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Mechanisms of Manual Therapy

Permanent Link: http://ufdc.ufl.edu/UFE0022635/00001

Material Information

Title: Mechanisms of Manual Therapy
Physical Description: 1 online resource (103 p.)
Language: english
Creator: Bialosky, Joel
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: carpal, manual, pain, therapy, tunnel
Rehabilitation Science -- Dissertations, Academic -- UF
Genre: Rehabilitation Science thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Musculoskeletal pain is a common complaint requring billions of dollars in medical care and lost work time. Manual therapy (MT) is an effective form of treatment for musculoskeletal pain; however, the mechanisms though which MT works are undetermined. Biomechanical and neurophysiological effects are associated with MT and are suggested as potentially pertinent mechanisms. A shortcoming of the literature is that studies have considered individual mechanisms without thought to the potential collaboration between mechanisms. We present a model for the mechanistic study of MT to provide a framework for the design of future studies and allow better interpretation of past studies. Additionally, we present the results of 3 pilot studies and a dissertation study which have assessed components of the model. The three pilot studies explored potential mechanisms of a MT force applied to the low back of both healthy participants and those experiencing low back pain. In the first two studies, we observed c- fiber mediated hypoalgesia to standard thermal stimuli which was attributed to a spinal cord mediated effect of MT. As indicated by the model, a shortcoming of these studies was the failure to account for potential supraspinal mediated mechanisms. Subsequently, we manipulated participant expectation for experimental pain in the third study and observed a significant hyperalgesic effect of MT in individuals whose expectations were altered to expect greater pain. The findings of the three pilot studies suggest a consistent c- fiber mediated effect of MT at the dorsal horn of the spinal cord with the potential for a supraspinal effect (expectation) to further influence outcomes. Our study explored potential mechanisms of a specific MT technique to the upper extremity of individuals experiencing carpal tunnel syndrome (CTS). Participants were randomly assigned to receive a direct MT technique known to stress the median nerve or an indirect technique designed to minimize stress to the median nerve and underwent up to six sessions of MT over three weeks. Group differences were not observed in expectation for pain in response to treatment or in perception of which technique was received suggesting the indirect MT technique provides similar expectation and believability as the direct MT. Group differences were present in experimental pain perception with changes in c- fiber mediated pain observed in participants receiving the direct MT technique but not the indirect MT technique. An immediate hypoalgesic effect was observed in clinical pain in response to the MT which was independent of group assignment. Neither group dependent changes nor main treatment effects in clinical pain were reported over the 3 week period of the study. A small improvement in function was observed over the 3 week period of the study independent of group assignment. While controlling for baseline pain, both baseline immediate clinical pain hypoalgesic response to MT and baseline expectation for pain following the study were predictive of pain at the completion of the study. We present a model for the mechanistic study of MT along with 4 studies which have been guided by the model and assess specific parts of the model.
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 Joel Bialosky.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: George, Steven E.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022635:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022635/00001

Material Information

Title: Mechanisms of Manual Therapy
Physical Description: 1 online resource (103 p.)
Language: english
Creator: Bialosky, Joel
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: carpal, manual, pain, therapy, tunnel
Rehabilitation Science -- Dissertations, Academic -- UF
Genre: Rehabilitation Science thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Musculoskeletal pain is a common complaint requring billions of dollars in medical care and lost work time. Manual therapy (MT) is an effective form of treatment for musculoskeletal pain; however, the mechanisms though which MT works are undetermined. Biomechanical and neurophysiological effects are associated with MT and are suggested as potentially pertinent mechanisms. A shortcoming of the literature is that studies have considered individual mechanisms without thought to the potential collaboration between mechanisms. We present a model for the mechanistic study of MT to provide a framework for the design of future studies and allow better interpretation of past studies. Additionally, we present the results of 3 pilot studies and a dissertation study which have assessed components of the model. The three pilot studies explored potential mechanisms of a MT force applied to the low back of both healthy participants and those experiencing low back pain. In the first two studies, we observed c- fiber mediated hypoalgesia to standard thermal stimuli which was attributed to a spinal cord mediated effect of MT. As indicated by the model, a shortcoming of these studies was the failure to account for potential supraspinal mediated mechanisms. Subsequently, we manipulated participant expectation for experimental pain in the third study and observed a significant hyperalgesic effect of MT in individuals whose expectations were altered to expect greater pain. The findings of the three pilot studies suggest a consistent c- fiber mediated effect of MT at the dorsal horn of the spinal cord with the potential for a supraspinal effect (expectation) to further influence outcomes. Our study explored potential mechanisms of a specific MT technique to the upper extremity of individuals experiencing carpal tunnel syndrome (CTS). Participants were randomly assigned to receive a direct MT technique known to stress the median nerve or an indirect technique designed to minimize stress to the median nerve and underwent up to six sessions of MT over three weeks. Group differences were not observed in expectation for pain in response to treatment or in perception of which technique was received suggesting the indirect MT technique provides similar expectation and believability as the direct MT. Group differences were present in experimental pain perception with changes in c- fiber mediated pain observed in participants receiving the direct MT technique but not the indirect MT technique. An immediate hypoalgesic effect was observed in clinical pain in response to the MT which was independent of group assignment. Neither group dependent changes nor main treatment effects in clinical pain were reported over the 3 week period of the study. A small improvement in function was observed over the 3 week period of the study independent of group assignment. While controlling for baseline pain, both baseline immediate clinical pain hypoalgesic response to MT and baseline expectation for pain following the study were predictive of pain at the completion of the study. We present a model for the mechanistic study of MT along with 4 studies which have been guided by the model and assess specific parts of the model.
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 Joel Bialosky.
Thesis: Thesis (Ph.D.)--University of Florida, 2008.
Local: Adviser: George, Steven E.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022635:00001


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1 MECHANISMS OF MANUAL THERAPY By JOEL ERIC BIALOSKY 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 2008

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2 2008 Joel Eric Bialosky

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3 To Laurie, Justin, and Walter whose lives were turned upside down so that I could pursue my Ph.D. You not only supported this endeavor, but also served as an inspiration for me to succeed. This would not have been possible without your love and encouragement during these past four years. What an adventure it has been. I loved sharing it with you and look forward to our next adventure.

