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Perception and Subjective Ratings of Multiple Breath Resistive Loads in Males and Females

Permanent Link: http://ufdc.ufl.edu/UFE0021679/00001

Material Information

Title: Perception and Subjective Ratings of Multiple Breath Resistive Loads in Males and Females
Physical Description: 1 online resource (114 p.)
Language: english
Creator: Miller, Sarah N
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: aversive, estimation, magnitude, perception, respiration
Veterinary Medicine -- Dissertations, Academic -- UF
Genre: Veterinary Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Resistive (R) load magnitude estimation (ME) and subsequent subjective ratings were measured over multiple breaths in healthy subjects in two experiments. It was hypothesized that multiple breaths against a small resistive load will result in a decreased perceived load magnitude as the number of inspiratory efforts increase. It was further hypothesized that multiple breaths against large resistive loads will increase the perceived load magnitude as well as subjective ratings with increased breath number. The subjects were screened by the experimenter, seated in a sound isolated room and respired through a non-rebreathing valve, the inspiratory port connected to the loading manifold. For study one, the subject inspired to a peak airflow target for each breath. Each R load and no-loads were presented for 10 continuous breaths. The subject estimated the load at breath 1, 5, and 10 using a modified Borg scale. Each load was presented in a randomized block 3 times each in a single experimental session. For study two, each R load and no-loads were presented for 20 continuous breaths. The subject estimated the load at breath 1, 10, and 20 using a modified Borg scale. Each load was presented in a randomized block 3 times each in a single experimental session. For study 1, there was no significant sex group difference between the ME for breath 1 and 10 for small R loads, but a significant sex group difference for large R loads. The ME for males did not change between breath 1 and 10 for the small load magnitudes, but decreased with large loads. The ME for the 10 breath of the large R load was greater than the 1st breath for females. Males estimated the large R load on the 1st breath the same as females but the ME on the 10th breath was significantly less for males compared to females. For study 2, there was no significant sex group difference between the ME for breath 1 and 20 for small R loads, but a significant sex group difference for large R loads. The ME for males did not change between breath 1 and 20 for the small load magnitudes, but decreased with large loads. The ME for the 20th breath of the large R load was greater than the 1st breath for females. Males estimated the large R load on the 1st breath the same as females but the ME on the 20th breath was significantly less for males compared to females. Subjective responses of fear, fear of suffocation, happiness, chest pressure, faintness, dizziness, fear of losing control, trembling, tingling and unreality were significantly greater for females. For study 1, these results demonstrate that magnitude estimation of large resistive loads with a sustained 10-breath trial elicits a significant increase in ME for females, but a significant decrease in males. The increase in ME may represent increased respiratory discomfort. For study 2, these results demonstrate that magnitude estimation of large resistive loads with a sustained 20-breath trial elicits a non-significant increase in ME in females, but a significant decrease in ME for males. The increase in ME may represent increased respiratory discomfort. Loads larger than 15 cmH2O/L*s-1 elicited significant negative affect.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Sarah N Miller.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Davenport, Paul W.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2008-06-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021679:00001

Permanent Link: http://ufdc.ufl.edu/UFE0021679/00001

Material Information

Title: Perception and Subjective Ratings of Multiple Breath Resistive Loads in Males and Females
Physical Description: 1 online resource (114 p.)
Language: english
Creator: Miller, Sarah N
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: aversive, estimation, magnitude, perception, respiration
Veterinary Medicine -- Dissertations, Academic -- UF
Genre: Veterinary Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Resistive (R) load magnitude estimation (ME) and subsequent subjective ratings were measured over multiple breaths in healthy subjects in two experiments. It was hypothesized that multiple breaths against a small resistive load will result in a decreased perceived load magnitude as the number of inspiratory efforts increase. It was further hypothesized that multiple breaths against large resistive loads will increase the perceived load magnitude as well as subjective ratings with increased breath number. The subjects were screened by the experimenter, seated in a sound isolated room and respired through a non-rebreathing valve, the inspiratory port connected to the loading manifold. For study one, the subject inspired to a peak airflow target for each breath. Each R load and no-loads were presented for 10 continuous breaths. The subject estimated the load at breath 1, 5, and 10 using a modified Borg scale. Each load was presented in a randomized block 3 times each in a single experimental session. For study two, each R load and no-loads were presented for 20 continuous breaths. The subject estimated the load at breath 1, 10, and 20 using a modified Borg scale. Each load was presented in a randomized block 3 times each in a single experimental session. For study 1, there was no significant sex group difference between the ME for breath 1 and 10 for small R loads, but a significant sex group difference for large R loads. The ME for males did not change between breath 1 and 10 for the small load magnitudes, but decreased with large loads. The ME for the 10 breath of the large R load was greater than the 1st breath for females. Males estimated the large R load on the 1st breath the same as females but the ME on the 10th breath was significantly less for males compared to females. For study 2, there was no significant sex group difference between the ME for breath 1 and 20 for small R loads, but a significant sex group difference for large R loads. The ME for males did not change between breath 1 and 20 for the small load magnitudes, but decreased with large loads. The ME for the 20th breath of the large R load was greater than the 1st breath for females. Males estimated the large R load on the 1st breath the same as females but the ME on the 20th breath was significantly less for males compared to females. Subjective responses of fear, fear of suffocation, happiness, chest pressure, faintness, dizziness, fear of losing control, trembling, tingling and unreality were significantly greater for females. For study 1, these results demonstrate that magnitude estimation of large resistive loads with a sustained 10-breath trial elicits a significant increase in ME for females, but a significant decrease in males. The increase in ME may represent increased respiratory discomfort. For study 2, these results demonstrate that magnitude estimation of large resistive loads with a sustained 20-breath trial elicits a non-significant increase in ME in females, but a significant decrease in ME for males. The increase in ME may represent increased respiratory discomfort. Loads larger than 15 cmH2O/L*s-1 elicited significant negative affect.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Sarah N Miller.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Davenport, Paul W.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2008-06-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0021679:00001


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1 PERCEPTION AND SUBJECTIVE RATINGS OF MULTIPLE BREATH RESISTIVE LOADS IN MALES AND FEMALES By SARAH MILLER 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 2007

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2 2007 Sarah Miller

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3 To my daughter, Amelia: Always follo w your dreams. And breathe deeply.

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4 ACKNOWLEDGMENTS First of all, I thank God for giving me so many opportunities. I thank my mentor, Dr. Davenport, for making me a part of his family and welcoming me to a life of learning and teaching me more than I ever imagined Id lear n, about respiratory physiology as well as life. I thank my mom for teaching me when I was a little girl that no one could ever take away my education. I thank my dad for teaching me that I can truly do anything I dream of and being my inspiration to pursue my doctorate. I thank my sib lings, Ben & Jodi, for thei r love and laughter. I appreciate all of Jodis help with this project. I thank my husband for his love and care during my graduate school years. I thank our daught er Amelia, for making me laugh after my hard drive crashed, the week before my defense, and I felt I was going insane from analyzing data. Lastly, I thank NIH and the University of Flor ida for their generous funding and I thank my subjects for their willing participation in my experiments.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........7 LIST OF FIGURES................................................................................................................ .........8 LIST OF ABBREVIATIONS........................................................................................................10 ABSTRACT....................................................................................................................... ............11 CHAPTER 1 INTRODUCTION..................................................................................................................13 Inspiratory Loading............................................................................................................ ....13 Breathing Mechanics............................................................................................................ ..14 Breathing Response to Loads.................................................................................................16 Multiple Breath Resistive Loads............................................................................................20 Perception of Breathing........................................................................................................ ..21 Sex Differences................................................................................................................ .......24 Anxiety and Respiration........................................................................................................ .27 Measures of Anxiety and Emotion.........................................................................................30 Aversive Respiratory Stimuli.................................................................................................32 2 PERCEPTION OF 10BREATH RESISTIVE LOADS.......................................................35 Introduction................................................................................................................... ..........35 Methods and Materials.......................................................................................................... .38 Results........................................................................................................................ .............40 Discussion..................................................................................................................... ..........41 3 PERCEPTION AND SUBJECTIVE RATINGS OF 20-BREATH RESISTIVE LOADS IN MALES AND FEMALES.................................................................................................49 Introduction................................................................................................................... ..........49 Methods and Materials.......................................................................................................... .52 Data Analysis.................................................................................................................. ........55 Results........................................................................................................................ .............57 Discussion..................................................................................................................... ..........59 Conclusion..................................................................................................................... .........67 4 PERCEPTION AND SUBJECTIVE RATINGS OF SUSTAINED BREATH RESISTIVE LOADS IN MALES A ND FEMALES FINAL DISCUSSION........................97

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6 APPENDIX A DIAGNOSTIC SYMPTOMS QUESTIONNAIRE..............................................................101 B SUBJECTIVE ASSESSMENT MANIKEN........................................................................103 C BORG RATINGS.................................................................................................................10 6 LIST OF REFERENCES.............................................................................................................105 BIOGRAPHICAL SKETCH.......................................................................................................114

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7 LIST OF TABLES Table page 2-1 Mean ME (standard deviation) for ma les and females for each load magnitude and breath number.................................................................................................................. ..44 3-1 Lack of significant difference between sexes for airflow..................................................68 3-2 Lack of significant difference between sexes for time......................................................68 3-3 Mean magnitude estimation for each re sistive loads at breath 1, 10, and 20, along with the corresponding p-values and standard deviations.................................................69 3-4 Mean logs and the ME log-log slope fo r each resistive loads at breath 1, 10, and 20, along with the corresponding p-valu es and standard deviations.......................................69 3-5 Mean subject demographic data and pulmonary function test results...............................70 3-6 Mean emotional subjective responses................................................................................70 3-7 Mean bodily subjective responses.....................................................................................70 3-8 Male and Female Delta STAI Scores.................................................................................73

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8 LIST OF FIGURES Figure page 2 -1 Experimental set up for experiments 1 and 2.....................................................................45 2-2 Mean 10breath ME scores of all subjects according to load magnitude and breath number......................................................................................................................... ......46 2-3 Mean ME scores of males and female s according to load magnitude and breath number......................................................................................................................... ......47 2-4 Mean ME ( standard deviation) for A) males and B) females on breath 1 and 10 for the 40 cmH2O/L*sec-1 resistive load..................................................................................48 3-1 Experimental set up for experiment 2. Subj ects were seated in a sound isolated room and separated from the experiment to avoid any detection and observation of experimental manipulations by the subject........................................................................74 3-2 Mean airflow for A) males and B) females against each load magnitude.........................75 3-3 Mean inspiratory time for A) males and B) females against each load magnitude...........76 3-5 Mean magnitude estimation for A) males and B) females at breaths 1, 10 and 20 against each load magnitude..............................................................................................78 3-6 Mean magnitude estimation for the group at breaths 1, 10 and 20 against each load magnitude...................................................................................................................... .....79 3-7 Logs of the magnitude estimation for A) females and B) males at breaths 1, 10 and 20 against each load magnitude.........................................................................................80 3-8 Log-log slope of the magnitude estimati on for males and females at breaths 1, 10 and 20 against each load magnitude.........................................................................................81 3-9 Subjective reporting of the general level of fear on a 0-10 scale in males and females....82 3-10 Subjective reporting of the general level of fear of suffocation on a 0-10 scale in males and females..............................................................................................................83 3-11 Subjective reporting of the level of distress according to the Self-Assessment Maniken (SAM) Rating Scale in males and females.........................................................84 3-12 Subjective reporting of the level of control according to the Self-Assessment Maniken (SAM) Rating Scale in males and females.........................................................85 3-13 Subjective reporting of the level of ches t pressure according to the Self-Assessment Maniken (SAM) Rating Scale in males and females.........................................................86

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9 3-14 Subjective reporting of the level of dyspnea according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................87 3-15 Subjective reporting of the level of fa intness according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................88 3-16 Subjective reporting of the level of di zziness according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................89 3-17 Subjective reporting of the fear of losi ng control according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................90 3-18 Subjective reporting of the level of tr embling according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................91 3-19 Subjective reporting of the level of ti ngling according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................92 3-20 Subjective reporting of the sense of unreality according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................93 3-21 Subjective reporting of the level of palp itations according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Ques tionnaire in males and females.....................94 3-22 Raw preand poststat e-trait anxiety scores.....................................................................95 3-23 Delta trait anxiety levels................................................................................................ ....96

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10 LIST OF ABBREVIATIONS DSQ Diagnostic symp tom questionnaire FEV Forced expired volume FVC Forced vital capacity LTA Life threatening asthmatics ME Magnitude estimation R Resistive SAM Self-Assessment Manikin, an affective ra ting system to asses the three dimensions of pleasure, arousal and dominance STAI State Trait Anxiety Index, a 20-items que stionnaire measuring anxiety as a trait or as a state TV Tidal volume

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11 Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy PERCEPTION AND SUBJECTIVE RATINGS OF MULTIPLE BREATH RESISTIVE LOADS IN MALES AND FEMALES By Sarah Miller December 2007 Chair: Paul W. Davenport Major: Veterinary Medicine Resistive (R) load magnitude estimation (ME) and subsequent subjective ratings were measured over multiple breaths in healthy subject s in two experiments. It was hypothesized that multiple breaths against a small resistive load will result in a decreased perceived load magnitude as the number of inspiratory efforts increase. It was further hypothesized that multiple breaths against large resistive loads will increase the perceived load magnitude as well as subjective ratings with increased breath number. Subjects were screened by the experimenter, seat ed in a sound isolated room and respired through a non-rebreathing valve, the inspiratory port connected to the loading manifold. For study 1, the subject inspired to a peak airflow ta rget for each breath. Each R load and no-loads were presented for 10 continuous breaths. The subj ect estimated the load at breath 1, 5, and 10 using a modified Borg scale. Each load was pr esented in a randomized block 3 times each in a single experimental session. For study 2, each R load and no-loads were presented for 20 continuous breaths. The subject estimated the load at breath 1, 10, and 20 using a modified Borg scale. Each load was presented in a randomized block 3 times each in a single experimental session.

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12 For study 1, there was no significant sex group di fference between the ME for breath 1 and 10 for small R loads, but a signi ficant sex group difference for large R loads. The ME for males did not change between breath 1 and 10 for the small load magnitudes, but decreased with large loads. The ME for the 10 breath of the large R load was greater than the 1st breath for females. Males estimated the large R load on the 1st brea th the same as females but the ME on the 10th breath was significantly less for males compared to females. For study 2, there was no significant sex group difference between the ME for breath 1 a nd 20 for small R loads, but a significant sex group difference for large R loads. The ME for ma les did not change between breath 1 and 20 for the small load magnitudes, but d ecreased with large loads. The ME for the 20th breath of the large R load was greater than the 1st breath for females. Males estimated the large R load on the 1st breath the same as females but the ME on the 20th breath was signi ficantly less for males compared to females. Subjective responses of fear, fear of suffocation, happiness, chest pressure, faintness, dizziness, fear of losing control, trembling, tingling and unreality were significantly greater for females. For study 1, these results demonstrate that ma gnitude estimation of large resistive loads with a sustained 10-breath trial e licits a significant increase in ME for females, but a significant decrease in males. The increase in ME may repr esent increased respirator y discomfort. For study 2, these results demonstrate that magnitude estimation of large resistive loads with a sustained 20-breath trial elicits a non-signi ficant increase in ME in female s, but a significant decrease in ME for males. The decrease in ME may represent increased adaptation to load. Loads larger than 15 cmH2O/L*s-1 elicited significant negative affect.

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13 CHAPTER 1 INTRODUCTION Inspiratory Loading Inspiratory loading has been used to st udy the perceptual mechanisms underlying and mediating respiratory mechanical sensation a nd perception. There are several parameters to evaluate for breathing against loads: the mechan ical effects on volume, flow or pressure; perceptual changes, magnitude estimation and an xiety response; changes in the nervous system; and blood chemical changes. To analyze perceptu al changes in magnitude estimation and anxiety responses to inspiratory loads, it is necessary to analyze breathi ng pattern changes, perceptual reports, and subjective feelings associ ated with the inspiratory loads. Most perceptual studies have examined the e ffect of a single-breath resistive inspiratory load. Single breath loading has been used to avoi d the complication of changes in arterial blood gas and respiratory drive. One disadvantage of th is is that single-breath mechanical loads are a poor simulation of disease states and may be of limited clinical signif icance. Physiologically induced inspiratory loads, such as those that occu r during an asthma attack, require the patient to have sustained breathing periods agai nst increased mechanical loading. There are two primary cognitive components to the perception of increased respiratory load. The first is the somatosensory event. Th e second component is the cognitive evaluation of the load. Fundamentally, this means that the firs t event makes the subject aware that their load to breathing has changed and the second component involves the subject determining if the load is pleasant or unpleasant. Subjects seldom repor t unpleasant evaluations of single breath loads. However, it is likely that as a person increases the duration of breathing time against a load, subsequent unpleasant sensations arise. The cognitive response to breathing against sustained inspiratory loads has not been investigated.

