-1423. Mosier, K. M., Liu, W. C., Maldjian, J. A., Shah, R., & Modi, B. (1999b). Lateralization of cortical function in swallowing: a functional MR imaging study. AJNR Am J Neuroradiol, 20(8), 1520-1526.

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BIOGRAPHICAL SKETCH Emily Kate Plowman was raised in Australia and graduated from Carine Senior High School, Perth, Western Australia, in 1995. She then went onto study speech and hearing sciences at Curtin University of Technology. In 1999, Emily graduated with First Class Honors in Speech and Hearing Sciences. Upon graduation, Emily worked as a Speech-Language Pathologist at a major teaching hospital for one year. Her interest in evidence-based-medicine lead her to enroll in a doctorate in Rehabilitation Sciences at the University of Florida (UF) in fall 2001. During her time at UF, Emily received awards for academic and scientific merit. In November 2001, Emily was awarded the American Speech and Hearing Association Division 13 New Investigator grant. At that same time, she was also awarded the best platform presentation at the annual dysphagia research society meeting in New Mexico. In May 2002, Emily received the award for Outstanding International Academic Scholar in the College of Health Professions. The following year she received the Kenneth-Bzoch award for research in speech pathology. Emily graduated in May of 2005. 97