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4 ACKNOWLEDGMENTS I thank Steve George for providing an oppor tunity to chase a dream I never thought possible and the mentoring to successfully complete the journey. I thank Mark Bishop for helping to integrate me from a clinical to an academic mindset. I thank Mike Robinson and Don Price for taking on a narrowminded physical ther apist and opening my eyes to thoughts and ideas I had never considered. As for my committee as a whole, I cannot thank them enough for the time devoted, the knowledge shared, and the professional behaviors modeled. I thank Anthony Delitto for his friendship and mentori ng who, on a rainy summer night in his living room in Pittsburgh, gave me the c onfidence to move to Florida in pursuit of a dream. I thank Krista Vandenborne whose drive an d desire were major factors in my decision to come to the University of Florida and for whose personal con cern and actions for the well being of my family I will always be grateful. I thank my family for their support and understanding while their kids/grandkids/nephews/cousins moved across the country. Finally, I thank my father whose support of this decision gave me great peace of mi nd when deciding to come to the University of Florida.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................4LIST OF TABLES................................................................................................................. ..........8LIST OF FIGURES.........................................................................................................................9LIST OF ABBREVIATIONS........................................................................................................ 10ABSTRACT...................................................................................................................................12 CHAP TER 1 INTRODUCTION..................................................................................................................142 LITERATURE REVIEW OF MECHANISMS OF MANUAL THERAPY......................... 16Biomechanical Mechanisms................................................................................................... 16Neurophysiological Mechanisms............................................................................................ 17Peripheral Mechanisms:.................................................................................................. 17Spinal Cord Mechanisms:................................................................................................ 17Pain perception.........................................................................................................18Afferent discharge....................................................................................................18Motoneuron pool excitability................................................................................... 19Muscle activity.........................................................................................................19Supraspinal Mechanisms:................................................................................................ 20Nonspecific mechanisms....................................................................................... 20Sympathetic response............................................................................................... 21Opioid response........................................................................................................21Limitations of the Current Mechanistic Literature................................................................. 223 COMPREHANSIVE MODEL OF THE ME CHANISMS OF MANUAL THERAPY ........24Limitations of Proposed Model..............................................................................................254 IMPLEMENTATION OF COMPREHENSIVE MODEL..................................................... 28Pilot Study #1: Effect of MT on Experi mental Pain in Healthy Participants........................ 28Pilot Study #2: Effect of MT on Experimental Pain in Participants with Low Back Pain.... 29Pilot Study #3: The Influence of Expectati on on Hypoalgesia Following MT in Healthy Participants..........................................................................................................................30Summary of Pilot Studies.......................................................................................................32

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6 5 METHODS.............................................................................................................................43Specific Aims:........................................................................................................................43Research Hypothesis:..............................................................................................................43Participants:............................................................................................................................43Measures:................................................................................................................................44Demographics..................................................................................................................44Expectation......................................................................................................................44Psychological Questionnaires.......................................................................................... 45Fear of pain questi onnaire-III (FPQ-III):.................................................................45Pain catastrophizing scale (PCS):............................................................................45Tampa scale of kinesiophobia (TSK):...................................................................... 45Visual analog scale:..................................................................................................45Functional Questionnaires............................................................................................... 46Disability of the arm, shoulder, and hand questionnaire (DASH):.......................... 46Boston questionnaire:...............................................................................................46Pain Measurement...........................................................................................................46Mechanical visual analog scale (MVAS):................................................................ 46Numeric rating scale (NRS):.................................................................................... 47Nerve Conduction Study : ................................................................................................47Physical Examination...................................................................................................... 47Intervention:....................................................................................................................48Procedures:.............................................................................................................................48Statistical Analysis:.......................................................................................................... ......50Believability of Placebo.................................................................................................. 50Treatment Effects............................................................................................................50Predictors of Outcomes................................................................................................... 516 RESULTS...............................................................................................................................55Believability of Placebo....................................................................................................... ...55Perceived Group Assignment:.........................................................................................55Expectation for Pain at Completion................................................................................ 55Treatment Effects....................................................................................................................56Associated Experimental Pain Perception....................................................................... 56Evaluation pre to post NDI.......................................................................................56Discharge pre to post NDI........................................................................................56Baseline evaluation to discharge post NDI.............................................................. 57Nerve Conduction Studies...............................................................................................57Associated Clinical Pai n, Symptoms, and Function........................................................ 57Immediate change in clinical pa in and symptoms (Figure 6-5)............................... 57Change in clinical pain and symptoms over 3 weeks............................................... 58Three week change in function................................................................................ 58Predictors of Outcomes................................................................................................... 59Predictors of pain at 3 weeks....................................................................................59Predictors of function at 3 weeks.............................................................................59

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7 7 DISCUSSION.........................................................................................................................75Believability of Placebo....................................................................................................... ...75Treatment Effects....................................................................................................................77Response to Experimental Pain....................................................................................... 77Implications to the Model of the Mechanistic Study of MT...........................................79Clinical Pain and Symptoms Response........................................................................... 80Implications to the Model of the Mechanistic Study of MT...........................................82Predictors of Outcomes......................................................................................................... ..83Predictors of Pain and Disability.....................................................................................83Implications to the Model of the Mechanistic Study of MT...........................................84Clinical Implications:......................................................................................................... .....84Limitations:................................................................................................................... ..........87Future Directions....................................................................................................................88LIST OF REFERENCES...............................................................................................................92BIOGRAPHICAL SKETCH.......................................................................................................103