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14 Cognitive analysis of respiratory challenges can vary among subjects. Davenport and Kifle (2001) reported that estimation of the magnitude of inspiratory resistive loads was reduced in children with life threatening asthma. It is known that patients experiencing increased mechanical loads to breathing have an increased incidence of affective di sorders such as anxiety (Put 1999). Some subjects, such as females a nd high trait anxiety s ubjects, magnify their perception of loads, which in turn increases their negative affect. The purpose of this study was to determine th e ventilatory adaptati on of breathing pattern against sustained loads and the changes in percep tion of breathing as the su bject respired against an elevated load over a prolonged period of time. It is also likely that ther e are sex differences in the responses in ventilatory patt ern, airflow and timing to breathi ng against elevated inspiratory loads. Thus, a second component of this st udy is to determine the relationship between perception of loads applied over multiple breat hs and sex. We hypothesized that prolonged inspiratory loading alters ventilation, percepti on, and subjective ratings of the loads in both males and female subjects. We further hypothesi ze that males and females differ in their subjective and objective discrimination of the load, but will not differ in their ventilatory response. Breathing Mechanics Ventilation of the lung is a mechanical proce ss. The respiratory muscles act as a pump to generate the driving force for ai r to flow and increase the lung volume. Application of extrinsic mechanical loads of sufficient magnitude will a lter this mechanical process and lead to a conscious awareness of the loads (Wiley 1966 ; Noble 1972; Campbell 1961; Buki 1983; Bennet 1962). The mechanical output of breathing is commonly measured in terms of tidal volume and frequency. Thereby all the complex movements of the respiratory system are integrated into a

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15 minute ventilation (Mead 1973). There are two compone nts to the volume dimension: the first is the volume displacement of the rib cage, and th e second is of the abdominal surface. Muscles intrinsically compensate for loads which limit respiratory muscle shortening. The diaphragm is predominantly positioned to res pond intrinsically to a common and natural form of loading. However, certain loads, such as rib compression and steady positive pressure breathing, tend to increase the degree of di aphragmatic shortening. Body wall expansion is mainly in the antero -posterior (A-P) direc tion in humans. At a given lung volume, with the spine held in a fixed attitude, it is possible to change the shape of the body wall, mainly in the A-P dimension (Mea d, 1973). If airway pressure is held near atmospheric to avoid large change s in pleural pressure, these changes in shape involve reciprocal movements of the rib cage and abdomen (M ead, 1973). As the rib cage is expanded, the abdomen is pulled in. If substantial changes in pl eural pressure are allowe d, the A-P diameter of the rib cage can be changed without reciprocal changes in the abdomen. The A-P diameter will decrease as pleural pressure decreases. The diaphragms action on the rib cage is twofold, both direct and indirect. The diaphragm acts directly on the rib cage by elevat ing the costal arch a nd indirectly by lowering pleural pressure (Kuno and Mead, 1973). Changes in rib cage characteristic s are due to the action of the passively tensed diaphragm on the rib cage. As lung volume is decreased, the relaxed diaphragm is lengthened and deve lops passive tension. When exte rnal pressure (mechanical or physiological) is applied from the outside to th e respiratory system, the pressure is dispersed across the lungs and the chest wall. The applie d pressure drives the two in series. When ventilation is increased, the action of the abdomin al muscles is to reduce the swing in abdominal pressure to take the load off the diaphragm.

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16 Breathing Response to Loads Loads : Loads can be inspiratory or expiratory. Mechanic loads are divided into three main types: resistive loads, in which the load is propo rtional to the flow; elastic loads, in which the load is proportional to displacement; and threshold loads, in which the load is independent of flow or displacement (pressure breathing) (Otis 1973, Howell 1973). Magnitude estimation and load detection studies have been done using inspiratory resistive loads (Wiley and Zechman, 1966; Muza 1984; Davenport 2000; We bster and Colrain, 2000). The detection of added resistance to expiration or insp iration follows the same relationship, as reported by Wiley and Zechman (1966). Similar muscle receptors and ne ural processing systems are utilized in the estimation of added loads involving either insp iratory or expiratory muscle groups (Muza 1984). For the experiments in this di ssertation, inspiratory resistiv e loads were used. Freedman and Campbell (1970) investigated the ability to tolerate ma ximum levels of the three types of loads: elastic, resistive, and threshold, the latter being equivalent to a fixed pressure which had to be developed before a ny gas flow could occur. Elastic and threshold loading resulted in inter-individu al variation, with a non-significan t increase in all submaximal loads. The pattern of breathing was consistently altered by elastic and resistive loads. Resistive loading has been shown to slow the frequency of breathing compared to elastic loading (McIlroy et al., 1956; Pope, Holloway and Campbell, 1968). Th is is due to a prolongation of the phase of respiration that is loaded and the prolongation is proportional to the size of the load (Zechman, Hall and Hull, 1957). Experimentally applied external loads to breathing are generally symmetrical in the sense that they load the system in its common path, the airway (Mead et al., 1973). They are tightly controlled and uniformly given across subject populat ions. Natural loads are more commonly asymmetrical, influencing one part of the system more than another. Most pulmonary diseases

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17 have as increased respiratory lo ad as one component to the disease process. The central nervous system is adapted to compensate for changes in natural loads. For example, when nasal resistance is excessive, we sw itch to mouth breathing,. Natural lo ading also occurs with sleepinduced increased airway resistance, and increas ed abdominal loading in the form of tight clothing or pregnancy result in an increased drive to breathe. Ventilatory response to loads : Breathing pattern responses to added resistive and elastic loads are affected by both brainstem neural refl exes and supramedullary behavioral reactions following conscious perception of altered breat hing mechanics (Daubens peck & Rhodes, 1995). Adding resistive loads ( Rs) to respiration changes airflo w, volume, and pressure and the magnitude of the external load determines the degree of change (Kellerman et al. 2000). Most people, when presented with a moderate inspirator y resistive load, adjust breathing pattern to the type and magnitude of the load and maintain cons tant alveolar ventilation (Laviettes et al., 2000). The compensation of ventilation with maximally tolerable loads is to reduce subjective discomfort (Freedman and Campbell 1970) and ve ntilatory pattern is optimized to reduce respiratory sensory input to minimize uncomfortab le breathing sensations (Cherniack et al., 1996; Oku et al. 1993). Individual di fferences in load responses ar e primarily due to behavioral (i.e. voluntary) responses in an effort to mini mize abnormal respiratory sensations (Younes et al., 1995). Inspiratory airflow and volume change little when respiring against small loads near the detection threshold, but transdia phragmatic pressure increases significantly (Zechman et al., 1985). It is common for some subjects, including asthmatic patie nts, to decrease inspiratory flow during a resistive loaded breath (K ifle et al., 1997). Resistive lo ads are airflow-dependent loads and a decrease in the inspiratory airflow reduces the pressure and airflow changes associated with the increased load. Tidal volume (VT) is usually preserved when conscious humans are

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18 made to breathe against an inspiratory resist ance. This compensation is accomplished through increasing pressure peak amplitude, increasing duration of the pressure rising phase, and the rising phase becoming more concave to the time ax is (Hof et al., 1986). The ventilatory response to added mechanical loads can be regarded as the sum of two components: one representing the effect of the passive respiratory syst em and one representing the effect of neural load-compensating mechan isms (Axen et al., 1982). The load compensating component represents the action of neural mech anisms that modify the pressure developed by loaded respiratory muscles (Zhao et al., 2002) Receptors in lung and lower airways can contribute to these neural adjustments. In both double lung transplant (DLT) patients and healthy subjects, increases in the magnit ude of resistive loads results in an increased mouth pressure (Pm), inspiratory time (TI) and pressure and a decreased inspiratory volume (VI), airflow, expiratory time (TE), frequency (f) and expi ratory volume (VE) (Zhao et al. 2002). This indicates that in conscious human s, load compensation can occur in the absence of vagal afferent input, as long as the remaining afferent pathways are intact. The cerebral cortex plays a significant role in the processing of sensory information related to mechanical effort and many aspects of respir ation. Consequently, the cerebral cortex is one neural component mediating the magnitude es timation of a load applied to breathing. The estimation of the magnitude of a load, along with initial detection of that load, is mediated by cortical processes, presumably within primar y somatosensory and association areas (Webster 2000). The activation of cortical neurons by mech anical loads has been studied using evoked potential techniques similar to techniques used in other somatosensory systems (Davenport 2000; Davenport 1996; Davenport 1986; Logie 1998; Reve lette 1990; Strobel 1993). Previous human studies have shown that inspiratory and expirato ry occlusion and mechanical loading will elicit

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19 EEG activity in the form of a respiratory re lated evoked potential (RREP). (Davenport et al., 2000; Gora et al., 1999, 2002; We bster et al., 2002; Webste r and Colrain, 1998, 2000a, b, 2002). Human subjects are consciously aware of breathing against mechanical loads (Williams et al., 1988). Respiratory psychophysiological research demonstrates that the regulation of breathing is significantly impacted by behavior ally controlled pro cesses in higher brain centers (Wientjes & Grossman 1998; Cherniack 1996; Oku et al., 19 93; Plassman, Lansing & Foti 1987; Shea & Guz 1992; Wientjes, Grossman & Gaillard 1998). There are several aspects to consider when applying external loads to the respiratory system. Precise measures of breath-to-breath vari ations in ventilation are allowed when subjects breathe on a mouthpiece with a nose-clip in pl ace, but breathing through equipment alters respiratory somatosensation and output. The tw o main variables that influence respiratory recordings are apparatus and instructions (Harver and Lorig, 2000). Golla and Antonovich (1929) reported that any attempt to breathe th rough an open mouthpiece or mask, which is to say a piece of apparatus with cente rs the subjects attention on his breathing, invariably gives rise to an abnormal type of respir ation. For this reason, it is necessary to include no-load presentations (R=0 cm H20/l/s) to control for apparatus or instructional effects. The second interference to consider is the effect that occu rs when an experimenter instructs a subject on a breathing task and with the subject s response to increase airflo w resistance (Wigal et al., 1997). Improvement in respiratory function followe d suggestions of bronchodilation, and when suggestions of bronchoconstriction were presented, deterioration in respiratory function was seen (Falkner 1941; Kotses 1998). This has been dem onstrated in both healthy subjects as well as patients with lung disease (Kostses et al., 1987a; Ketses et al 1989) The effects of suggestion are derived from the anticipation of the administration of the substance, as a component of the threat

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20 of aversive stimulation (Kose et al., 1989). Instru ction to subjects to br eathe normally will often result in arrhythmic and irregular breathing pa tterns (Harver and Lorig, 20 00), which is why it is necessary for the subject to breathe through the mouthpiece for several minut es to adapt to the experimental apparatus. Multiple Breath Resistive Loads Axen et al. (1983) examined load-compensating behavior using the ventilatory response to 10-breath resistive loads by me n and women with 160 subjects (80 males and 80 females) and found the sex related responses similar but not identical. They reported in conscious humans, sustained breathing with mechanical loading ac tivates neural load-compensating mechanisms, the range of these neural adjustments varies with both load size and type, and the stimulus to initiate this behavior was mainly non-chemical During the first, fift h and tenth consecutively loaded breath, individual responses ranged from a rapid-shallow to slow-deep breathing pattern; strong tidal volume defenders em ployed longer inspirations than weak tidal volume defenders; and individual frequency responses were mediat ed by changes in inspiratory or expiratory timing. The group response was qualitatively sim ilar on the 1st, 5th, and 10th breath. Tidal volume responses do not differ significantly. Axen et al. (1984) demonstrat ed that men actively prolonged inspiration more than women during re sistive loading and women actively shortened inspiration more than men during elastic load ing. In response to extended loads, mean inspiratory airflow response of women exceeded those of men by an amount attributable to womens higher intrinsic respirator y resistance. However, no studi es have been done to compare the ventilatory response of extended loads or the magnitude estimation of these loads. Laviette et. al (2000) examined the perception on a modified Borg score of dyspnea as well as the ventilatory response to small sustai ned resistive loads of 1.34 cmH2O/l*sec-1 and 3.54 cmH2O/l*sec-1. This study demonstrated that there was a subset of subjects who, when

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21 compared with the remainder of the study group, consistently reported increased dyspnea with repeated inspiratory loads. The authors reported that any differences in Borg score responses between groups could not be explained by differe nces in physiological re sponses to the load, since subjects maintained constant ventilation despite increasing scores of dyspnea. However, although Borg scales of dyspnea were measure d, magnitude estimation of loads were not examined, and their subject pool was predominantly female so no sex effects were analyzed. Perception of Breathing Respiratory perception is a result of the physi cal awareness (what is sensed) and affective judgment (how it feels) and appears to be a 2stage process. Stage 1 is the discriminative dimension and includes the awareness of the spa tial, temporal and intensity components of the respiratory disruption. In this st age, respiratory somatosensati on generated by the discriminative awareness of respiratory stimuli is determined by the interaction between multiple respiratory afferent groups and brainstem respiratory mo tor drive. The second stage, the affective dimension, is a potentially important but little explored aspect of respiratory sensory processing. Subsequent to initial somato sensation, respiratory stimuli can evoke distress and motivate cognitive behavior. It is possi ble that distressing respiratory sensations may condition human subjects to have a heightened awareness of their breathing and may even induce respiratory related anxiety. Humans can easily discriminate th e presence and type of respiratory mechanical loads, estimate the size of the loads and s cale these respiratory mechanical stimuli. The perception of respiratory se nsations has been examined by asking subjects to estimate the sensory magnitude of a suprathreshold loa d, using a numerical sc ale (Kelsen 1982, Kifle 1997; Killian 1981; Lansing 1996; Moy 2000), visual analogue scale (Lansing 1996; BijlHofland 2000), and cross-modality matching (Burki 1984; Burki 1983). These studies have been done using single-breath resistive lo ads. The subjects then estimate what they feel as a numerical

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22 correlate of the load magnitude on a scale of 0-10. For the pres ent study, we chose to utilize a numerical scale for magnitude es timation to represent respirator y perception and numerical and visual scales for subjective responses. Some subject groups, such as children with a history of life-threatening asthma, have a unique decreased perceptual r eactivity to resistive loads, which cannot be explained by differences in respiratory effort, airway mechan ics, or task performance ability (Kifle, Seng & Davenport, 1997; Kikuchi et al., 1994). These patients have a unique perceptual processing deficit to respiratory loads (Dav enport, et al 2000). Webster and Colrain (2000) reported that this deficit may be due to a problem in the transduc tion of afferent neural signals originating in muscle stretch receptors and projecting to somatomo tor cortical regions. It is possible that there are additional subject groups affected by blunted respiratory perception. Knafelc and Davenport (1997) investigated th e relationship of the respiratory related evoked potential to the perception of inspiratory resistive load, using increasing magnitudes (2, 9, and 21 cmH2O/l*sec-1). The reported that the amplitude of P1 significantly increased (R2=0.99) with increases in resistive load magnitude. Th ere was a significant log-log relationship (R2=0.996) between magnitude estimation and RREP P1 amplitude. Knafelc and Davenport (1999) also reported si milar results using two direct measures of inspiratory mechanical effort, transdiaphragmatic pressure and esopha geal pressure. Human subjects can easily detect and scale mech anical loads (Kelsen et al., 1982, Kifle et al., 1997; Killian et al., 1981; Lansing et al., 199 6; Bijl-Hofland et al., 2000; Taguchi et al., 1991; Burki et al., 1984; Burki et al., 1983; Burki et al., 1978; Bennett et al., 1962). The respiratory load detection threshold is a ps ychophysical measure of respiratory perception (Zechman et al., 1986). Zechman et al., (1986) reported that the per ceived magnitude of a load is

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23 linearly related to the added lo ad when a log-log transformation is used. The slope of this relationship is an index of the pe rceptual sensitivity for the type of load presented. A low slope value is indicative of poor perc eption (Julius et al., 2002). Alte rnatively, a high slope value is indicative of increased perception. Numerous stud ies conclude that resp iratory perception with added inspiratory resistive loads follows Steven s psychophysical power law (Burki et al., 1980; Gottfried S et al., 1981; Killian et al., 1982; Killian et al., 1981; Wiley et al., 1978). Consequently, perceived magnitude ( ) of a stimulus is related to the physical magnitude of the stimulus ( ) by a constant (k) and an exponent (n): =k n., where k is a measure of the threshold and the exponent, n, is a measure of pe rceptual sensitivity. The exponent is determined by calculating the slope of the log-log relationship be tween load magnitude ( ) and magnitude estimation ( ). In inspiratory resistive loading studies, the stimulus is the magnitude of the added inspiratory resistance. It has been suggested that the sensory per ception of the pres sure generated by inspiratory muscles against resistive loads might be important in assessing the magnitude of these loads (Killian et al., 1982; Altose et al., 1981). Individual differences in the perception of a dded loads do not correlate with differences in age or measures of lung function (Freedman a nd Campbell, 1970; Julius 2002). Several studies have determined that intolerance of the loads could not be explai ned as being due to any of the following variables reaching a critical or limiti ng value: ventilation, tidal volume, frequency, peak mouth pressure, peak inspiratory flow rate added inspiratory work or power and end-tidal PCO2 (Freedman and Campbell, 1970; Julius et al., 2002). Since simp le ventilatory and mechanical parameters to explain the subjects ab ility or otherwise to tolerate (or not) certain levels of loading were insufficient, subject ive psychological factors may be important in determining load perception.