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8 LIST OF TABLES Table page 4-1 Descriptive statistics of sample (healthy participants) for pilot study #1 .......................... 344-2 Change in A fiber mediated pain in pilot study #1.......................................................... 344-3 Descriptive statistics of sample (partici pants with low back pain) for pilot study #2....... 364-4 Change in A fiber mediated pain in pilot study #2.......................................................... 364-5 Descriptive statistics of sample (healthy participants) for study 3.................................... 396-1 Baseline comparison of direct and indirect NDI groups in self report measures.............. 626-2 Baseline comparison of the direct an d indirect NDI groups on the physical examination.................................................................................................................... ....646-3 Comparison of perceived to actual group assignment....................................................... 656-4 Immediate effects of NDI on pain perception to QST on evaluation................................ 666-5 Immediate effects of NDI on pain perception to QST at discharge................................... 676-6 Longitudinal effect of ND I on pain perception to QST..................................................... 686-7 Baseline to 3 week measures of pain symptoms, and function for entire sample............ 696-8 Correlation matrix for prediction of rating of pain at 3 weeks..........................................706-9 Regression model for pain at 3 weeks (Full Model).......................................................... 706-10 Regression model for pain at 3 weeks (Individual Variables)........................................... 716-11 Parsimonious regression model fo r pain at 3 weeks (Full Model).................................... 716-12 Parsimonious regression model for pa in at 3 weeks (Individual Variables).....................726-13 Correlation matrix for prediction of rating of disability at 3 weeks..................................726-14 Regression model for disabil ity at 3 weeks (Full Model).................................................. 736-15 Regression model for disability at 3 weeks (Individual Variables)................................... 74

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9 LIST OF FIGURES Figure page 3-1 Comprehensive model for the study of the m echanisms of manual therapy..................... 27 4-1 cfiber mediated hypoalgesia for stationa ry bicycle, lum bar extension, and spinal manipulation......................................................................................................................35 4-2 cfiber mediated hypoalgesia for stationa ry bicycle, lum bar extension, and spinal manipulation......................................................................................................................37 4-3 Model pathway depicting studies 1 and 2. ....................................................................... 38 4-4 Group changes in expectation for pain in the trunk to quantit ative sensory testing following MT. ..................................................................................................................40 4-5 cfiber mediated hypoal gesia observed in study 3. ........................................................... 41 4-6 Model pathway depi cting studies 3. ................................................................................. 42 5-1 Examples of randomly assigned interventions. ............................................................... 53 5-2 Flow diagram repres enting study protocol. .....................................................................54 6-1 Summary of recruitment, enrollme nt, random ization, allocation, follow up, and analysis for the study......................................................................................................... 61 6-2 Immediate effect of NDI on self report of pain to sta ndardized painfu l stimuli dur ing evaluation. .................................................................................................................. ......66 6-3 Immediate effect of NDI on self report of pain to sta ndardized painfu l stimuli dur ing discharge. .........................................................................................................................67 6-4 Pain perception to standardized thermal st im uli measured longitudinally i.e. baseline at first session to following NDI at 3 weeks. ..................................................................68 6-5 Immediate effect of NDI on self report of current car pal tunnel related pain and sym ptoms. .................................................................................................................... ....69 7-1 Model pathway depic ting dissertation study. ................................................................... 90 7-2 Model depicting neurophys iological effects also asso ciated with placebo. ....................91

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10 LIST OF ABBREVIATIONS ACC Anterior cingular cortex ASI Anxiety sensitivity index CAM Complimentary and alternative medicine CSI Combined sensory index CSQ-R Coping strategies questionnaire revised CTS Carpal tunnel syndrome DASH Disability of arm, shoulder, and hand questionnaire EMG Electromyographic FPQ Fear of pain questionnaire HReflex Hoffman reflex LBP Low back pain MRI Magnetic resonance imaging MT Manual therapy MVAS Mechanical visual analog scale NCS Nerve conduction study NDI Neurodynamic intervention NIH National Institutes of Health NRS Numerical rating scale PAG Periaquaductal gray PASS Pain anxiety sensitivity scale PCOQ Patient centered outcome questionnaire PCS Pain catastrophizing scale QST Quantitative sensory testing ROM Range of motion

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11 RVM Rostral ventromedial medulla STAI State trait anxiety inventory TSK Tampa scale for kinesiophobia ULTT Upper limb tension test VAS Visual analog scale

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12 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 MECHANISMS OF MANUAL THERAPY By Joel Eric Bialosky August 2008 Chair: Steven Z. George Major: Rehabilitation Science Musculoskeletal pain is a common complaint re quring billions of do llars in medical care and lost work time. Manual therapy (MT) is an effective form of treatme nt for musculoskeletal pain; however, the mechanisms though which MT works are undetermined. Biomechanical and neurophysiological effects are associated with MT and are suggested as potentially pertinent mechanisms. A shortcoming of the literature is that studies have considered individual mechanisms without thought to the potentia l collaboration between mechanisms. We present a model for the mechanistic study of MT to provide a framework for the design of future studies and allow better interpreta tion of past studies. Additiona lly, we present the results of 3 pilot studies and a dissertation study which have assessed components of the model. The three pilot studies explored potential m echanisms of a MT force applied to the low back of both healthy participants and those experiencing low back pain. In the first two studies, we observed cfiber mediated hypoalgesia to sta ndard thermal stimuli which was attributed to a spinal cord mediated effect of MT. As indica ted by the model, a shortcoming of these studies was the failure to account for potential supraspi nal mediated mechanisms. Subsequently, we manipulated participant expecta tion for experimental pain in the third study and observed a significant hyperalgesic effect of MT in individuals whose expectations were altered to expect

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13 greater pain. The findings of the three pilot studies suggest a consis tent cfiber mediated effect of MT at the dorsal horn of the spinal cord with the poten tial for a supraspinal effect (expectation) to further influence outcomes. Our dissertation study explored potential mechanisms of a specific MT technique to the upper extremity of individuals e xperiencing carpal tunnel syndrome (CTS). Participants were randomly assigned to receive a direct MT techni que known to stress the median nerve or an indirect technique designed to minimize stress to the median nerve and underwent up to six sessions of MT over three weeks. Group differen ces were not observed in expectation for pain in response to treatment or in perception of which technique was received suggesting the indirect MT technique provides similar expectation and belie vability as the direct MT. Group differences were present in experimental pain perception with changes in cfiber mediated pain observed in participants receiving the direct MT technique but not the indirect MT technique. An immediate hypoalgesic effect was observed in clinical pain in response to th e MT which was independent of group assignment. Neither group dependent changes nor main treatment effects in clinical pain were reported over the 3 week period of the study. A sma ll improvement in function was observed over the 3 week period of the st udy independent of group assignment. While controlling for baseline pain, both baseline immedi ate clinical pain hypoalgesic response to MT and baseline expectation for pain following the study were predictive of pain at the completion of the study. We present a model for the mechanistic study of MT along with 4 studies which have been guided by the model and assess specific parts of the model.

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14 CHAPTER 1 INTRODUCTION Musculoske letal pain is a common complaint. For example, greater than two percent of physicians visits in the United St ates are due to low back pain (Deyo et al., 2006). Additionally, prevalence rates of up to twen tysix percent for low back pain,(Deyo et al., 2006;Strine & Hootman, 2007) fourteen percent for neck pain ,(Deyo et al., 2006;Strine & Hootman, 2007) and fiftytwo percent for upper extremity pain ha ve been reported (Walker-Bone et al., 2004). The financial burden of musculoskeletal pain is substantial. The cost of medical care for musculoskeletal pain was estimated at 193 billion dollars in 1996 (Yelin et al., 2001) and loss of work production has been estimated at 61 billion do llars (Stewart et al., 2003). Specific to low back pain, loss of production has been estimated at 7.4 billion dollars in workers in the United States between the ages of fort y and sixtyfive (Ricci et al., 2006). The prevalence and cost of musculoskeletal pain suggest a significant public health problem. Subsequently, treatments effective in the resolution of musc uloskeletal pain are desirable. Manual therapy (MT) is a complimentary a nd alternative medicine (CAM), classified by the National Institutes of Health (NIH) under manipulative and body based practice. MT is a general term encompassing numerous techniques wh ich are similar in the application of a force to given structures of the body. Generally, MT ma y be categorized into techniques directed at the joints (mobilization and mani pulation), the soft tissue (massa ge), or the nerves (neural dynamic interventions). MT is effective in the treatment of musculoskele tal disorders including low back pain (Childs et al., 2004;Cleland et al ., 2006b;Cleland et al., 2006a;Licciardone et al., 2003), carpal tunnel syndrome(Akalin et al., 2002;Rozmaryn et al., 1998), knee osteoarthritis(Deyle et al., 2000), and hip osteoart hritis (MacDonald et al., 2006). Furthermore, individuals with musculoskeletal pain are seeking complimentary a nd alternative treatments such

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15 as MT at an increasing rate. For example, a su rvey from 2002 estimated that sixtytwo percent of adults used a form of CAM over the previous year (Barnes et al., 2004). Despite the apparent clinical effectiveness and increasing usage, the mechanisms through which MT works are not established. The purposes of this manuscript are to first, review the current literature regarding the potential mechanisms behind MT. Second, presen t a model to guide future studies of MT. Finally, present the findings of three prior studies and the curr ent dissertation study which have focused on specific aspects of the model to a ssess the potential mechanisms of MT.

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16 CHAPTER 2 LITERATURE REVIEW OF MECHANISMS OF MANUAL THERAPY MT likely works through biom echanical an d/or neurophysiological mechanisms. A biomechanical mechanism is suggested by co mmon clinical practice in which evaluation techniques are directed at loca ting malaligned or hypo mobile tissue or joints followed by the application of MT to reposition or restore mobi lity. Neurophysiological mechanisms include changes in the nervous system which are associat ed with MT and have a potential role in the clinical outcomes. Biomechanical Mechanisms Biom echanical effects are a ssociated with MT as force and movement have been quantified with these techniques (Colloca et al., 2006;Coppiet ers & Butler, 2007;Coppieters & Alshami, 2007;Gal et al., 1997) Despite the empirical and clin ical support of a biomechanical mechanism, the implications for clinical outcomes are questionable. A biomechanical mechanism implies a specific dysfunction requi ring MT is identified and treated using a precisely applied technique to produce a lasting change in the biomechanical properties of the target site. While movement accompanies MT (Colloca et al., 2006;Coppieters & Butler, 2007;Coppieters & Alshami, 2007;Gal et al., 199 7), the literature does not support a sole biomechanical mechanism of action. First, biom echanical assessment is not reliable. Palpation for positional faults and hypomobility has demons trated poor reliability (Seffinger et al., 2004;Troyanovich et al., 1998) and th is suggests an inability to accu rately determine a specific location requiring MT. Second, MT interventions l ack precision as techniques are not specific to a given location (Herzog et al., 2001;Kleinrensink et al., 2000;Ross et al., 2004) and different kinetic parameters are observed between clinicians in the performance of the same technique (Hessell et al., 1990;Ngan et al., 2005). Finally, only transient biomechanical effects are