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24 Load detection, used to measure the ability of subjects to detect lo ads, has a resistive threshold which is the resistive load magnitude at which 50% of the presentations will be detected. The load-detection th reshold has been shown to be a constant fraction of the background load intrinsic to th e respiratory apparatus and th e subjects intrinsic airway resistance (Wiley et al., 1966). The second perceptu al process includes diffe rentiation of the load type and the accompanying estimation of the load magnitude (ME). Subjects are usually presented a single breath load a nd required to provide an estimate of the sensory magnitude of a suprathreshold load using a numerical scale or cross-modality matching, such as handgrip tension sensation to match the magnitude of resp iratory sensation. In the present study, we will build upon previous studies in our lab testing th e subject response to sustained loads measuring magnitude estimation and subjective symptoms. Psychophysical studies of respiratory load pe rception have been conducted in asthmatic and non-asthmatic subjects using external resistances (Julius et al., 2002). These studies have shown considerable variation among subjects in the detection and ME of both intrinsic and extrinsic resistive loads and the perceived effort of breathing. Hudgel et al. (1982) reported that anxious subjects selected from normal hospital wo rkers, required higher in spiratory resistances for load recognition than non-anxious subjects. It has also been de monstrated that subjects with generalized anxiety or panic di sorder were unable to grade the magnitude of a series of inspiratory resistances (Tiller 1987). This sugge sts that psychological state significantly contributes to or alters the pe rception and scaling of loads. Sex Differences Female lungs tend to be smaller and weigh le ss at necropsy than male lungs (Thurlbeck et al., 1982). Typically, females have smaller lung vol umes, lower maximal expiratory flow rates and smaller diffusion surfaces than males, which result in lower maximal pulmonary ventilations

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25 (Mead et al., 1980; McClaran et al. 1998). Women tend to be of smaller stature and trunk size than men, but these differences remain when body size is taken into acc ount (Mead et al., 1980; Thurlbeck et al., 1982; McClaren et al. 1998). Tatsumi et al. (1991) did systematic comparisons of resting ventilation and hypoxi c ventilatory response in aw ake male and female cats, determining no physiological differences in ba seline ventilation once body size was accounted for. Discrepancies in reports dem onstrating sex differences in mean ventilation are seen (Kilbride et al. 2003), although some reports of sex differe nces in resting mean ventilation have been reported, with higher mean ventilation in males co mpared to females (White et. al. 1983; Aitken et al. 1986; Goldstein et al., 1987; Regensteiner et al. 1988). The control of breathing is influenced by sex-specific events such as cha nges in the estrus cycle, pregnancy, and menopause (Regensteiner et al., 1989). Males have reported higher urge to br eathe during exercise, but this difference can be accounted for due to the absolu te workload for males being higher than for females due to body size differences (Kilbride et al., 2003). However, the sex-related perceptual differences in magnitude estimation of sustaine d resistive loads have never been studied. Men and women have differences in their phys iological makeup that could result in a minor difference in responses to inspiratory re sistive loads. Men activ ely prolong inspiration more than women during resistive loading, and women actively shorten inspiration more than men during elastic loading (Axe n 1984), although these differen ces do not reach statistical significance. The load-compensati ng behavior exhibited by men a nd women is similar and tidal volume responses to loading do not differ (Axen 1984). In addition to physiological differences, Axen et al. (1984) first suggested that men and women could percei ve the same load differently, due to the fact that load detection capabi lity depends on intrinsic impedance (Wiley 1966). Intrinsic impedance is due to mechanical properties of the respiratory apparatus.

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26 Sociocultural factors also play a role in the sex differences in the perception, reporting, and diagnostic interpretation of respiratory sympto ms such as shortness of breath, cough, sputum production, and sleep disordered brea thing (including snoring) with all except shortn ess of breath being less commonly reported by women than by men (Schwab et al., 1999, Knauffman et al., 1996). Shortness of breath is a symptom commonly reported in chronic obstructive pulmonary disease (COPD) (Dodge 1986), and is consistently higher for females than males (Dales et al., 1989; Krzyzanowski et al., 1992; Krzyzanowski et al., 1986; Guslvik et al ., 1979) despite higher mortality rates due to COPD in males (Thom 1989; Vollmer et al., 1992). A study of over 20,000 participants spread over 7 cities in France demo nstrated reporting rates for shortness of breath decreased with increasing levels of forced ex pired volume (FEV1) in a similar fashion in both men and women, at all levels of FEV1 reportin g rates were higher in women than in men (Knauffman 1996; Krzyzanowski 1988). These sex differences not only remained but increased after standardizing for potential confounders such as smoking, occupational exposure, educational level, obesity, and FEV1 le vel (Knauffman 1996; Becklake 1999). The perception of altered respiratory functi on by women may be more sensitive but less specific than by men (Becklake and Knauffman, 1999) Dyspnea is perceived as more important in womens quality of life scal es than in mens (Jones 1992). Becklake and Knauffman (1999) also reported psychological factors such as de pression have been linke d to the reporting of respiratory symptoms, though sex di fferences in rates of reporti ng by psychological status have not been examined. The current study further ex pands this research by examining psychological measures with an altered respiratory load by adding inspiratory resistive loads. Takano et. al. (1997) and Becklake et al. (1999) reported that differences may exist between males and females in the perception of respiratory discomfort. Women with respiratory

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27 disorders such as COPD self-re port more psychological distress than men (Laurin et al., 2007). Laurin et al. (2007) reported th at psychiatric disorders, which are three times more common in COPD patients than in healthy subjects. Among COPD patients, ps ychiatric disorders are nearly two times higher in women than in men (Laurin et al., 2007). Female patients are more exposed to psychological impairment that correlates we ll with the dyspneic component of chronic obstructive pulmonary disease (Di Marco et al. 2006). When patients are affected by pulmonary disease, women report less confidence in their abili ty to control their respiratory symptoms and have less total and activity-rela ted quality of life compared to men (Laurin et al., 2007.) In general, psychiatric disorders are more common in women than in men (Laurin et al., 2007; Kessler et al 1994). In addi tion to psychiatric disorders, a dults admitted into the hospital with asthma are significantly more likely to be female (Woods et al., 2003 ; Senthilselvan et al., 1995; Hyndman et al., 1956; Wilkins et al., 1993 ; Rao et al., 2003). Measures of asthma morbidity have been shown to be disproportiona tely higher in females (Woods et al., 2003) and there is a higher trend for female readmission (Chen et al., 2003). Females tend to have a greater sensitivity to their perception of physical stimuli. Edwards et al. (2003) reported significantl y greater pain sensitivity in fe males for both experimental and clinical pain. Females in the ge neral population report a greater fr equency, intensity and duration of pain-related symptoms than adult males do (Edwards et al., 2003). Thus, it is hypothesized that females and males will differ in subjectiv e symptom expression with sustained breathing against inspiratory resistive loads. Anxiety and Respiration Anxiety can be broadly defined as an emotion that entails the appraisal of threat that is uncertain or uncomfortable (Rachman, 1998; Speiberg er, 1972) and is associat ed with subjective feelings of apprehension about impending or an ticipated harm. Five items in the Autonomic

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28 Perception Questionnaire (Mandler et al., 1958) relate to changes in breathing that occur with anxiety, and respiratory signals are prominent indicators (a long with cardiovascular and electrodermal signals) of dececption (Horowitz et al. 1997; Patrick & Iacono 1991). Anxiety is associated with respiratory changes such as hyperventilation and dyspnea. Increased ventilation is a physiological state change and is a compone nt of a defense mechanism, the fight-or-flight response, which is an adaptive response to dange r that is largely sympathetically mediated and prepares an individual for imme diate action (Van Diest et al., 2001; Gardner 1994). This increase in ventilation can lead to a drop in PCO2 level (hypocapnia). Ley & Yelich, 1998, showed that hypocapnia can be induced experimentally in healthy individuals by making them anxious. Respiratory pattern reflect emotions to the sa me extent as facial muscles (Feleky 1916). Variations in the ratio of inspiratory and expira tory times for disgust, pleasure, anger, pain, wonder, and fear provide compelling evidence for the specificity of emo tional expression in the respiratory system (Harver and Lorig, 2000). As the perception of ambiguous and unpleasant sensation serves to exacerbate symptoms, patients emotional reaction to a sense of br eathlessness exacerbate s their perception of breathlessness (Bailey et al, 1994). Anxious pati ents report the subjec tive experience of an inability to get enough air into the lungs and a sense of oppre ssion or suffocation (Christie 1935). Several studies suggest that stress/anxiety is related to th e over-perception of respiratory symptoms, but the mechanism underlying this associ ation remains unclear (P ut et al., 1999; Put et al., 2000). Subjects that asso ciate high ratings of dyspnea with relatively small inspiratory loads are considered symptom amplifiers (Lavietes et al., 2000). Although the ventilatory response to loads is governed primarily by respir atory system mechanics, respiratory reflexes, behavioral and cognitive factors may play a role in this res ponse as well (Hudgel et al., 1982;

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29 Tiller et al., 1987). Cognitive f actors can modify a subject s load response by symptom amplification, or they may exhibit an exaggera ted subjective response to a load. Subjects who exaggerate subjective responses tend to be more anxious, self-conscious and have low self esteem, and may be more likely to report other sy mptoms as well (Schwartz et al. 1978; Taylor et al., 1953; Lipman et al., 1969). Also, subjects with anxiety or depression may demonstrate enhanced physiological or ventilatory responses to a load when compared to control groups. Laviete et al. (2000) showed that subjects with hi gher ratings of perception also had increased Ve in the presence of small and large loads, and were more unlikely to maintain constant ventilation. This suggests that subjects who are symptom amplifiers or overperceivers may have increased ventilation with inspiratory loads. High anxious subjects had a hi gher minute ventilation to a CO2 challenge in conditions of minimal information and control when CO2 is given first, suggesting an important order effect for high-anxiety subjects. The subjects continue th is breathing pattern during room air trials, and the pattern is not observed when the placebo is given first or when the trial was predictable and controlled (Van De Bergh et al, 1995). This suggests a respirator y learning effect, which can be offset by providing verbal inform ation about the procedure. There are many cortical and sub cortical projec tions to the brainstem, where the respiratory center is located, that may infl uence breathing. As a result, even a brief thought of a stressful event may significantly influence breathing patte rn. Masaoka and Homma, (2000) demonstrated an increase in respiratory frequency was observe d during anticipation of anxiety. They used the dipole tracing method to invest igate brain activity synchronized with physiological responses. Neural activity (electric current sources during anticipation of anxiety) was found in the right temporal pole and left amygdala and synchronized with the onset of inspiration. The amygdala

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30 plays a role in human emotions such as fear and anxiety (Davis et al., 1992). These areas associated with anxiety directly produce respir atory change. Respirator y discomfort has been demonstrated in brain imaging st udies to involve the activation of the limbic and cerebellar regions of the brain. Breathing is controlled unc onsciously but can be consci ously modulated. Similarly, human fear and anxiety respons es are clearly mediated by bo th conscious and unconscious processes. Respiratory instabilit y may reflect a thinking style that emphasizes intensely stressful cognitions. Individual levels of a nxiety affect respiratory frequenc y, especially expiratory time in normal subjects (Masaoka and Homma, 1997). Ma saoka and Homma (2001) determined that trait anxiety not only determines the strength of the emotion of a nxiety in individuals, but also influences behavioral breathing independently from metabolic demands Anxiety itself may enhance involuntary muscle contraction a nd possibly cause a respiratory change. Disruption to breathing can be highly distressful. Harver and Lorig (2000) report that Individuals sensitive to their br eathing continue to be concerne d about their physiological state, and in a classic feed-forward loop, exhibit furt her hyperventilation and an array of symptoms including shortness of breath, di zziness, chest tightness and chest pain. The event itself becomes anxiety-provoking, and individuals become fearful of repeating th e incident, effectively making the next even seem more stressful and there by continuing the feed-for ward nature of the cascade. Measures of Anxiety and Emotion In addition to subjective measures of anxiet y, heart rate is a widely used measure of physiological response. Heart rate acceleration has been observe d when subjects are asked to imagine participating in fea r-provoking scenes (Bauer and Cr aighead, 1979). Bradley et al. (1993) and Greenwald et al. (1989) showed that unpleasant slides tend to be associated with

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31 greater cardiac decelera tion. This difference between the tw o findings (heart rate acceleration with fearful imagery and heart rate decelerati on with unpleasant slides ) demonstrates that because of its great sensitivity to attentional and response factor, h eart rate performs poorly as a reliable measure of emotional state (Bauer 1998). Unlike skin conductance, the direction and pattern of heart rate changes de pend to a large extent on the nature of the stimulus and the manner in which the individual interacts with task demands. For the present study, we will monitor heart rate with a pulse sensor. Emotional judgments can be standardized a nd assessed using a simple dimensional view which assumes emotion can be defined as a coin cidence of values on a number of different strategic dimensions (Lang et al. 1997). Osgood et al (1957) founded the view in which factor analyses conducted on a wide va riety of verbal judgments indicated that the variance in emotional assessments were accounted for by th ree major dimensions: two primary dimensions of affective valence (pleasant to unpleasant) and arousal (calm to excited) and a third dimension of dominance or control. Lang (1980) devised the Self-Assessment Manikin (SAM), an affective rating system to asses the three dimensions of pleasure, arousal and dominance. A graphic figure is used to depict each of th e three dimensions to indicate emotional reactions. The valance dimension (Appendix A, 1) consists of 5 figur es which range from a smiling, happy figure to a frowning, unhappy figure. The arousal dimension (Appendi x A, 2) represents arousal (likened to the sensation elicited by running up a flight of stairs ) caused by chest pressure, ranging from absolutely no chest pressure and arousal to maximum chest pressure and arousal. The third dimension of dominance or control is represented with a large figure (total control) to a small figure (dominated).

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32 Aversive Respiratory Stimuli A mechanism that may underlie the link betwee n overperception of dys pnea and anxiety is interoceptive conditioning, a learning process by wh ich initially neutral, low-level interoceptive (respiratory) sensations become predictiv e for subsequent dyspnea and anxiety (US, unconditioned stimulus). The extent to which the degree of airway pathology corresponds with self-reported symptoms varies strongly among pulmonary patients. For example, some patients hardly notice significant changes in respirat ory functioning ("underperceivers"), while others report symptoms in excess of physiological abnormalities ("over perceivers") (Nguyen et al, 1996). The latter group is characterized by excessi ve medication intake, unwarranted illness behavior and hospitalization (Put et al, 1999; Put et al, 2000). Within the two-dimensional affective space of emotions (Lang, Bradley & Cu thbert, 1990) respiration covaries particularly with arousal. Nyklicek, Thayer and Van D oornen (1997) found that emotions can be discriminated most successfully by the respirat ory component, which is related to the arousal dimension. Inhalation of 20% CO2 has been used previously as a US in fear conditioning studies in a normal population (Forsyth, 1998). In addition to the more traditionally used CO2 stimulus, preliminary studies in this labor atory have shown that inspirat ory loads are aversive. Using a differential conditioning paradigm, we tested whether interoceptive hypercapnic conditioning could be established in healthy subjects. An increased pressure on the upper arm (40 mmHg) served as conditional stimuli (CSs); a 20 s inhalation of 20% CO2 enriched air and an inspiratory resistive load (15 cmH20) serv ed as unconditional stimuli (U S). Both the training and the extinction phase consisted of 3 CS+ and 3 CS presentations (semi-randomized). SCR, EEG, pulse rate, FETCO2, mouth pressure, airflow and tidal volume were recorded during stimulus presentations. Following each trial, participants rated the trial on 3 emotional dimensions of

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33 pleasantness, arousal and dominance. Subjects al so rated fear, breathle ssness and other panic symptoms experienced after each stimulus pres entation. The subjective rating results indicate that the inspiratory resistive load and CO2 inhala tion were equally aversive The inspiratory load elicited greater breathlessness than CO2 inhala tion. Both load and CO 2 independently elicit panic symptoms. These results suggest that bot h CO2 inhalation and inspiratory loads elicit aversive subjective sensations. Thes e results further suggest that lo ads can be used to investigate panic symptoms. Van De Bergh et al. (1995) established a respiratory le arning model in a Pavlovian conditioning paradigm and analyzed the relations hip between respiratory responses and somatic complaints during acquisition and test. Occasiona l reductions in carbon dioxide may cause both somatic responses that underlie subjective complaints and subs equently increases in negative affectivity that then lower the perceptual th reshold for variations in somatic responses. Aversive respiratory stimuli may increase an in trospective, apprehensive, negativistic and vigilant perceptual/ atte ntional focus to their bodies which may lower the perceptual threshold for somatic sensation (Van De Bergh et. al., 1995). Likewise, it is concei vable that altering the breathing dimensions by applying extended loads will cause somatic responses which will in turn increase negative affectivity, lowering the perceptual threshold for breathing. The aversive subjective sensations induced during our CO2 conditioni ng studies suggest the need for further investigation of the unpleas antness of inspiratory resistive loads. These preliminary results are consistent with studies demonstrating that patie nts affected by chronic obstructive pulmonary disease are more likely to have depression and anxiety. This suggests that altered and disrupted breathing is not only unpleasant, but induces fear and altered perception of the true respiratory state.