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17 supported by studies which quantify motion and not a lasting positional change (Hsieh et al., 2002;Tullberg et al., 1998). The clinical effectiveness of MT despite the inconsistencies in the biomechanical evaluation and application suggests other mechanisms may be more influential. Neurophysiological Mechanisms The musculoskeletal pain experience includes complex interactions of both the peripheral and central nervous system. Neurophysiological effects are associated with MT and suggest a mechanism of action originating from specific poin ts of the nervous system. We will categorize neurophysiological mechanisms as those likely orig inating from a peripheral mechanism, spinal cord mechanisms, and/or supraspinal mechanisms. Peripheral Mechanisms MT has been suggested to exert an effect on the peripheral nervous system. For example, (Teodorczyk-Injeyan et al., 2006) observed a significant reduction of blood level cytokines in individuals receiving MT which was not observed in those receiving sham MT or in a control group. Additionally, changes of blood levels of -endorphin, anandamide, Npalmitoylethanolamide, serotonin, (Degenha rdt et al., 2007) and endogenous cannabinoids (McPartland et al., 2005) have been observed following MT. Finally, soft tissue biased MT has been shown to alter acute inflammation in response to exercise (Smith et al., 1994) and substance P levels in individuals with fibr omyalgia (Field et al ., 2002). Collectively, these studies suggest a mechanism of action of MT on musculoskele tal pain mediated by the peripheral nervous system. Spinal Cord Mechanisms MT m ay influence musculoskeletal pain through action at the level of the spinal cord. Direct evidence for such an effect comes from a study in which MT was applied to the lower extremity of rats following capsaicin injecti on (Malisza et al., 2003b). A spinal cord response

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18 was quantified by functional magnetic resonance imaging (MRI) during light touch to the hind paw following the injection. A trend was noted to wards decreased activati on of the dorsal horn of the spinal cord following the MT. Asso ciated neuromuscular responses following MT provide indirect evidence for a sp inal cord mediated mechanism. For example, MT is associated with changes in pain percepti on (George et al., 2006;Mohammadia n et al., 2004;Vicenzino et al., 2001), afferent discharge (Colloca et al., 2000;Colloca et al., 2003), motoneuron pool activity (Bulbulian et al., 2002;Dishman & Burke, 2003), and muscle activity (Herzog et al., 1999;Symons et al., 2000). Pain perception Studies have observed an immediate decrease in pain perception (hypoalgesia) associated with MT to the lumbar spine (George et al., 2006) cervical spine (Sterling et al., 2001), thoracic spine (Mohammadian et al., 2004), and extremiti es (Paungmali et al., 2004;Vicenzino et al., 2001). Hypoalgesia associated with MT has been at tributed to the dorsal hor n of the spinal cord in two studies due to the associated finding of a lessening of temporal summation (George et al., 2006;Bialosky et al., 2008). Additionally, Skyba et al ., (2003) performed MT to the knee joint of rats following capsaicin injection into the ankle joint. A hypoalgesic behavioral response was associated with MT; however, eliminated with bl ocking of the serotonin receptors in the spinal cord and lessened with blocking of the 2-adrenergic receptors in the spinal cord. The hypoalgesic response was not affected by blocking of the GABA receptors and opioid receptors. These findings suggest a mechanism of MT upon the neurotransmitters at the level of the spinal cord. Afferent discharge Increased af ferent discharge of lumbar para spinal mechanoreceptors (Pickar & Wheeler, 2001;Pickar & Kang, 2006;Sung et al., 2005) has been observed in the cat model in response to

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19 MT type loads. Similar observations have been ma de in human studies. For example, a series of studies (Colloca et al., 2000;Collo ca et al., 2003;Colloca et al., 2004) have recorded positive action potentials at the S1 ne rve root in response to MT in anesthetized subjects undergoing spinal surgery. Subsequently, MT may stimul ate afferent discharge with a corresponding lessening of pain due to modulation at th e spinal cord (Pickar & Wheeler, 2001). Motoneuron pool excitability A lessening of the alpha motone uron pool excitability has been associated with MT. A decrease in the Hoffman reflex (Hreflex) is associated with MT has been observed following MT in the lumbar (Bulbulian et al., 2002;Dishm an & Burke, 2003) and cervical spine (Dishman & Burke, 2003) and to the lower extremity (Mor elli et al., 1998;Sullivan et al., 1991) These findings suggest inhibition of the motoneuron pool a nd indicate a spinal cord mediated effect of MT with the potential to produce associated outcomes such as decreased pain and muscle spasm. In contrast one study has assessed motoneuron p ool activity supraspinally using transcranial magnetic stimulation and measured the change in motor evoked potentials in the gastrocnemius following MT to the lumbar spine (Dishman et al., 2002). An excitatory effect on the motoneuron pool was observed and suggests central motor facilitati on. The authors theorize MT may provide sensory input to the CNS which alleviates the gain in motoneuron pool excitability (Dishman et al., 2002). Muscle activity A ref lex link exists between the lumbar jo int capsule and the paraspinal musculature (Indahl et al., 1997;Solomonow et al., 1998). Specifically, paraspinal muscle activity has been elicited with stimulation of the lumbar disc (Indahl et al., 1997) and multifidus activity with stimulation of the supraspinous ligament (Solom onow et al., 1998). Additionally, saline injected into the facet joint has been shown to inhibit this response (Indahl et al., 1997). Subsequently,

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20 MT is postulated to alter muscle activity through the stimulation of this reflex link (Indahl et al., 1997). Further support for this theory comes fr om studies reporting tr ansient increases in electromyographic (EMG) activity associated with MT (Colloca & Keller, 2001;Colloca et al., 2003). The transient increases in EMG activity is then be followed by a decrease in resting EMG (DeVocht et al., 2005;Lehman et al., 2001) sugge sting a possible mechanism for the clinical outcomes of decreased pain and muscle spasm. Furthermore, clinical studies have noted both a decrease in muscle inhibition (Suter et al., 1999;Suter et al ., 2000) and decreased EMG activity in the superficial neck flexors (Sterling et al ., 2001) suggesting MT ma y have a longer lasting effect on motor function. Collect ively, the literature suggests both transient and lasting effects of MT on muscle activity potentially mediated through the spinal cor d. Clinically, decreased pain, decreased muscle spasm, and improved motor function may result. Supraspinal Mechanisms Finally, MT may influence musculoskeletal pa in through supraspinal structures. Direct support for a supraspinal mechanism of action of MT comes from Malisza et al., (2003a) who applied MT to the lower extremity of rats following capsaicin injection. Functional MRI of the supraspinal region quantified the response of the hind paw to light touch following the injection. A trend was noted towards decrease d activation of the supraspinal regions responsible for central pain processing. Indirect support for a supraspi nal mechanism comes from studies indicating a role for nonspecific mechanisms such as pla cebo and expectation, sympathetic responses, and opioid mechanisms. Nonspecific mechanisms Non-specific m echanisms are seemingly inert; however, may produce outcomes greater than those observed due to natural history a nd include potential mechanisms such as placebo, expectation, and psychological constr ucts such as fear and catastroph izing. For this manuscript,

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21 we categorize nonspecific mechanisms as ne urophysiological effects re lated to associated changes in the opioid system (Sauro & Greenberg, 2005), dopamine production (FuenteFernandez et al., 2006), and cen tral nervous system (Matre et al., 2006;Petrovic et al., 2002;Wager et al., 2004) which have been observed in studies unrelated to MT. Nonspecific mechanisms have a postulated involvement in the clinical effectiveness of MT (Ernst, 2000;Kaptchuk, 2002). For example, (Kalauokalani et al., 2001) reports on a secondary analysis of participants with low back pain randomized to r eceive either acupuncture or MT. Subjects with higher expectations for their assigned treatments demons trated significantly greater improvement in function. Additionally, a recent sy stematic review of th e literature has noted that MT is associated with improved psyc hological outomes (Williams et al., 2007). Sympathetic response An increase in sym pathetic activity has b een associated with MT (Moulson & Watson, 2006;Sterling et al., 2001;Vicenzino et al., 1998) and suggests a pot ential supraspinal mechanism of action. For example, clinical studies report an a ssociation between MT and changes in skin temperature, skin conduction (Ste rling et al., 2001;Vicenzino et al., 1998), and local blood flow (Vicenzino et al., 1998). Cortisol levels have been measured fo llowing MT as an indicator of stress and sympathetic function and do not appear to increase (Christian et al., 1988;Whelan et al., 2002). In fact some evidence suggests a d ecrease following MT (O uchi et al., 2006). Collectively, the literature suggests a sympathetic effect of MT; however, the direction of such an effect may vary. Opioid response Opioids hav e a potent analgesic effect and may work centrally or peripherally. Studies of (Vernon et al., 1986;Kaada & Torsteinbo, 1989) suggest an increase in endorphin levels following MT; however, follow up studies of have not supported this finding (Christian et al.,

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22 1988). Additionally, the effects of MT have been found to not change following injection of the opioid antagonist, Naloxone (Pa ungmali et al., 2004). Subseque ntly, an opioid mechanism of action of MT is not currently supported by the literature. Limitations of the Curren t Mechan istic Literature A limitation of the current literature is th e failure to acknowledg e the potential for a combined effect of the proposed mechanisms. Biomechanical effects and multiple neurophysiological effects are associ ated with MT and have the pot ential to work together to influence clinical outcomes. Prior studies have observed individual effect s associated with MT without full consideration of the potential for multiple effects or interaction of individual effects. Only recently are studies beginning to quantify bi omechanical and neurophysiological effects in relationship to each other (Colloca et al., 2006;Mc Lean et al., 2002;Sung et al., 2005;Pickar et al., 2007). For example, (McLean et al., 2002) assessed hypoalgesia, in response to varying levels of force application during MT and obs erved larger neurophysiological response with forces greater than 1.9 N/cm. A consider ation of the potential interaction between biomechanical and multiple neurophysiological effects is lacking in many prior studies and necessitates a comprehensive model to synthesi ze the current literature and direct future research. A second limitation of the current mechanistic literature is the failure to adequately account for nonspecific effects of MT. Subseque ntly, the magnitude of nonspecific effects in outcomes associated with MT is currently not kn own. A primary limitation in the determination of the magnitude of nonspecific effects in MT is that a validated model of placebo for MT does not currently exist. The lack of a consensu s has led to multiple unsubstantiated MT placebos including joint biased MT wit hout cavitation (Hoiriis et al ., 2004;Suter et al., 2005;TeodorczykInjeyan et al., 2006), sham laser (Preyde, 2000) and sham ultrasound (Deyle et al., 2000).

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23 Additionally, in prior studies which have attemp ted to validate an MT placebo (Hawk et al., 2005;Vernon et al., 2005), a prere quisite is an inert placebo whic h does not significantly affect the outcome of interest. Such requirements ma y be unreasonable when the magnitude of the placebo effect on pain in other studies is considered (Price et al., 1999;Vase et al., 2003). Subsequently, an adequate model of placebo for MT is lacking wh ich produces similar expectations as active MT and has a known treatment effect size.