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34 It is hypothesized that sustained pres entation of resistive loads above 15 cmH2O/l*sec-1, will increase negative affectivity as load duration increases, resulting in increased magnitude estimation and subjective symptom expression.

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35 CHAPTER 2 PERCEPTION OF MULTIPLE BR EATH RESISTIVE LOADS Introduction A patients emotional reaction to a sense of breathlessness exacerbate s their perception of breathlessness (Bailey et al., 2004).The extent to which the degree of airway pathology corresponds with self-r eported symptoms varies strongl y among pulmonary patients. For example, some patients hardly notice signi ficant changes in re spiratory functioning ("underperceivers"), while others report symp toms in excess of physiological abnormalities ("overperceivers") (Woods et. al., 2003). The latter group is characterized by excessive medication intake, unwarranted illness behavior and hospitalization (Put et al., 1999; Put et al., 2000). The respiratory mechanical load to breathing is increased in most pulmonary diseases. Asthma is a common pulmonary disease that is asso ciated with increases in respiratory resistance and decreased respiratory compliance. This incr eases the mechanical load to breathing. An asthma attack is characterized by a transient, episodic increased resistance and decreased compliance that is sustained for minutes to hou rs. This means that the patient must make multiple inspiratory efforts against an increase d load related to the bronchoconstriction. The patient initially experiences a single-breath type of load but then progresses to experience a multiple-breath load application. This is one reason why single-breath loading only partially simulates the sensations related to an asthmatic attack (Buki et al., 1987). There has never been a systematic investigation of the perception of increased resistance when applied for multiple breaths, which is a closer representation of natu rally occurring transient airway obstructive event such as an asthma attack. Further, previous studies have shown decreased sensitivity to increased mechanical loads in asthmatic subjects but only using relatively small loads (up to 8

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36 cmH2O/l*sec-1) (Bonnel et al.,1987). Adults admitted into the hospital with asthma are significantly more likely to be female (Woods et al., 2003; Senthilselva n et al., 1995; Hyndman et al., 1956; Wilkins et al., 1993;, Rao et. al., 2003) Measures of asthma morbidity have been shown to be disproportionately higher in female s (Woods et al., 2003) and there is a higher trend for female readmission (Chen et al., 2003). Ventilation of the lung is a mechanical proce ss. The respiratory muscles act as a pump to generate the driving force for ai r to flow and increase the lung volume. Application of extrinsic mechanical loads of sufficient magnitude will a lter this mechanical process and lead to a conscious awareness of the loads (Wiley et al., 1966; Noble et al .,1972; Campbell et al.,1961; Buki et al., 1983; Wiley et al., 1966). Respirat ory load perception is commonly studied using only single breath load applicati on (Wiley et al., 1966). The inspir atory load is applied for a single breath and there are 2-6 unloaded breath s before another load is applied. Studies of background loading have used small resistive loads (<8 cmH2O/l*sec-1) applied continuously (Wiley et al., 1966). Subjects usually accommodate to the background load (Ro) and do not report perception of the background within 2-3 mi nutes. It is also known that an elevated background load increases the thre shold for resistive load detec tion (Bennett et al., 1962). The perception of respiratory mechanical events is dependent on two processes. The first is load detection, which has been studied by using di fference threshold methods (Campbell et al., 1961; Wiley et al., 1966; Buki et al., 1983 ). The magnitude that elicits de tection of 50% of the stimulus presentations is defined as the detection thres hold. The load-detection threshold has been shown to be a constant fraction of the background load intrinsic to the respiratory apparatus and the subject (Wiley et al., 1966). Hence, an increased background load will require a greater added load for detection to occur. Th e second perceptual pr ocess is cognitive evaluation of the load.

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37 This includes differentiation of the load t ype and accompanying estimation of the load magnitude (ME). Subjects are usually presented a single breath load and required to provide an estimate of the sensory magnitude of a supra-de tection-threshold load using a numerical scale such as the modified Borg scale, or cross-moda lity matching, such as hand grip tension sensation to match the magnitude of respiratory sensation. These studies show that the perceived estimate of the load magnitude is linearly related to the load magnitude when a log-log transformation is used. The slope of the line is a measure of the sensitivity of the subject to the stimulus. Again, these studies are done using only si ngle-breath load presentations. We wanted to determine if the perception of an inspiratory load changes as a function of the nu mber of continuous inspiratory efforts against the load. With a small increase in sustai ned extrinsic resistance (Ro<5 cmH2O/l*sec-1), such as background loading used in previ ous load detection studies (Wile y et al., 1966), have reported that subjects accommodate to the load but did not investigate the perception of the increased, sustained background load, only load added to the background (Wiley et al., 1966). Higher load magnitudes have not been used as elevated extr insic background loads so it is unknown if this accommodation occurs over the range of inspiratory resistance (5-50 cmH2O/l*sec-1) commonly reported with an asthma attack. We hypothesi zed that multiple breaths against a small (>15 cmH2O/l*sec-1) resistive load would result in a decr eased perceived load magnitude as the number of inspiratory efforts increase (accommod ation). We further hypothesized that increasing the resistance would increase the perceived load magnitude (amplification) with increased breath number for resistive lo ads greater than 15 cmH2O/l*sec-1. We tested these hypotheses using magnitude estimation of multiple breaths (10 breaths) against a range of inspiratory resistance (5-40 cmH2O/l*sec-1). We reasoned that if the perceived magnitude of the load decreased from

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38 breath 1 to breath 10, then the subject accommoda ted to the load. Conversely, if the subject estimated the load as greater on breath 10 th an breath 1, then the s ubject amplified their perception of the load. Methods and Materials The study was approved by the University of Florida Institutional Review Board. Consent was obtained from each subject prior to the beginning of the study. The subjects were asked to refrain from strenuous physical activity, large meals and caffeine for at least four hours prior to the tests. The subjects intrinsic respir atory resistance was measured using the forced oscillation method, which utilizes sound waves to determine the airway re sistance. The subjects were seated in front of the apparatus and brea thed normally through the mouthpiece, with their cheeks supported by both of their hands. Appr oximately 10 tidal breaths were collected continuously to determine airw ay resistance (Jaeger Toennies Medizintechnikmit System, V. 4.5). The test was repeated at least three times for each subject with a one-minute rest between repetitions. The average of three measures of the resistance at 5 Hz was used as the subjects respiratory system resistance. Subjects were seated in a lounge chair in a sound isolated chamber separated from the experimenter and the experimental apparatus (Figure 2-1). The subjec t respired through a mouthpiece connected to a non-rebreathing valve w ith their nose clamped. The inspiratory port of the valve was connected to the resistive load manifold. The inspiratory airflow signal was displayed on the oscilloscope in front of the subj ect. Initially, the subject was asked to breathe normally with eyes closed. A line was placed on the oscilloscope screen that coincided with peak inspiratory flow rate with quiet breathing. This wa s the target flow rate. The subject opened their eyes and continued to breathe normally while watching the osci lloscope screen. They were instructed to have the peak of the airflow with each breath hit the target line during the entire

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39 experiment. The subjects were instructed that when the red light above the oscilloscope was illuminated, the next breath would be loaded. The light was illuminated during expiration, cueing the subject that the next 10 breat hs had a load and they should br eathe to their airflow target on each breath. A green light was illuminated on th e 1st, 5th and 10th loaded breath cueing the subject to estimate their perceived magnitude of the load. They estimated the perceived load magnitude using a 0-10 modified Borg categor y scale according to how difficult it was to breathe-in. A series of test loads was presented in a practice session to familiarize the subject with load sensation, the perception task and the range of loads. After practice, the subject was given a 5-minute rest. There were a total of 2 experime ntal sessions. During th e experimental session, the subject listened to music of their choice, which masked experiment sounds. There were a total of 6 resistive lo ad magnitudes: 5 cmH2O/l*sec-1, 10 cmH2O/l*sec-1, 15 cmH2O/l*sec-1, 20 cmH2O/l*sec-1, 30 cmH2O/l*sec-1, and 40 cmH2O/l*sec-1. Each load was presented for 10 consecutive breaths. At loaded breaths 1, 5, and 10, the subject provided a magnitude estimation of their difficulty of breathing. A minimum of a 10-breath period with unloaded breathing separated each load presentation to allow the subj ect to recover. The loads were presented in a randomized block design. A total of 3 presentati ons of each load were applied in the first experimental trial. A 5-minute break was given before repeating the load presentation protocol in the second experimental trial. Th is resulted in a total of 6 10-br eath presentations of each load magnitude over 2 experimental trials. The subj ect was monitored by the experimenter with a video camera that did not reco rd the subjects image. Data Analysis: The Borg scores for breath 1, 5 and 10 for each individual subject were averaged for the 6 presentations of each load ma gnitudes. The averages were then grouped into a

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40 male group and female group by load magnitude. Three-way repeated measures analyses of variance were used to examine the effects of sex, load magnitude, and breath number on the magnitude estimation of the resistive load. If any 3-way ANOVA results indicated a significant main effect of training at = 0.05, then a t-test of dependent variables was performed. Statistical comparisons were conducted with Sigma Stat so ftware, with a significance level of p<0.05. The dependent variables for breaths 1, 5, and 10 were averaged for each load magnitude trial. The results are presented in Table 2-1. A total of 13 subjects were tested for this study. Results The results of the 3-way ANOVA in dicated that the main effect of load magnitude on load magnitude estimation (F = 64.793, p< 0.001). There wa s a significant effect of sex on breath number (F = 4.379, p< 0.014). There was no si gnificant sex by load magnitude by breath number interaction (F = 0.377, p=0.955). Overall, the group (Figure 2-2) did not ch ange their magnitude estimation by breath number for resistive loads ranging from 5 cmH2O/l*sec-1 to 15 cmH2O/l*sec-1 but had a significant difference in magnitude es timation for breath number of 30 cmH2O/l*sec-1 and 40 cmH2O/l*sec-1. The ME response for breaths 1,5 and 10 for the combined subject groups, males and females is presented in Table 2-1. There was no significant group difference betwee n the ME for breath 1 and 10 for R loads of 5 cmH2O/l*sec-1, 10 cmH2O/l*sec-1, 15 cmH2O/l*sec-1, and 20 cmH2O/l*sec-1 but there was a significant group difference for large R loads of 30 cmH2O/l*sec-1 and 40 cmH2O/l*sec-1 (Table 2-1). For the male group, the average ME rati ng for the smallest resistive load (5 cmH2O/l*sec-1) for the first breath was not signifi cantly different than the 10th breath. Similarly, the average ME rating for females for this load magnitude was not significantly different by the 10th breath (Figure 2-3). The ME for males did not change between breath 1 and 10 for the 5 cmH2O/l*sec-1,

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41 10 cmH2O/l*sec-1, 15 cmH2O/l*sec-1, 20 cmH2O/l*sec-1 and 30 cmH2O/l*sec-1 load magnitudes, but decreased with the 40 cmH2O/l*sec-1 load (Table 2-1, Figure 2.3). The ME for the 5th and 10th breaths of the 20 cmH2O/l*sec-1, 30 cmH2O/l*sec-1 and 40 cmH2O/l*sec-1 R loads was greater than the 1st breath for females (Tab le 2-1, Figure 2-4). Males estimated the 40 cmH2O/l*sec-1 R load on the 1st breath the same as females but the ME on the 10th breath, the male ME for 40 cmH2O/l*sec-1 was significantly less than females. These results demonstrate that magnitude estimation of resi stive loads greater than 15 cmH2O/l*sec-1 with a sustained 10breath trial significantly increases in females, but either did not change or significantly decreased in males. Discussion The ventilatory response to added mechanical loads can be regarded as the sum of two components: one representing the effect of the passive respiratory syst em and one representing the effect of neural load-compensating mechan isms (Axen et al., 1982). Although the ventilatory response to loads is governed primarily by re spiratory system mechanics and by reflexes, behavioral and cognitive factors pl ay a role in this response as we ll (Hudgel et al., 1982; Tiller et al., 1987). Cognitive factors can modify a subject s load response by symptom amplification, or they may exhibit an exaggerated subjective respon se to a load. In the present experiment, all subjects are presented with the same types and sizes of loads, eliciting similar neural loadcompensation reflexes. There was no significant group difference between the ME for breath 1 and 10 for R loads of 5 cmH2O/l*sec-1, 10 cmH2O/l*sec-1, 15 cmH2O/l*sec-1, and 20 cmH2O/l*sec-1 but there was a significant group difference for large R loads of 30 cmH2O/l*sec-1 and 45 cmH2O/l*sec-1. This indicates that subjects similarly perceive loads below 15 cmH2O/l*sec-1, and respond differently to large loads, 30 and 45 cmH2O/l*sec-1. These larger loads induce a psychophysiological response that may result in be havioral load compensation.

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42 Subjects who exaggerate subj ective responses tend to be more anxious, self-conscious and have low self esteem, and may be more likel y to report other symptoms as well (Schwartz et al. 1978; Taylor 1953; Lipman 1969). Also, subjects with psychological characteristics such as anxiety or depression may demonstrate altered phys iological and ventilatory responses to a load when compared to control groups. While the pr esent study showed an increasein perception of loads greater than 20 cmH2O/l*sec-1 it remains unknown if the psycholog ical state of the subjects was altered by sustained loaded breathing. Futu re studies are needed to include subjective measurements to determine psychological st ate related to sustai ned loaded breathing. Axen (1984) reported that men actively pr olong inspiration more than women during resistive loading, and women actively shorten in spiration more than men during inspiratory loading, although these differences do not reach st atistical significance. The load-compensation behavior exhibited by men and wo men was similar and tidal volume responses to loading do not differ (Axen 1984). In addition to physiological di fferences, Axen (1984) suggested that men and women could perceive the same load differently, due to the fact that load detection capability depends critically on intrinsic impedance (Wiley 1966). Intrinsic impedance is due to mechanical properties of the subjects respiratory system. While the subjects in the current study had sex predicted normal pulmonary mechanics, there were respiratory mechanical differences between males and females. Thus, the results of the pr esent study support the s uggestion that men and women perceive the same load diffe rently in part due to sex differe nces in respiratory mechanics. Females tend to have a greater sensitivity to their perception of physical stimuli. As previously reviewed (Edwards 2003), females dem onstrate significantly great er pain sensitivity for both experimental and clinical pain. Women with respiratory disorders such as COPD selfreport more psychological distress than men ((Laurin 2007; Di Marco et al. 2006). Female

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43 patients are more disposed to anxiety that co rrelates well with the dyspneic component of chronic obstructive pulmonary disease (Di Marc o et al. 2006). When females are affected by pulmonary disease, they report less confidence in their ability to control their respiratory symptoms and have less total a nd activity-related quali ty of life compared to men (Laurin 2007.) These sex-related predispositions and differences are consistent with thesustained loaded breathing magnitude estimati on difference demonstrated in the present study. The perception of altered respiratory functi on by women may be more sensitive but less specific than by men, and socio-cultural factors (w hat a patient feels is socially acceptable or expected) also play a role in the sex differences in the pe rception, reporting, and diagnostic interpretation of respiratory symptoms (Beck lake and Knauffman, 1999). Psychological factors such as depression have also been linked to the reporting of respirat ory symptoms, though sex differences in rates of reporting by psychological status have not been examined (Becklake and Knauffman, 1999). Further research is necessary to determine the psychological responses and differences in magnitude estimation of sustaine d inspiratory loads betw een the two sexes. These results suggest that the difference between the ME for breath 1 and breath 10 may be a function of the change in ventilatory state and may reflect the induction of an affective component to the load sensation. It remains unknown what cognitive and emotional responses are induced during multiple-breath resistive loads. It is also unknown if specific subject groups are more susceptible to aversive respiratory stimuli. For this reason, we chose to extend this study to include ventilatory response and subjective measures of multiple breath resistive loads. These results lead us to our ne xt study of the subjective and c ognitive responses to sustained breath for multiple loads.