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24 CHAPTER 3 COMPREHANSIVE MODEL OF THE MECHANISMS OF MANUAL THERAPY Overview of Model We propose a m odel as a framework for conducting research into the mechanisms of MT which provides a compilation of the existing litera ture as to how MT likely exerts its effects (Figure 3-1). Prior studies have focused on individual biomechanica l or neurophysiological effects and the model encourages consideration of multiple mechanisms. The model suggests the effects of MT are initiated by a mechanical stimul us to a given tissue. As previously noted, the MT literature suggests a mechanical force is asso ciated with MT; however likely not causative of outcomes. Subsequently, the model suggests a mechanical stimulus initiates a cascade of neurophysiological responses in th e periphery or in the CNS wh ich are then responsible for clinical outcomes. Specific mech anisms within the nervous system are frequently not directly measurable in human studies. Subsequently, th e mechanistic literature is based primarily upon inferences from associated responses rather than direct measurements. For example, MT is suggested to exert an effect at the periaquaductal gray (PAG) due to associated hypoalgesia and sympathetic responses (Wright, 1995) and at the dorsal horn of th e spinal cord due to lessening of temporal summation (George et al., 2006). Th e model provides implications of specific mechanisms through the reporting of measurable a ssociated relationships when direct measures are not possible. As indicated in figure 3-1, MT may exert its e ffect at the peripheral level (as measured by associated responses such as changes in inflammato ry mediators), at the spinal cord (as indicated by associated responses such as neuromuscular changes), and at the supraspinal level (as indicated by associated responses such as aut onomic or endocrine changes). The model further recognizes that associated relationships may occur between neural and psychological constructs.

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25 For example, placebo has a postulated role in the outcomes associated with MT (Astin & Ernst, 2002;Ernst, 2000). A relationshi p may be observed between the neural construct (pain modulatory circuitry) and a psychol ogical construct (expectation) as measured by an associated response (measure of expectation) and suggest a nonspecific supr aspinal effect of MT. Finally, Figure 3-1 clearly shows how the model addresses a specific limitation of the current literature by encouraging the considera tion of multiple potential mechanisms and their potential interaction. For example, placebo st udies of experimental pain have noted a conditioning response. If a painful stimulus is surreptitiously lessened immediately following the suggestion of a placebo, upon returning the s timulus to its prior intensity, a more robust hypoalgesic effect is noted (Collo ca & Benedetti, 2006;Price et al ., 1999). Similar events could occur following MT. Specifically, the mechanical stimulus associated with MT may produce an afferent discharge with subseque nt transient hypoalgesi a through a spinal cord mediated effect. The resultant hypoalgesia could th en strengthen a nonspecific supraspinal mediating effect (placebo) due to expectation of lessening of pain perception. The model encourages the measurement of different mediating effects so th at their individual contributions to the overall mechanisms may be determined. Limitations of Proposed Model The m odel is intended to be applicable to al l forms of MT. MT ma y be categorized into specific techniques which are theorized to affect the joints, soft tissue, or individual nerves. While the forces associated with individual tech qniques may differ, the current literature does not support the specificity of biomechanical mechanism with regards to pain relief. Subsequently, the related neurophys iological responses are simila r and adequately encompassed within the model given the cu rrent state of knowledge. Th e proposed model provides a

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26 framework, currently lacking in th e literature, to empi rically test hypotheses related to different neurophysiological effects spec ific to types of MT. The proposed comprehensive model is intende d to guide methodology in studies specific to the mechanisms of MT on musc uloskeletal pain. MT has a postu lated role in the treatment of disorders of other body systems such as asthma (Balon & Mior, 2004) and high blood pressure (Plaugher & Bachman, 1993); however, those effects are beyond the sc ope of the current model. Finally, the model is stric tly intended to guide resear ch questions regarding the mechanisms of MT. A body of literature alrea dy exists suggesting the effectiveness of MT (Childs et al., 2004;Deyle et al., 2000;MacDonald et al., 2006). The model is intended to compliment this line of clinical research and provide underlying explanations for the effectiveness of MT.

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27 Figure 3-1. Comprehensive mode l for the study of the mechanisms of manual therapy. The model suggests a transient, mechanical stim ulus to the tissue produces a cascade of neurophysiological effects. Solid arrows denote a direct mediating effect. Broken arrows denote an associativ e relationship. Bold boxes i ndicate the measurement of a construct. ACC = anterior cingular co rtex; PAG = periaqueductal gray; RVM = rostral ventromedial medulla

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28 CHAPTER 4 IMPLEMENTATION OF COMPREHENSIVE MODEL The model provides a framework for mechanistic studies of MT through which researchers may clearly identify domains that have been previous ly studied, as well as domains that have been understudied. Perhaps most importantly, the model elucidates multiple interactions between different body systems and ou tlines how these factors may inhibit pain, and how these factors can be measured. Studies designed to evaluate potential mechanisms currently lacking adequate consideration or account for the comple x interactions involved in pain inhibition are of future interest. We have performed three pilot st udies leading up to a dissertation proposal which have tested limited domains of the model. Pilot Study 1: Effect of MT on Exp erimenta l Pain in Healthy Participants Our first study assessed the effect of MT on thermal pain sensitivity in pain free participants (George et al., 2006). Inclusion criteria were ages 18 to 60 years old and English speaking. Exclusion criteria were systemic medical conditions (e.g. diabetes, hypertension), psychiatric illness, pregnant women, and regular use of prescription medication for management of pain. Baseline quantitative sensory testing (QST) was performed using protocols specific to A and cfiber mediated pain perception (Price et al., 2002;Staud et al., 2001). Participants were then randomly assigned to ride a stationary bike perform low back range of motion exercises, or receive MT. Immediately following the interven tion, QST was repeated. 60 individuals agreed to participate and signed an informed consent form. Table 4-1 indicates the baseline characteristics of the groups. A group time interactions was not observed for A fiber mediated pain in the lower extremity at 47C (F(1,57) = 2.40, p = 0.10, partial 2 = 0.08) or at 49C (F(1,57) = 1.30, p = 0.27, partial 2 = 0.05). However, a significan t treatment effect in the lower extremity at each temperature was obs erved (Table 4-2). A significant group time