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44 Table 2-1 The mean ME (standard deviation) for males and females for each load magnitude and breath number. The indicated significan t difference (p<0.05) for ME between breath number for a load magnitude. The # indicates a significant difference (p<0.05) between sexes for the corresponding load magnitude and breath number. Group Load (cmH2O/l*sec-1) Breath 1 Breath 5 Breath 10 R=5 1.5 (.9) 1.3 (.9) 1.4 (.9) R=10 2.2 (.1) 2.3 (.3) 2.4 (.3) R=15 3.1 (.4) 3.3 (.2) 3.3 (.6) R=20 3.8 (.2) 4.4 (.2) 4.7 (.6) R=30 4.9 (.6) 5.8 (.6) 5.9 (.4) R=40 6.1 (.1) 6.9 (.7) 6.9 (.0) Male Load (cmH2O/l*sec-1) Breath 1 Breath 5 Breath 10 R=5 2.1 (.8) 1.7 (.8) 1.7 (.9) R=10 2.6 (.0) 2.5 (.9) 2.6 (.1) R=15 3.8 (.5) 3.4 (.4) 3.5 (.4) R=20 4.1 (.3) 4.0 (.0) 4.1 (.1) R=30 5.2 (.2) 5.5 (.0) 5.3 (.0) R=40 6.7 (.5) 6.3 (.5) 5.6 (.5)*# Female Load (cmH2O/l*sec-1) Breath 1 Breath 5 Breath 10 R=5 1.1 (.6) 1.1 (.9) 1.3 (.8) R=10 1.8 (.9) 2.0 (.4) 2.2 (.3) R=15 2.9 (.7) 3.1 (.0) 3.1 (.6) R=20 3.5 (.9) 4.7 (.2)* 5.1 (.7)* R=30 4.7 (.7) 6.0 (.7)* 6.4 (.5)* R=40 5.6 (.2) 7.0 (.9)* 7.4 (.9)*#

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45 Figure 2 -1.Experimental set up for experiments 1 a nd 2. Subjects were seated in a sound isolated room and separated from the experiment to avoi d any detection and observation of experimental manipulations by the subject. Their image was ob served via video camera but not recorded, and the resistive manifold was attached to the mouthpiece.

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46 0 1 2 3 4 5 6 7 8 9 10 1 5 10 Breath Number R5 R10 R15 R20 R30 R40* *All Subjects Figure 2-2. The mean ( standard deviation) ME scores of all subjec ts according to load magnitude and breath number. The ve rtical axis is the ME scores The horizontal axis is the breath number the ME for each load magnitude wa s made. The indicate d significant difference (p<0.05) for ME between breath number for a load magnitude.

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47 0 1 2 3 4 5 6 7 8 9 10 1510 Breath Number R5 R10 R15 R20 R30 R40A. Male *# 0 1 2 3 4 5 6 7 8 9 10 1510 Breath Number R5 R10 R15 R20 R30 R40* * *#B. Female Figure 2-3. The mean ( standard deviation) ME scores of males and females according to load magnitude and breath number. The ve rtical axis is the ME scores The horizontal axis is the breath number the ME for each load magnitude. A) The average ME scores for males. B) The average ME scores for females. The indicate d significant difference (p<0.05) for ME between breath number for a load magnitude. The # indica tes a significant difference (p<0.05) between sexes for the corresponding load magnitude and breath number.

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48 Male Male Female Female 0 1 2 3 4 5 6 7 8 9 10Breath Number One Breath Number TenMagnitude Estimation *# Figure 2-4. The mean ( standard deviation) ME for males and females on breath 1 and 10 for the 40 cmH2O/L*sec-1 resistive load. The indicated significant difference (p<0.05) for ME between breath number for a load magnitude. Th e # indicates a significa nt difference (p<0.05) between sexes for the corresponding lo ad magnitude and breath number.

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49 CHAPTER 3 PERCEPTION AND SUBJECTIVE RATINGS OF 20-BREATH RESISTIVE LOADS IN MALES AND FEMALES Introduction Inspiratory loading has been used to st udy the perceptual mechanisms underlying and mediating respiratory mechanical sensation and perception. There are load related parameters mediating respiratory sensation, specifically, the mechanical effects on volume, airflow and pressure; perceptual changes, magnitude estimati on and anxiety responses; changes in the central neural activity; and blood chem ical changes. To fully analyze perceptual changes such as magnitude estimation and anxiety responses to in spiratory loads, it is necessary to analyze breathing pattern changes, percep tual reports, and subjective feelings associated with the inspiratory load changes. Breathing is unique among autonom ic nervous system functions in its easy susceptibility to both conscious and unconscious control (Sinha et al., 2000). Although br eathing is not always consciously controlled, a brief thought of breathi ng or a disruption of normal breathing will cause immediate conscious awareness of respiration. Hu man fearful responses, lik e breathing, are also mediated by both conscious and unconscious pro cesses (Sinha et al., 2000). Inter-individual psychological variables can be expected to modul ate the perception of br eathing and response to aversive respiratory loads. CO2 inhalation produces anxiety and frank panic in panic disorder patients more so than in controls (Sinha et. al 2000). Our Preliminary Studies have demonstrated that a 15 cmH2O/lps inspiratory R load has equal measures of aversiveness to 20% CO2. (Miller abstract, 2006, 2007; Van Diest abstract, 2006). It is, however, unknown if ventilation against an increased inspiratory load elicits subjective aversive feelings. Many of the chemical inductors of animal fearful responses that mimic panic attacks (caffeine, CRF, yohimbine, lactate and cholecystoki nin) also stimulate re spiration as well as

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50 produce somatically uncomfortable sensations (Sinha et al., 2000). During breathing, increases in respiratory rate or minute ventil ation appear to correlate substa ntially with subjective anxiety (Sinha et al., 2000). During panic attacks, compla ints of air hunger, dyspne a, and rapid breathing are common (Papp et. al, 1993). This leads us to the suggestion that re spiration is directly linked to subjective feelings of anxiety a nd panic, and in turn, respirator y stimuli may be aversive. Anxiety is most commonly used to describe an unpleasant emo tional state or condition. An emotional state exists at a given moment in time and at a particular leve l of intensity. Anxiety states are characterized by subj ective feelings of tension, appr ehension, nervousness, and worry, and by activation or arousal of the autonomic nervous system (Speilberger et al., 1966, 1972, 1976, 1979). Although these states may be transitor y, they can recur when evoked by appropriate stimuli and may endure over time if the evoking condi tions persist. Personality traits, on the other hand, are conceptualized by Campbell et al. (1963 ) as acquired behavioral positions. They dispose an individual to view th e world in a particular way to manifest object consistent tendencies. Trait Anxiety refers to relatively stable individual differences in anxiety-proneness (STAIS Manual). It is the differences between people in the tendency to perceive stressful situations as dangerous or threat ening and to respond to such situa tions with elevations of their state anxiety. Emotional judgments can be standardized a nd assessed using a simple dimensional view which assumes emotion can be defined as a coin cidence of values on a number of different strategic dimensions (Lang et al. 1997). Osgood et. al (1957) used factor analyses conducted on a wide variety of verbal judgments to indicate th at the variance in emotional assessments were accounted for by three major dimensions: two primary dimensions of affectiv e valence (pleasant to unpleasant) and arousal (calm to ex cited) and a third dimension of dominance or control. In 1980,

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51 Lang devised the Self-Assessment Manikin (SAM), an affective rating system to asses the three dimensions of pleasure, arousal a nd dominance. A graphic figure is us ed to depict each of the three dimensions to indicate emotional reactions. The va lance dimension (Appendix A, 1-1) consists of 5 figures which range from a smiling, happy fi gure to a frowning, unhappy figure. The arousal dimension (Appendix A, 1-2) represents arousal (likened to the sensat ion elicited by running up a flight of stairs) caused by chest pressure, ranging from absolutely no chest pressure or arousal to maximum chest pressure and arousal. The third dimension (Appendix A, 1-3) of dominance or control is represented with a la rge figure (dominating or total control) to a small figure (dominated or total lack of c ontrol). The relationship of thes e emotional dimensions to load induced changes in breathing is, however, unknown. Based on the results of study 1, which demonstr ated a significant sex difference in response to sustained breathing against insp iratory loads, we incorporated the perception of extended loads with subjective measurements to determine the em otional effects of multiple-breath resistive loads in males and females. The extended load presenta tion was increased from 10 breaths to 20 breaths to allow the subject to adapt t o, perceive, and discriminate/eva luate the load. A prolonged load presentation is more representative of respir atory disease states. We included a no-load presentation (R=0 cm H20/l/s) to control for apparatus or instructional effects. Golla and Antonovich (1929) reported that any attempt to breathe through an open mouthpiece or mask, which is to say a piece of apparatus with centers the subjects attention on his breathing, invariably gives rise to an abnormal type of respiration. Examining th e ventilatory pattern, subjective responses, and magnitude estimation of multiple breath resistive loads demonstrated the connection between objective and s ubjective responses to aversive respiratory stimuli. It was hypothesized that sustained resistive load pr esentations, above the threshold of 15 cmH2O/l*sec-1,

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52 will increase negative affectivity as load durati on and magnitude increase, resulting in increased magnitude estimation and subjective estimations of fear of suffoca tion and sensations of dyspnea. It was further hypothesized the females would have greater negative affectiv ity than males. The following experiments te st these hypotheses. Methods and Materials Subjects. A total of 22 subjects were tested fo r this experiment. The average subject information is listed in Table 3-5. All subjects we re required to satisfy th e inclusion and exclusion criteria. Subjects were required to be in good general heath with no significant medical history of neurological, cardiovascular, resp iratory or any other major medical disorder. Subjects had to be free of any acute respiratory distress or, nasal congestion. The study was approved by the University of Florida Institutional Review Board. Consent was obtained from each subject prior to the beginning of the study. Subj ects were divided into high and low negative affectivity (NA) participants, using a median split of the State-Tr ait-Anxiety-Index (STAI) scores (Van den Bergh et al., 1998). Three subjects were excluded from the final data in clusion for the following reasons: poor subject compliance, failure to self-report exclusion criteria (the subject was discovered to be a smoker after the experiment), and equipment failure. Subjects were required to comply with the study by answering each question and reporting load magnitude and subjective responses following each load presentation. Failure to respo nd to the experimenters questions and evaluate loads resulted in exclusion of one subject due to poor compliance. Experimental Protocol. The subjects were asked to refr ain from strenuous physical activity, large meals and caffeine for at least four hours prior to the tests. Simple instructions were given to inform the subject how to complete the questionn aires, complete the pulm onary function test and breathe through the mouthpiece. A pulmonary function test (FVC, FEV1 and FEV1/FVC) recorded with forced expiratory maneuvers was performed. Subjects with less than 70% predicted

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53 FEV1 and FVC were excluded from the experiment All subjects met these criteria. The subjects intrinsic respiratory resistance was measured us ing the forced oscillation method. The subjects were seated in front of the apparatus and brea thed normally through the mouthpiece, with their cheeks supported by both hands. Approximately 10 tidal breaths were coll ected continuously to analyze respiratory resistance by computer (Jaeg er Toennies, Medizintech nikmit System, V. 4.5). The test was repeated at least three times fo r each subject with a one-minute rest between repetitions. The average of three measures of the resistance at 5 Hz was used as the subjects respiratory system resistance. Subjects were seated in a lounge chair in a sound isolated chamber separated from the experimenter and the experimental apparatus (Fig. 3-1). Prior to load testing, each subject was given a The State Trait Anxiety Inventory (S TAI), a 20-items questi onnaire (Appendix A) measuring anxiety as a trait or as a state (Spiel berger, C. D 1970). The STAI was repeated after the entire experiment was completed. The subject wa s then connected to the breathing apparatus and respired through a mouthpiece connected to a non -rebreathing valve with their nose clamped. The inspiratory port of the valve was connected to the resistive load manifold. The subjects were informed that at any time during the experiment, they could remove the mouthpiece if they felt they could not breathe. They were also informed that at no time would they be at risk of injury due to lack of oxygen or airflow, and with pr oper effort, could always maintain constant ventilation. At no time were they info rmed of the specifics of the load magnitude. Each subject was given a packet of the subjec tive responses prior to experimental trials. They followed along with the experimenter, who carefully explained each question, word meaning, and illustration. The subject was allowed to ask qu estions to clarify the me aning of the subjective responses. They were informed that the experime nter would give them a survey after each 20-

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54 breath load presentation, for a to tal of 15 surveys. They demonstr ated the ability to perform the task by completing a sample survey along with the experimenter. The subjects were instructed that when the light in front of them was illuminated, the next breath would be loaded. They were also given a verbal cue, Please rate your next breath using the magnitude estimation box. This verbal cue was not changed, regardless of inspiratory load strength or individual subject. The verbal cue was given a nd light illuminated during expiration, cueing the subject that the next 20 breaths had a load and they would be estimating the magnitude of that upcoming load. A red light was illuminate d on the 1st, 10th and 20th loaded breath cueing the subject to estimate their perc eived magnitude of the load. They estimated the perceived load magnitude using a 0-10 modified Borg category scale (Borg 1982) according to how difficult it was to breathe against the inspired load. A series of test loads was presented in a pr actice session to familiarize the subject with load sensation, the perception task and the range of loads. Initially, th e subject was asked to breathe normally. After a minimum of five normal breaths, they were given an example of a very small load of 5 cmH2O/l*sec-1. Then they were given an example of a large load of 30 cmH2O/l*sec1. They demonstrated proficiency and comprehens ion of the magnitude es timation by routinely pressing all buttons from 0-10. Th is also provided a reference for magnitude estimation results during data analysis. Af ter practice, the subject was given a 5-minute rest. There were a total of 3 experimental sessions over a maximum of 3 hour s. During the entire experiment, the subject listened to music of their choice, which masked experiment sounds. There were a total of 5 resistive load magnitudes: 0, 5 cmH2O/l*sec-1, 15 cmH2O/l*sec-1, 30 cmH2O/l*sec-1, and 45 cmH2O/l*sec-1. Each load was presented for 20 cons ecutive breaths, with the individual presentations separated by a minimum of 20 breat hs. At loaded breath 1, 10, and 20, the subject

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55 provided a magnitude estimation of their perceived difficulty of breathing. The subject then had a breathing period with no loads presented to allow the subject to recover. The 5 load magnitudes were presented once in a randomized block design during the experimental trial. There were 3 trials with the 5 load magnitude presentation order independently randomized for each trial. A 5minute break separated the experimental trials. This resulted in a total of three 20-breath presentations of each load magnitude over 3 experi mental trials. The subject was monitored by the experimenter with a video camera that di d not record the subjects image. After each 20-breath resistive load presentation, the subject wa s given a 4 page packet to enter their subjective responses (Appendix B). They were asked to rate the following: Fear of suffocation on a 0-10 m odified Borg scale (Borg 1982) General level of fear on a 0-10 m odified Borg scale (Borg 1982) SAM Ratings: The subject can select any of th e 5 figures comprising each scale, resulting in a 5-point scale for each dimension. Ratings are scored so that 5 represents a high rating on each dimension (high displeasure, high arous al, high dominance) and 1 represents a low rating on each dimension (low displeasur e, low arousal, and low dominance). Body Sensation Questionnaire: The Diagnosti c Symptoms Questionnaire (DSQ; Rapee et al., 1992) is a 15-item measure of the presence and intensity of 12 somatic and three cognitive DSM-III-R (American Psychiatric As sociation, 1987) panic symptoms. Intensity ratings for each endorsed symptom are made on a 4 point Likert-type scal e (0 = not at all to 4 = very strongly felt). A Likert-type scale pr esents a set of attitude statements. The following composite measures can be derive d from the DSQ: total number of physical symptoms and catastrophic and noncatastr ophic thought, mean intensity of physical sensations, cognitive symptoms and reported fear. Data Analysis The Borg scores for breath 1, 10 and 20 for each individual subject were averaged for each load magnitude and trial. The averages were then grouped into a male group and female group. Statistical comparisons were conducted w ith SigmaStat and SPSS software. Three-way repeated measures analyses of variance were used to examine the effects of sex, load magnitude, and breath number on the ME of the resistiv e load. If any 3-way AN OVA results indicated a

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56 significant main eff ect of training at = 0.05, then a t-test of depe ndent variables was performed. Statistical analysis of the magnitude estimati on was done by blinding the analyst to the sex to avoid any bias during data analys is. Differences between groups were evaluated for ventilatory, ME and subjective measures, with a significan ce level of p<0.05. Ventilatory pattern was examined using Powerlab software, Excel, and Sigm aStat. All 20 breaths of inspiratory resistiveloaded trial were selected for each subject in Powe rLab software, then translated into quantitative numerical correlates using Excel. Mouth pressure, inspiratory time, and maximum airflow were selected along with the subject s self-reported magnitude estimation. A total of 60 breaths from all 3 trials for each load were selected for each subj ect, resulting in a total of 300 loaded breaths per subject. Breaths 1, 10, and 20 were averaged for each load magnitude trial. The loaded breaths were binned or analyzed separately by load magn itude, trial number and se x before being analyzed in SigmaStat. A 3-way ANOVA of breathing pattern was done for sex, load magnitude and breath number for dependent variables airflow, inspir atory time and mouth pressure. The results are presented in Table 3-1. The subject estimated the load magnitude for each load at breaths 1, 10, and 20. The magnitude estimations were averaged across trials then analyzed using SigmaStat with a 3way repeated measures ANOVA for sex, load magnitude and breath number. All pairwise multiple comparisons were made using the Holm-Sidak method. Subjective measures were self -reported after each 20-breath presentation of each load magnitude for a total of 15 subjective reports (4 pages each). These results were transferred into SPSS and grouped by sex, load magnitude and breath number for each symptom estimate, then analyzed using a 3-way ANOVA. Post-hoc anal ysis for ANOVA was performed using the HolmSidak method.

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57 Results Ventilatory response : Breath number between load magn itudes were compared for each load (R=0 cmH2O/l*sec-1, 5 cmH2O/l*sec-1, 15 cmH2O/l*sec-1, 30 cmH2O/l*sec-1 and 45 cmH2O/l*sec-1) and breath 1, 10, and 20. Non-similar breat h numbers across load magnitude were not compared (i.e. breath 10, R=5 cmH2O/l*sec-1 with breath 20, R=15 cmH2O/l*sec-1). There was a significant effect of load magnitude on ai rflow, mouth pressure and inspiratory time. Importantly, for mouth pressure, airflow and time, there were no sex differences (Table 3-1). The group differences related to load magnitude are re flected in both males and females. Table 3-1 demonstrates the lack of significance between sexe s for airflow, and table 3-2 demonstrates the lack of significant difference between sexes for time The greatest difference in time and airflow is seen between the smallest of resistances (R=5cmH2O/l*sec-1) and the largest of resistances (R=45 cmH2O/l*sec-1) and is demonstrated in Figures 3-2 and 33. There is a linear increase in time and decrease in airflow as a functi on of load magnitude. Inspiratory time (Ti) lengthens as load magnitude increases and airflow decreas es as load magnitude increases. Magnitude estimation : A three-way repeated-measures ANOVA showed main effects for sex, load magnitude and magnitude estimation of the load (table 3-3). The effects of load magnitude and sex, as well as load duration, were found to be significant in subjects magnitude estimation of the load (Figures 3-4, 3-5, and 3-6). Load R=30 cmH2O/l*sec-1 and R=45 cmH2O/l*sec-1 were found to have significant differences for breaths 10 and 20 between males and females. For R= 15 cmH2O/l*sec-1, the magnitude estimation was signi ficantly different for breath 20 between groups. Within sexes, the male group had an overall decreasing magnitude estimation trend for R= 15, 30, and 45 cmH2O/l*sec-1, between breaths 1 and 20 (Figures 3-4, 3-5, and 3-6). Although females demonstrated no significant diffe rence between breaths 1 and 20 within their

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58 group, the figures in the ME data (Figures 3-4, 3-5, and 3-6) demonstrate a trend to increase in the ME for all load magnitudes with ME p=0.06 for R 45 cmH2O/l*sec-1 between breath 1 and 20. The log-log slopes (table 34) were analyzed with a repeated-measure ANOVA, and also demonstrated main effects for sex, load magnitude and magnitude estimation of the load (Figure 36). Although breath 1 of R=45 cmH2O/l*sec-1 was not found to be significantly different, breaths 10 and 20 demonstrated group significant differen ces. Significant differences were found for the ME of all loads between breaths 1 and 20, demonstr ating an alteration in perception of each load after sustained presentation of load. Female subj ects had a lower slope in dicating a compression of the perceptual score range. Fema les on breath 20 had a higher R5 score than males (they rated the smallest load greater than the males). Female ME slope decreases and male slope increases at breath 20 (figure 3-4, bar graph for slopes), be cause females compressed all their magnitude estimation into the higher score range. Subjective responses : A 3-way ANOVA showed main effects for sex (F= 121.299, p<0.001), load magnitude (F=100.976, p<0.001) a nd breath number (F=137.515, p<0.001) to the subjective response. There was a significant intera ction between sex and load (F= 12.469, p<0.001), sex and symptom magnitude estimati on (F=2.764 p<0.001) and load and symptom magnitude estimation (F=5.738, p<0.001). These result s are presented in ta bles 3-6 and 3-7 and Figure 3-7. As a group, load levels resulted in su bjective increases in fear fear of suffocation, distress, arousal due to chest compression, faintne ss, dizziness, trembling, and dyspnea. There were significant sex differences for the following subjective responses: fear, fear of suffocation, happiness, arousal due to chest compression, fear of losing control, faintness, dizziness, trembling and tingling. There were no signi ficant group differences for sense of control, dyspnea, and palpations.

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59 A repeated-measures ANOVA showed non-significan t effects for sex in the mean scores of the State-Trait Anxiety Index (STAI) for subject s pre-experiment and po st-experiment. KruskalWallis One Way Analysis of Variance on Ranks of the delta-scores of the difference preand postexperiment did demonstrate signi ficant differences for men in trait anxiety post experiment. A multiple pairwise comparisons procedure (Dunns method) was used. Females had no significant change. These results are demonstrated in table 3-8 and Figures 3-9 and 3-10. Discussion Human subjects can easily detect and scale respiratory mechanical loads (Kelsen 1982, Kifle 1997; Killian 1981; Lansing 1996; Bijl -Hofland 2000; Taguchi 1991; Burki 1984; Burki 1983; Burki 1978; Bennett 1962). The respiratory load detection threshold is a psychophysical measure of respiratory sensation (Zechman 1986). Re spiratory perception is a result of the physical awareness (what is sensed) and affective judgment (how it feel s). Respiratory perception with added inspiratory resistive loads follows St evens psychophysical power law (Burki 1980; Gottfried S 1981; Killian 1982; Killian 1981; Wi ley 1978). Consequently, perceived magnitude ( ) of a stimulus is related to the physical magnitude of the stimulus ( ) by a constant (k) and an exponent (n): =k n. Most load perception studies have ex amined the perception of single breath resistive loads. This is the fi rst study to combine behavioral m easures, ventilatory analysis, and magnitude estimation with multiple breath resistive loads. These results demonstrate that the difference between the ME for breath 1 and breath 20 is a function of sex, th e change in ventilatory state from breath 1 to 20, and reflects the i nduction of an affective component to the load sensation. The results of the present study demonstr ate that the affective responses indicate that prolonged breathing against respiratory loads of moderate to high magnitude are aversive and cause negative affect.

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60 Ventilatory response : The ventilatory response to added mechanical loads can be regarded as the sum of two components: one representing th e effect of the passive respiratory system and one representing the effect of neural load-compensating mechanisms (Axen 1982). The load compensating component represents the action of neural mechanisms that modify the pressure developed by loaded respiratory muscles (Zhao et al. 2002). In conscious humans, repeated mechanical loading activates neural load-compe nsating mechanisms. The range of the neural adjustment varies with both load size and type, and is mainly a non-chemical stimulus initiating this behavior (Axen 1983). The present study demonstrated that, for airf low and time, there are no sex differences in breathing pattern. This finding agrees with previous studies examin ing the sex-related ventilatory response to multiple breath resistive loads (Axen 1983; Axen 1984). Tidal volume responses do not differ between sex, and the combined group respons e to sustained loads is qualitatively similar. The present study extended this by identifying group differences related to load magnitude reflected in both males and females. Table 3-1 de monstrates the lack of significance between sexes for airflow, and Table 3-2 demonstrates the lack of significant difference between sexes for time. Hence, both sexes exhibit similar load compensati on ventilatory responses to sustained breathing against resistive loads. Adding resistive loads ( Rs) to respiration changes airflo w, volume, and pressure and the magnitude of the external load determines the degree of change (Kellerman 1999). The greatest load dependent difference in time and airflow is s een in between the smallest of resistances (R=5 cmH2O/l*sec-1) and the largest of resistances (R=45 cmH2O/l*sec-1). The inspiratory time is prolonged to allow for the decrease d airflow to fill the lung to th e same or greater tidal volume, maintaining alveolar ventilation. The change in time and airflow is a linear function of load

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61 magnitude. As the load magnitude increases, insp iratory time lengthens and airflow decreases. This load compensation modulation of breathing pattern is sustained ove r the entire 20-breath trial. Magnitude estimation : The cerebral cortex is a significan t component of the neural system processing sensory information related to mech anical effort and pattern of respiration. Consequently, the cerebral cortex is one neural com ponent mediating the magnitude estimation of a load applied to breathing. The es timation of a magnitude of a load, along with initial detection of that load, is mediated by cortical processes, presumably within primary somatosensory and association areas (Webster, 2000). Human subjects are consciously aware of breathing against mechanical loads, and can easily discriminate th e presence and type of respiratory mechanical loads, estimate the size of the loads and scale th ese respiratory mechanical stimuli (Williams et al., 1988). As increasing resistance oppo ses the respiratory pump, magnit ude estimation of the applied respiratory load increases proporti onally to the magnitude of the R. This was evident in the present study, as load magnitude increased, magn itude estimation increased accordingly (Table 35). Ti increased and airflow decreased along with load magnitude. Davenport et al.,(1991) used an animal model to examine detection of inspiratory loads in dogs. A tracheal stoma was used to eliminate the upper airway and tracheal re ceptors as sources of afferent input. Chemoreceptors were also elim inated as an input, because blood gases did not change. Davenport et. al. (1991) c oncluded that respiratory muscle s are the most likely site for afferent information related to load detection. The animal results are consistent with load magnitude estimation with douoble-lung transplant pa tients (Zhao et al., 2003) and load elicited cortical activity in tracheostomized patients (D avenport, et al., 2006). Th ey suggested that the respiratory pump muscle afferents mediate the sensory response to load compensation and the mechanisms mediating load detection and magnit ude estimation are different. Our results in the

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62 present study support this hypothesis, demonstrat ed by the differing magnitude estimations of identical loads with similar breat hing patterns between sex groups. Magnitude estimation of inspiratory loads can be expressed in rela tion to magnitude of inspiratory pressure (Redline et al. 1991) This relationship can be attrib uted to the efferent command driving the respiratory system and magnit ude estimation may be centrally mediated. The perceived magnitude of a load is linearly related to the added load when a log-log transformation is used. The slope of this relationship is an index of the perceptual sensitivity for the type of load presented. A numerically low slope value is indica tive of poor perception sensitivity (Julius et al., 2002). A high slope is indicative of increased percep tion sensitivity. The log-log slopes (table 3-4) demonstrated main effects for sex, load magnitude and magnitude estimation of the load (Figure 36). Although breath 1 of R=45 cmH2O/l*sec-1 was not found to be significantly different, breaths 10 and 20 demonstrated significant group differences Significant differences were found for the ME of loads between breaths 1 and 20, demonstrati ng an alteration in percep tion of each load after sustained presentation of load. Female subjects had a lower slope indicating a compression of the perceptual score range. Female sl ope decreases and male slope incr eases at breath 20 (figure 3-4, bar graph for slopes), because females had a grea ter ME of R5 on breath 20 that compressed their magnitude estimation into the higher score range Males had a signifi cant decrease in the magnitude estimation between breaths 1 and 20 in the opposite direction of the females. This provides evidence for a sex effect with males desensitizing with increasing breath number and females sensitizing with in creasing breath number. Subjective responses : Respiratory perception is a 2stage process. Stage 1 is the discriminative dimension and includes the awar eness of the spatial, temporal and intensity components of the respiratory disruption. In this stage, respiratory somatosensation generated by

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63 the discriminative awareness of respiratory stim uli is determined by the interaction between multiple respiratory afferent groups and brainstem respiratory motor drive. The second stage, the affective state, is a potentially important but little explored aspect of respiratory sensory processing. Within the two-dimensional affectiv e space of emotions (Lang, Bradley & Cuthbert, 1990) respiration covaries particularly with ar ousal. Nyklicek, Thayer and Van Doornen (1997) found that emotions can be discriminated most su ccessfully by the respiratory component, which is related to the arousal dimension. Subsequent to initial somatose nsation, respiratory stimuli can evoke distress and motivate cognitive behavior. It has been previously shown that stress and anxiety is related to the over pe rception of respiratory symptoms but the mechanism behind this connection is unclear (Put, 1999; Put, 2000). It is possible that distressing respiratory sensations may condition human subjects to have a heightened awareness of their breathing and may even induce respiratory related anxiety. Ventilation is controlled primarily by respirator y system mechanics, arterial blood gases and neural reflexes. However, behavi oral and cognitive f actors also play a significant role in ventilatory neural response to loads (Hudgel 1982; Tiller 1987). Cognitive factors can modify a subjects load response by sympto m amplification, or they may e xhibit an exaggerated subjective response to a load. Subjects who exaggerate subjective responses tend to be more anxious, selfconscious and have low self esteem, and may be more likely to report other symptoms as well (Schwartz et al. 1978; Taylor 1953; Lipman 1969). Al so, subjects with anxiety or depression may demonstrate altered physiological or ventilatory responses to a lo ad when compared to control groups. Differences in the perception associated with loading between su bjects and groups reflect differences in the subjective responses to loads.

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64 Some subject groups, such as lif e-threatening asthmatics, have a unique decreased perceptual reactivity to resistive loads, whic h cannot be explained by differences in respiratory effort, airway mechanics, or task performance ability (Kif le, Seng & Davenport, 1997; Kikuchi et al., 1994). These patients have a unique perceptual proc essing deficit to respiratory loads and were predominantly males. Webster and Colrain (2000) reported that this defi cit may be due to a problem in the transduction of afferent neural signals originating in muscle stretch receptors projecting to somatomotor cortical regions. Males in the present study demonstrated a perceptual decrease to sustained loads, which is evident by their decreasing magnitude estimation of the loads (figure 3-6). Further research is n eeded to determine if this male-related decrease in perception is due to a sex difference in the neural mechan isms mediating respirat ory load perception. It is possible that individuals with altered lo ad perceptual sensitivity have an altered central neural threshold of respiratory pe rceptual gating. Sex differences in sensory gating can explain the altered subjective responses to lo ad levels of 15, 30 and 45 for the sensation of fear, fear of suffocation, faintness and arousal. Females have a lo wer threshold for these respiratory sensations and symptoms, hence they express a greater than 0 response at a lower load than men. At the highest load (R=45 cmH2O/l*sec-1), the significant difference disa ppears because the males begin to express a positive number rating for the subj ective sensations. Thus, the men have a higher threshold for these symptoms and when they are expressed, men have a lower average but eventually approach the symptom score of the females when the aversive respiratory stimuli gets large enough. The difference between male and female subjective symptom resistive load threshold may be due to differen ces in central neural gating. Although there was no significant difference betw een groups for state anxiety scores, the delta scores for trait anxiety significantly decr eased in males, and approached a significant

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65 increased in females. Trait anxiety implies di fferences between people in the disposition to respond to stressful situations with varying amounts of state anxiety. As a result differences of trait anxiety depends on the perception of a specifi c situation as psychol ogically dangerous or threatening, and depends on a pers ons past experience and backgr ound. High trait anxiety subjects exhibit state anxiety elevations more frequently because they tend to inte rpret a wider range of situations as dangerous or threat ening. Trait anxiety scores are ge nerally not influenced by stress and is relatively impervious to the conditions under which it has been given (Auerbach, 1973; Lamb, 1969; Spielberger et. al., 1973). This is s een in the male population who had a significant decrease in their trait anxiety, yet no increase in state anxiety. A subject who associates a high degree of dyspnea with the in troduction of a small inspiratory load to the airway can be considered a symptom amplifier (Laviette 2000). There was no group difference in the sensation of dyspnea, and dyspneic ratings incr eased linearly across both subject groups. Therefore, none of the subjects tested in this experiment were dyspnea symptom amplifiers, and their subjective results were representative of the respiratory aversiveness of the sustained inspiratory loads. Individuals with high measures of state-trait anxiety have increased S2/S1 ratios with auditory and somatosensory stimulation suggestin g reduced ability to gate-out some sensory stimuli (ODonnell et al., 2007; Chou et al., 2007). This suggests that indi viduals with existing conditions of anxiety have an al tered perceptual process, although this area needs to be examined in relation to respiratory sens ation. Inducing anxietylike responses with respiratory aversive stimuli also disrupts normal somatosensory percep tion in some subjects, as demonstrated by the magnitude estimation differences and di fferences in subjective responses.

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66 Sex differences : The most likely source of the difference lies in the cognitive and emotional realm. Not only was there a lack of sex differenc e seen in physiological measurements, males and females changed their magnitude estimation scores in opposite directions. It is important to note that there was no sex difference in the first br eath baseline magnitude estimation values, which represents the discriminative component of respir atory somatosensation. This indicates that during the course of 20 breaths of load presentation, th e emotional component of respiratory perception was recruited by female subjects to enhance their pe rception of the load, resu lting in a significantly different evaluation of the load. Sex differences in the response and over-percepti on of symptoms are seen with many disease states. When patients are affected by pulmonary disease, women report less confidence in their ability to control their respirator y symptoms and have less total a nd activity-related quality of life compared to men (Laurin 2007). Female patients are more exposed to psychological impairment that correlates well with the dys pneic component of chronic obst ructive pulmonary disease (Di Marco et al. 2006), which may correlate with th e psychological changes demonstrated in the present study after prolonged brea thing against inspiratory loads. Females tend to have a greater sensitivity to their perception of physical stim uli. Edwards (2003) demonstrated significantly greater pain sensitivity in females for both experi mental and clinical pain. Females in the general population report a greater frequency, intensity a nd duration of pain-related symptoms than males (Edwards 2003). The perception of altered respiratory function by women may be more sensitive but less specific than by men (Becklake and Kn auffman, 1999). Dyspnea is perceived as more important in womens quality of life scales than in mens (J ones 1992). Becklake and Knauffman (1999) also reported psychological f actors such as depression have been linked to the reporting of respiratory symptoms, though sex differences in rates of repor ting by psychological status have not

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67 been examined. This sex difference in respir atory symptom perception is supported by the sex related modulation of affective symptoms by resistive load in the present study. Conclusion In conclusion, this experiment demonstrates a significant sex difference in the perception, subjective ratings, and affective re sponse to sustained inspiratory re sistive loads. Sustained loads over 15 cmH2O/l*sec-1 elicit more negative affect response s in females, as demonstrated by increased ratings of fear, fear of suffocation, arousal, chest pre ssure, dizziness, fear of losing control, and sense of unreality. Sustained loads elicit sensatio ns of dyspnea in both males and females, indicating that subjects do not adapt or accommodate their sens e of dyspnea to large loads, but rather have to work ha rder to adjust to them. This is also evident in the ventilatory response of increasing airflow and time across both groups.

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68 Table 3-1 The peak airflow for each resistive lo ad magnitude, breath the ME was made and sex. There was there no significant difference between sexes for airflow. Female Airflow (L/sec) Mean Std Dev Male Airflow (L/sec) Mean STD DEV q Value P R=0 Breath 1 0.10 0.02 R=0 Breath 1 0.12 0.03 0.39 >0.05 Breath 10 0.09 0.02 Breath 10 0.10 0.03 0.34 >0.05 Breath 20 0.10 0.02 Breath 20 0.10 0.03 0.02 >0.05 R=5 Breath 1 0.10 0.02 R=5 Breath 1 0.13 0.07 Ns >0.05 Breath 10 0.09 0.02 Breath 10 0.10 0.04 Ns >0.05 Breath 20 0.09 0.02 Breath 20 0.11 0.05 Ns >0.05 R=15 Breath 1 0.09 0.02 R=15 Breath 1 0.09 0.03 Ns >0.05 Breath 10 0.08 0.02 Breath 10 0.07 0.01 Ns >0.05 Breath 20 0.07 0.02 Breath 20 0.08 0.02 Ns >0.05 R=30 Breath 1 0.08 0.02 R=30 Breath 1 0.07 0.02 Ns >0.05 Breath 10 0.07 0.02 Breath 10 0.06 0.02 Ns >0.05 Breath 20 0.07 0.02 Breath 20 0.07 0.02 Ns >0.05 R=45 Breath 1 0.06 0.02 R=45 Breath 1 0.07 0.02 0.49 >0.05 Breath 10 0.06 0.02 Breath 10 0.05 0.01 0.28 >0.05 Breath 20 0.06 0.01 Breath 20 0.06 0.03 0.80 >0.05 Table 3-2 The inspiratory time for each resistive load magnitude, breath the ME was made and sex. There was no significant difference be tween sexes for inspiratory time. Female Time (sec) Mean STD DEV Male Time (sec) Mean STD DEV q Value P R=0 Breath 1 3.34 0.70 R=0 Breath 1 2.85 0.55 0.90 >0.05 Breath 10 3.02 0.75 Breath 10 3.03 0.96 0.49 >0.05 Breath 20 2.91 0.63 Breath 20 2.73 1.10 0.66 >0.05 R=5 Breath 1 3.87 0.84 R=5 Breath 1 3.29 0.98 Ns >0.05 Breath 10 3.58 0.63 Breath 10 3.29 0.62 Ns >0.05 Breath 20 3.67 0.61 Breath 20 2.68 0.81 Ns >0.05 R=15 Breath 1 4.55 1.27 R=15 Breath 1 3.93 1.06 Ns >0.05 Breath 10 4.01 0.92 Breath 10 3.58 0.80 Ns >0.05 Breath 20 4.09 0.89 Breath 20 3.76 0.93 Ns >0.05 R=30 Breath 1 4.85 1.14 R=30 Breath 1 4.24 1.16 Ns >0.05 Breath 10 3.97 1.31 Breath 10 4.02 1.19 Ns >0.05 Breath 20 4.16 0.99 Breath 20 4.26 1.10 Ns >0.05 R=45 Breath 1 5.56 1.46 R=45 Breath 1 4.62 1.06 0.59 >0.05 Breath 10 5.00 1.63 Breath 10 4.32 0.91 0.10 >0.05 Breath 20 4.99 1.48 Breath 20 4.38 1.12 0.37 >0.05

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69 Table 3-3 Mean magnitude estimation for each re sistive loads at breath 1, 10, and 20 for males and females. The mean ( standard deviati on) and corresponding pvalues between load magnitude and between sex is presented when significantly different. Female ME Breath 1 Breath 10 Breath 20 t (M vs F) P-value P-value between sexes R=0 0.08 (0.16) 0.18 (0.23) 0.18 (0.20) 0.212 R=5 1.37 (1.18) 1.44 (1.10) 1.47 (1.14) 2.262 R=15 3.35 (1.54) 3.47 (1.92) 3.48 (1.90) 2.472 p<0.02 (Breath 10) R=30 5.73 (1.48) 6.1 (1.39) 6.27 (1.30) 5.981 p<0.005 (Breath 10) p<0.00006 (Breath 20) R=45 6.37 (1.98) 7.42 (1.44) 7.62 (7.78) 5.077 *p=0.06 p<0.005 (Breath 10) p<0.0001(Breath 20) Male ME Breath 1 Breath 10 Breath 20 P-value P-value P-value between sexes R=0 0.02 (0.05) 0.07 (0.09) 0.17 (0.17) 0.212 R=5 1.37 (0.95) 1.44 (0.59) 1.47 (0.26) 2.262 R=15 3.19 (0.81) 2.51 (1.07) 2.34 (0.65) 2.472 p<0.01 p<0.02 (Breath 10) R=30 5.05 (1.37) 4.18 (1.36) 3.38 (1.17) 5.981 p<0.009 p<0.005 (Breath 10) p<0.00006 (Breath 20) R=45 6.49 (1.37) 5.57 (1.36) 4.68 (1.17) 5.077 p<0.02 p<0.005 (Breath 10) p<0.0001(Breath 20) Table 3-4 Mean ( standard deviation) log ME, l og resistive load and loglog slope are presented for breath 1, 10, and 20, along with the corr esponding between load p-values. Female ME logs Breath 1 Breath 10 Breath 20 P-val R=0 0.62 (0.28) 0.60 (0.28) 0.57 (0.24) R=5 0.03 (0.42) 0.02 (0.39) 0.10 (0.37) R=15 0.49 (0.18) 0.48 (0.24) 0.47 (0.27) R=30 0.75 (0.11) 0.78 (0.10) 0.79 (0.10) p<0.05 R=45 0.78 (0.14) 0.86 (0.09) 0.88 (0.08) p<0.05 ME Log-Log Slope 0.89 (0.41) 0.91 (0.39) 0.79 (0.44) p<0.05 Male ME logs Breath 1 Breath 10 Breath 20 P-val R=0 0.78 (0.00) 0.78 (0.00) 0.66 (0.21) R=5 0.09 (0.32) 0.23 (0.28) 0.36 (0.23) p<0.05 R=15 0.49 (0.13) 0.36 (0.20) 0.35 (0.15) p<0.05 R=30 0.69 (0.13) 0.60 (0.14) 0.51 (0.15) p<0.05 R=45 0.80 (0.10) 0.73 (0.11) 0.66 (0.12) p<0.05 ME Log-Log Slope 0.94 (0.34) 0.94 (0.41) 1.05 (0.30)

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70 Table 3-5 Mean ( standard deviation) subject demographic data for study 2. Male Female Age (yrs) 23.70 ( 3.4) 32.56 ( 10.81) Weight (lbs) 170.10 ( 24.07) 143.22 ( 21.01) Height (in) 70.55 (3.01) 67.56 (1.72) FVC (liter) 4.91 ( 0.45) 4.17 (0.13) FVC % Pred Avg 1.06 ( 0.16) 0.85 ( 0.00) FEV1 (liter) 4.59 ( 0.31) 3.35 (0.62) FEV1 % Pred Avg 1.11 ( 0.13) 1.27 (0.00)

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71 Table 3-6 Mean ( standard deviation) em otional subjective estimation responses to questionnaires. Significance between sexes is indicated by then asterisks. Fear Female Male F *P= <.05 R=0 0.06(0.19) 0(0) 0.81 R=5 0.15(0.22) 0.04(0.10) 1.87 R=15 0.67(0.57) 0.07(0.20) 7.92 R=30 1.18(1.07) 0.11(0.15) 8.01 R=45 1.70(1.77) 0.59(0.51) 2.92 Fear of Suffocation R=0 0.12(0.31) 0(0) 1.38 R=5 0.58(0.65) 0.30(0.39) 1.28 R=15 1.42(0.75) 0.56(0.58) 8.16 R=30 3(1.40) 1.30(1.20) 8.35 R=45 3.59(1.45) 2.37(1.31) 3.83 Happiness R=0 1.4(0.66) 1.41(0.97) 0.00 R=5 1.5(0.71) 1.48(0.96) 0.00 R=15 2.13(0.55) 1.52(1.04) 2.67 R=30 2.78(0.74) 1.67(0.99) 7.93 R=45 3.08(0.80) 2(1.09) 6.18 Sense of Control R=0 1.27(0.64) 1.33(0.78) 0.04 R=5 1.4(0.75) 1.41(0.76) 0.00 R=15 1.9(0.79) 1.63(0.90) 0.49 R=30 2.4(0.64) 1.82(0.87) 2.83 R=45 2.75(0.69) 2.56(0.83) 0.31 Chest Pressure R=0 1.13(0.32) 0.96(0.11) 2.27 R=5 1.4(0.66) 1.11(0.17) 1.61 R=15 1.77(0.74) 1.30(0.51) 2.55 R=30 2.32(0.79) 1.48(0.50) 7.39 R=45 2.68(0.93) 2.11(1.09) 1.47

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72 Table 3-7. Mean ( standard deviation) bodily subjective estimation re sponses to Diagnostic Symptom Questionnaire. Significance between sexes is indicated by the asterisks. Dyspnea Female Male F *P= <.05 R=0 0.15(0.31) 0(0) 2.11 R=5 0.38(0.57) 0.19(0.29) 0.85 R=15 0.91(0.75) 0.56(0.60) 1.32 R=30 1.36(0.74) 0.96(0.66) 1.61 R=45 1.82(0.94) 1.41(0.93) 0.97 Faintess R=0 0.09(0.22) 0(0) 1.59 R=5 0.24(0.52) 0(0) 1.84 R=15 0.42(0.50) 0.04(0.11) 5.21 R=30 0.70(0.61) 0.07(0.15) 9.03 R=45 0.89(0.63) 0.52(0.53) 2.01 Dizziness R=0 0.39(0.77) 0(0) 2.32 R=5 0.51(0.77) 0(0) 3.89 R=15 0.89(0.80) 0.04(0.11) 10.15 R=30 1.18(0.87) 0.11(0.17) 13.00 R=45 1.35(0.97) 0.22(0.29) 11.15 Tingling R=0 0.24(0.53) 0(0) 1.67 R=5 0.21(0.46) 0(0) 1.76 R=15 0.24(0.40) 0(0) 2.91 R=30 0.61(0.99) 0(0) 3.02 R=45 0.79(0.87) 0(0) 6.68 Trembling R=0 0.09(0.22) 0(0) 1.59 R=5 0.15(0.41) 0(0) 1.25 R=15 0.18(0.41) 0(0) 1.8 R=30 0.32(0.44) 0.04(0.11) 3.50 R=45 0.52(0.57) 0.04(0.11) 6.19 Unreality R=0 0(0) 0(0) R=5 0(0) 0(0) R=15 0.18(0.35) 0(0) 2.47 R=30 0.24(0.40) 0(0) 3.32 R=45 0.42(0.56) 0(0) 5.12

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73 Table 3-7. Continued Palpitations Female Male F R=0 0(0) 0(0) R=5 0(0) 0(0) R=15 0.05(0.15) 0(0) 0.81 R=30 0.15(0.23) 0(0) 3.89 R=45 0.30(0.64) 0(0) 2.00 Fear of Losing Control R=0 0.27(0.71) 0(0) 1.31 R=5 0.27(0.55) 0.04(0.11) 1.56 R=15 0.35(0.60) 0.04(0.11) 2.35 R=30 0.52(0.81) 0.11(0.17) 2.16 R=45 0.94(0.96) 0.26(0.32) 4.07 Table 3-8. Male and Female change in (Delta ) STAI Scores before and after the load presentation trial. The indica ted significant difference (p<0.05) for ME between breath number for a load magnitude. Group N Median 25% 75% Q P<0.05 Female Delta State Anxiety 12 2.5 -1.5 9.5 6.6 Male Delta State Anxiety 10 -0.5 -3 3 6.6 Female Delta Trait Anxiety 12 3.5 -0.5 7 17.6 Male Delta Trait Anxiety 10 -3 -4 -1 17.6

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74 Figure 3-1 Experimental set up for experiment 2. Subjects were seated in a sound isolated room and separated from the experiment to avoid any detection and observa tion of experimental manipulations by the subject. Their image was ob served via video camera but not recorded, and the resistive manifold was attached to the mouthpiece. A

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75 Airflow Males0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16 Breath 1Breath 10Breath 20 Breath # Against LoadAirflow (l/sec) Load 1 Load 2 Load 3 Load 4 Load 5 Airflow Females0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16 Breath 1Breath 10Breath 20 Breath # Against LoadAirflow (l/sec) Load 1 Load 2 Load 3 Load 4 Load 5 Figure 3-2. Mean ( standard deviation) airflow for A) males and B) females against each load magnitude. A B

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76 TIme Males0 1 2 3 4 5 6 7 8 Breath 1Breath 10Breath 20 Breath # Against LoadTime (sec) Load 1 Load 2 Load 3 Load 4 Load 5 TIme Females0 1 2 3 4 5 6 7 8 Breath 1Breath 10Breath 20 Breath # Against LoadTime (sec) Load 1 Load 2 Load 3 Load 4 Load 5 Figure 3-3. Mean ( standard de viation) inspiratory time (Ti) for A) males and B) females against each load magnitude. There was no si gnificant difference between the two groups. B A

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77 -10 -8 -6 -4 -2 0 2 4 6 8 100Breath 1 0 B reath 3 5B r eat h 2 15 B reath 1 1 5B r e a t h 3 30Breath 2 45 B reath 1 45Breath 3Breath and Load Number Male PCO2 Average Female PCO2 Average Figure 3-4. Mean ( standard deviation) PCO2 change for males and females against each load magnitude. PC02 levels mm HG

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78 Male 0 2 4 6 8 10 Breath 1Breath 10Breath 20 Estimation Breath NumberMagnitude Estimation Score R5 R15 R30 R45* * Female 0 2 4 6 8 10 Breath 1Breath 10Breath 20 Estimation Breath NumberMagnitude Estimation Score R5 R15 R30 R45 Figure 3-5. Mean ( standard deviation) magnit ude estimation for A) males and B) females at breaths 1, 10 and 20 against each load magnitude. A B

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79 0 1 2 3 4 5 6 7 8 9 10 Breath 1Breath 10Breath 20 Estimation Breath Number R45 Female R45 Male R30 Female R30 Male R15 Female R15 Male R5 Female R5 Male # # # # Figure 3-6. Mean ( standard deviation) magn itude estimation for both males and females at breaths 1, 10 and 20 against each load magnitude The indicated signifi cant difference (p<0.05) for ME between breath number for a load ma gnitude. The # indicates a significant difference (p<0.05) between sexes for the correspondi ng load magnitude and breath number. *

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80 Female -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 Zero Five Fifteen Thirty Forty-Five Log Added Resistance cmH2O/l/s Breath 1 Breath 10 Breath 20 Male -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 Lo g Added Resistance cmH2O/l/s Breath 1 Breath 10 Breath 20 Zero Five Fifteen Thirty Forty-Five Figure 3-7. Mean log of the magnitude estimation for A) females and B) males at breaths 1, 10 and 20 against each load magnitude. A B

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81 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 Breath 1Breath 10Breath 20 Estimation Breath Number Female Male Figure 3-8. Mean ( standard devi ation) log-log slope of the magn itude estimation-resistive load relationship for males and fema les at breaths 1, 10 and 20 against each load magnitude.

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82 -1 -0.5 0 0.5 1 1.5 2 2.5 3 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Females Males # # Figure 3-9. Mean ( standard devi ation) subjective reporting of th e general level of fear on a 010 scale in males and females. The # indicate s a significant difference (p<0.05) between sexes for the corresponding load magnitude and breath number.

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83 -1 0 1 2 3 4 5 6 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Male Female# # Figure 3-10. Mean ( standard deviation) subjec tive reporting of the gene ral level of fear of suffocation on a 0-10 scale in males and female s. The # indicates a significant difference (p<0.05) between sexes for the correspondi ng load magnitude and breath number.

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84 0 0.5 1 1.5 2 2.5 3 3.5 4 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Males Females Figure 3-11. Mean ( standard deviation) subjec tive reporting of the leve l of distress according to the Self-Assessment Maniken (SAM) Rating Scal e in males and females. The # indicates a significant difference (p<0.05) between sexes fo r the corresponding load magnitude and breath number.

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85 0 0.5 1 1.5 2 2.5 3 3.5 4 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Males Females Figure 3-12. Mean ( standard deviation) subjectiv e reporting of the level of control according to the Self-Assessment Maniken (SAM) Rating Scal e in males and females. The # indicates a significant difference (p<0.05) between sexes fo r the corresponding load magnitude and breath number. For this measurement, there was no significant difference between sexes.

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86 0 0.5 1 1.5 2 2.5 3 3.5 4 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Males Females # Figure 3-13. Mean ( standard deviation) subj ective reporting of the le vel of chest pressure according to the Self-Assessment Maniken (SAM) Rating Scale in males and females. The # indicates a significant differen ce (p<0.05) between sexes for th e corresponding load magnitude and breath number.

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87 -0.5 0 0.5 1 1.5 2 2.5 3 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Females Males * Figure 3-14. Mean ( standard deviation) subj ective reporting of the le vel of dyspnea according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The indicated signifi cant difference (p<0.05) for rating for a load magnitude. The # indicates a significant differen ce (p<0.05) between sexes for th e corresponding load magnitude and rating.

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88 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Females Males # # Figure 3-15. Mean ( standard deviation) subjec tive reporting of the leve l of faintness according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The # indicates a si gnificant difference (p<0.05) be tween sexes for the corresponding load magnitude and rating.

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89 -1 -0.5 0 0.5 1 1.5 2 2.5 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Females Males # # # Figure 3-16. Mean ( standard deviation) subj ective reporting of the le vel of dizziness according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The # indicates a si gnificant difference (p<0.05) be tween sexes for the corresponding load magnitude and rating.

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90 -1 -0.5 0 0.5 1 1.5 2 2.5 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Females Males Figure 3-17. Mean ( standard deviation) subj ective reporting of the f ear of losing control according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The # indicates a significant difference (p<0.05) between sexes for the corresponding load magnitude and rating.

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91 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Females Males # Figure 3-18. Mean ( standard deviation) subjec tive reporting of the leve l of trembling according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The # indicates a si gnificant difference (p<0.05) be tween sexes for the corresponding load magnitude and rating.

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92 -0.5 0 0.5 1 1.5 2 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Males Females # Figure 3-19. Mean ( standard deviation) subjec tive reporting of the leve l of tingling according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The # indicates a si gnificant difference (p<0.05) be tween sexes for the corresponding load magnitude and rating.

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93 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Male Female # Figure 3-20. Mean ( standard deviation) subjec tive reporting of the leve l of sense of unreality according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The # indicates a significant difference (p<0.05) between sexes for the corresponding load magnitude and rating.

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94 -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 1 1.2 zerofivefifteenthirtyfortyfive Loads cm H20/l*sec-1 Males Females Figure 3-21. Mean ( standard deviation) s ubjective reporting of the level of palpitations according to Diagnostic Symptoms Questionnaire (DSQ) Body Sensation Questionnaire in males and females. The # indicates a significant difference (p<0.05) between sexes for the corresponding load magnitude and rating.

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95 0 5 10 15 20 25 30 35 40 45 50 Pre S-AnxietyPost S-AnxietyPre T-AnxietyPost T-AnxietyWeighted Anxiety Score Female Male Figure 3-22. Mean ( standard de viation) STAI scores for state (S) anxiety and trait (T) anxiety. There were no significant differenc e preand postload presenta tion trial and between sexes for state and trait anxiety scores.

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96 -10 -5 0 5 10 15 20 FemaleMale Delta Anxiety Scores Delta S-Anxiety Delta T-Anxiety* Figure 3-23. Mean ( standard deviation) change (Delta) in STAI scores for state (S) anxiety and trait (T) anxiety preand postload presentation trial. There was no significant difference for female Delta S-anxiety and De lta T-anxiety preand post-lo ad presentation. Males had a significant decrease in Delta T-anxiety preand post-load presentation but no significant different for Delta S-anxiety.

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97 CHAPTER 4 PERCEPTION AND SUBJECTIVE RATINGS OF SUSTAINED BREATH RESISTIVE LOADS IN MALES AND FEMALES FINAL DISCUSSION Emotions can be discriminated most successf ully by the respiratory component (Nyklicek et. al., 1997). Central neural corre lates of anxiety, such as the amygdala and insulate cortex, are activated during respirat ory distress (Masaoka and Homma, 2000) Likewise, it is reasonable to deduce that respiratory distress elicits an affective response similar to anxiety. However, no study has been done to determine the relationshi p between emotional responses and respiratory resistive loads. This is the fi rst study to combine ventilatory pattern, magnitude estimation, and subjective measures with inspiratory loading. The results of this study demonstrate for all subjects, an increase in somato sensory and behavioral measures of stress and aversive responses as a function of increasing load and increasing duration of breathing ag ainst the loads. The results further demonstrate that males and fema les respond differently to sustained breathing against inspiratory resistive load s particularly within the realm of the affective dimension of respiratory somatosensation. Davenport and Kifle (2001) reported that ch ildren with life-threat ening asthma (LTA) have unique decreased perceptual sensitivity and processing deficit to inspiratory loads. While LTA patients include males and females, the as thmatic children that had reduced perception sensitivities and increased dete ction thresholds were males (Davenport and Kifle, 2001). This cannot be explained by differences in respiratory effort, airway me chanics, or task performance ability, but was reported to be due to central ne ural deficits evidenced by the absence of the respiratory-related evoked potenti al in LTA children with percep tual deficits (Kifle, Seng & Davenport, 1997; Kikuchi et al., 199 4; Webster and Colrain, 2000). However, these studies only investigated the perception of singl e-breath resistive loads, which ar e a poor clinical correlate for the perception of mechanical respiratory disord ers such as asthma and other forms of COPD.

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98 This study differentiates between single breath so matosensation and affective sensations related sustained breathing against respiratory loads. Th e present study demonstr ated a threshold for eliciting affective modulation of load perception (15 cmH2O/l*sec-1). For loads above this threshold, there was a relationship between the load magnitude, perceptual symptom reporting and number of breaths against the load. These resu lts suggest that as the subjects increased their respiratory drive to compensate for the increas ed respiratory work of breathing, perceptual symptoms changed. Of particular interest, was the significant sex e ffect in the respiratory load modulation of perception. Whereas females tend to potentiate their proces sing and perception of the sustained loads, males exhi bited symptom suppression in res ponse to sustained breathing the load. Males have higher mortality rates due to CO PD than females (Thom 1989; Vollmer et al., 1992). The male symptom suppression results of the present study suggest morbidity from respiratory disorders may be due to symptom s uppression. Males are less lik ely to seek medical care for respiratory disorders which may be due to an intrinsic tendenc y to decrease symptom perception and reduce the negative a ffect elicited from their illness. Dyspnea is perceived as less important for males on their quali ty of life scales than fema les (Jones 1992). As a result, decreased male patient initiation for medical car e makes them at a higher risk for unnecessary exacerbation of their disease and ultimately, at higher risk for death. One of the primary causes of death from asthma is a delay in treatment of an asthmatic attack. The male symptom suppression of an asthma exacerbation dependent increased load to breathing may predispose males to greater risk of morbidity from asthma due delays in recognition of an asthma attack severity.

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99 Alternatively, females will be more likely to seek medical care for discomfort and illness caused by respiratory distress. Contrary to the in crease in male morbidity due to COPD, females report higher shortness of breath (Dales 1989; Krzyzanowski 1992; Krzyzanowski 1986; Guslvik 1979). Aversive respiratory stim uli may increase introspection, apprehension, negativity and perceptual focus on the body, which in turn lo wers the perceptual threshold for somatic sensations (Van de Bergh 1995). As the present sustained-breath percep tual study demonstrates, females are not only more negatively affected by respiratory distress, they have a lower perceptual symptom threshold than men hence ar e more likely to quantify the extent of their increased respiratory load and respond more quickly. Although females will be more likely to seek tr eatment for respiratory disorders, they will also be more negatively affected by them. Women with respiratory disorders such as COPD selfreport more psychological distress than men (L auren et al., 2007). Females are also more exposed to the psychological impairment that co rrelates with the dyspneic component of chronic obstructive pulmonary disease (Di Marco et. al., 2006). In the prolonged respiratory loading of the present experiment, there was a significant in crease in female subjective responses such as fear, trembling, tingling, faintne ss, and fear of losing control. Women affected by pulmonary disease report less confidence in their ability to cont rol their respiratory symptoms and have reduced quality of life than men dealing w ith the same disease (Laurin et al., 2007). This increase in negative affectivity as well as exacerbation of the perception of the loads can result in a long-term state of anxiety or depression. Ps ychiatric disorders are three times more common in COPD patients, and are two times higher in females than in males (Laurin et. al., 2007). Psychological factors such as depres sion have been linke d to the reporting of respiratory symptoms, though sex di fferences in rates of reporti ng by psychological status have

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100 not been determined (Becklake and Knauffman, 1999). Hence, the results of this study support the hypothesis that obstructed breathing is aversi ve for all individuals and females should be more prone to respirat ory elicited anxiety. Males also differ from females in their effect of sustained breathing against inspiratory loads in the change in emotional state (state-tra it anxiety). Patients emotional reaction to a sense of breathlessness exacerbates their perception of breathlessness (Bailey et al., 1994), and females demonstrated a more emotional reaction to prol onged inspiratory loading, i.e females had a tendency to increase state and trait anxiety whereas males te nded to decrease preand post loaded breathing. Although these states may be transitory, they can recur when evoked by recurrent or inescapable appropriate stimuli fr om pulmonary disease and may endure over time particularly if the evoking stimuli condition th e subject to the aversive resistive load. The significantly increased incidence of anxiety disorders and lower quality of life in females experiencing respiratory diseases supports this mo st behavioral load conditioning effect. This can result in excessive medication intake, unwarranted illness behavior and hospitalization that is often seen in the overperceiver group of patients who report symptoms in excess of the physiological abnormality they are presente d (Put et. al, 1999; Put et. al., 2000). Thus, breathing and anxiety responses can be mediated by both conscious and subconscious processes. These responses differ be tween sexes and result in a varying perception and response to breathing disturbances. Awareness of these significant sex differences will allow clinicians to educate male patients to be s ubjectively aware of their respiratory disorders. Likewise, female patients should be manage d using preventative care immediately upon diagnosis of chronic obstructive pulmonary disease to avoid onset of depression or other anxiety disorders.

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101 APPENDIX A DIAGNOSTIC SYMPTOM QUESTIONNAIRE To which extent have you experienced the follo wing symptoms during the previous application stimulus? Please circle the correct answer. 1. Tingling sensations: 0 1 2 3 4 not at all slight moderate severe very severe 2. Fear of losing control: 0 1 2 3 4 not at all slight moderate severe very severe 3. Faintness: 0 1 2 3 4 not at all slight moderate severe very severe 4. Dyspnea: 0 1 2 3 4 not at all slight moderate severe very severe 5. Fear of dying: 0 1 2 3 4 not at all slight moderate severe very severe 6. Unreality: 0 1 2 3 4 not at all slight moderate severe very severe 7. Hot/cold flushes: 0 1 2 3 4 not at all slight moderate severe very severe

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102 8. Trembling: 0 1 2 3 4 not at all slight moderate severe very severe 9. Choking: 0 1 2 3 4 not at all slight moderate severe very severe 10. Fear of going crazy: 0 1 2 3 4 not at all slight moderate severe very severe 11. Abdominal Distress: 0 1 2 3 4 not at all slight moderate severe very severe 12. Chest pain: 0 1 2 3 4 not at all slight moderate severe very severe 13. Palpitations: 0 1 2 3 4 not at all slight moderate severe very severe 14. Sweating: 0 1 2 3 4 not at all slight moderate severe very severe 15. Dizziness: 0 1 2 3 4 not at all slight moderate severe very severe

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103APPENDIX B SUBJECTIVE ASSESSMENT MANIKEN RATING HAPPINESS, CHEST PRESSURE, AND CONTROL

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104APPENDIX C 0 Nothing at all 1 Very slight 2 Slight 3 Moderate 4 Somewhat severe 5 Severe (heavy) 6 7 Very severe 8 9 10 Very, very severe (almost maximal) 0 Nothing at all 1 Very slight 2 Slight 3 Moderate 4 Somewhat severe 5 Severe (heavy) 6 7 Very severe 8 9 10 Very, very severe (almost maximal) Please circle the level of fear of suffocation you have experienced during the previous application of the bodily stimulus Please circle the level of fear you have experienced during the previous application of the bodily stimulus

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105 LIST OF REFERENCES Aitken ML, Franklin JL, Pierson DJ, Schoene RB. Influence of body size and gender on control of ventilation. J Appl Physiol. 1986, 60 :1894-9. Altose MD, DiMarco AF, Gottfried SB, Strohl KP: The sensation of respiratory muscle force Am Rev Respir Dis 1982, 126: 807-811. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995, 152 (suppl): 77-121. Bailey P. The Dyspnea-Anxiety-Dyspnea Cycl eCOPD Patients Stories of Breathlessness: Its Scary When You Cant Breathe. Qualitative Heath Research 2004, 14 (6): 760-778. Bauer RM, Craighead WE. Physiological response to the imagination of fearful and neutral situations: the effect s of imagery instructions. Behav Ther 1979, 10 : 389-403. Bauer RM. Physiologic measures of emotion Review. J Clin Neurophysiol Sept. 15 1998, 5: 388-96. Becklake MR, Kauffmann F. Gender differences in airway behaviour over the human life span. Thorax 1999, 54: 1119-1138. Bennett ED, Jayson MIV, Rubenstein D, Campbell EJM. The ability of man to detect added non-elastic loads to breathing Clin Sci 1962, 23: 155-162. Bijl-Hofland ID, Cloosterman SGM, Van Scha ych CP, Van der Elshout FLL, Akkermans RP, Folgering HTM. Prevention of respiratory sensatio n assessed by means of histamine challenge and threshold loading tests. Chest 2000, 117: 954-959. Bonnel AM, Mathiot MJ, Jungas B, Grimaud C Breathing discomfort in asthma: role of adaptation level Bull Eur Physiopathol Respir 1987, 23 : 19. Borg, GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exercise 1982, 14 : 377-381. Boulet LP, Leblanc P, Turcotte H. Perception scoring of indu ced bronchoconstriction as an index of awareness of asthma symptoms. Chest 1994, 105 : 430-433. Bradley MM, Greenwald MK, Hamm AO. Affec tive picture processing. In: Birbaumer N, hman A, eds. The organization of emotions Toronto: Hogrefe-Huber, 1993, 48-65. Bradley MM, Lang PJ. Measuring emotion: the Self-Assessment Manikin and the Semantic Differential. J Beh Ther Exp Pyschiatry 1994, 1: 49-59.

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114 BIOGRAPHICAL SKETCH I received my Bachelor of Science in h ealth science education in May, 2003, from the College of Health and Human Performance at the Univ ersity of Florida in Gainesville, FL, with a specialization in health studies. I began working as a research a ssistant in Dr. Paul Davenports lab in the Department of Physiological Sciences in 2000, and joined the lab as a graduate student in June, 2003. I was admitted to PhD candidacy in spring, 2006. I was awarded an NIH T32 Neuroplasticity fellowship in 2006 and de fended my dissertation in October, 2007.