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29 interaction for cfiber mediated pain was observed in the lower extremity (F(1,57) = 3.70, p = 0.03, partial 2 = 0.12) (Figure 4-1). Posthoc testing revealed that MT had a larger hypoalgesic effect in the lower extremity than riding a sta tionary bicycle (p = 0.04), but similar as lumbar extension exercise (p = 0.11). Pilot Study 2: Effect of MT on Experimental Pain in Part ic ipants with Low Back Pain The second study was identical to the first with the exception of including participants currently experiencing low back pain. These data have not yet been published. Inclusion criteria for this study consisted of curre ntly experiencing low back pain and able to speak and understand English. Exclusion criteria included any systemic medical conditions (e.g. diabetes, hypertension), history of lumbar surgery or fr acture, or psychiatric illness, and currently receiving lumbar extension exercise or spinal mobilization for treatment of low back pain. 34 individuals agreed to participat e and signed an informed consent form. Baseline characteristics are displayed in table 4-3. Group differences were noted in sex distribution and in fear of pain; however, a significant correlation was not observe d between fear of pain and the outcomes measures of post intervention cfiber mediated pain (r2= -0.13, p= 0.50), A fiber mediated pain at 47 C (r2= 0.25, p= 0.18), and at 49 C (r2= 0.27, p= 0.14). Additionally, sex differences were not observed in cfiber me diated pain perception (F(1,29)= 0.03, p= 0.86, partial 2< 0.00) or A fiber mediated pain at 47 C (F(1,32)= 0.59, p= 0.45, partial 2= 0.02) or at 49 C (F(1,32)< 0.01, p= 0.95, partial 2< 0.00). Subsequently, the decision was made to use a repeated measure ANOVA model without controlling for fear or sex. A group time interactions was not observed for A fiber mediated pain in the lower extremity at 47C (F(2,31) = 0.54, p = 0.59, partial 2 = 0.03) or at 49C (F(2,31) = 0.05, p = 0.96, partial 2 <= 0.01). A significant treatme nt effect in the lower extremity at each temperature was also not obs erved (Table 4-4). A significant group time interaction for cfiber mediated pain was not observed in the lower extremity (F(2,28) = 2.40, p =

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30 0.11, partial 2 = 0.14). Due to the p-value approaching 0.05 and the moderate effect size, the decision was made to perform an exploratory po sthoc analysis to see if any group difference existed in perception of cfiber mediated pain. Post-hoc testing revealed that similar to healthy individuals, individuals with low back pain receiving MT reported a significant decrease in cfiber mediated pain perception (mean differe nce 7.49 (24.23), p= 0.05) which was not observed in participants riding the stationary bike (mean differ ence= -3.96 (25.04), p= 0.31) or performing spinal extension exercises (mean difference= 3.81 (30.54 ), p= 0.40) (Figure 4-2). Pilot Study 3: The Influence of Expectation on Hypoalgesia Follow ing MT in Healthy Participants A shortcoming of the design of the prior two studies was that a spinal cord mediating effect (temporal summation) was monitored indirectly via QST; however, the potential interaction with supraspinal medi ating effects was not considered. Figure 4-3 depicts the model pathway of the prior two studies. Subsequentl y, in a follow up study, we attempted to replicate these prior findings while accounting for potential supraspinal influence and these data have been published (Bialosky et al., 2008). Sixty he althy participants signed an informed consent form and agreed to participate. Inclusion and exclusion criteria were identical to study 1. Baseline characteristics of the sample are summ arized in table 4-5. Participants underwent baseline quantitative sensory tes ting to the low back and leg usi ng the same protocols from the prior studies. Due to MT differentiating itself fr om other interventions in the effect on cfiber mediated pain in our prior studies we chose to only analyze the effect of MT on cfiber mediated pain perception in this study. Immediately fo llowing the baseline pain perception testing, participants were randomly assigned to receive one of three expectati on instructional sets. Participants receiving a positive ex pectation instructional set were informed they should feel less heat pain following the application of MT. Participants receiving a negative expectation

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31 instructional set were informed th ey should feel more heat pain following the application of MT. Participants receiving a neutral instructional set were informed it was not known what effect the MT would have on their pain perception. Imme diately following the in structional set, all participants received MT and then underwent repeat pain pe rception testing. A three way interaction was not present be tween expectation of pain by body area and group assignment (Wilks Lambda= 0.92, F(2,53)= 2.47, p= 0.09, partial 2= 0.09). A 2 x 3 ANOVA of change in expectation was significant for an interac tion in the low back (Wilks Lambda= 0.85, F(2,53)= 4.55, p= 0.02, partial 2 = 0.15), indicating a differe ntial effect of the instructional set for the low back. Post hoc testing of the low back indicate d a significant decrease in expected pain in the positive expectation group (mean difference +7.70, sd= 14.9, p=0.03, Cohens d effect size= 0.52), a significant increase in expected pain in the negative expecta tion group (mean difference .98, sd= 15.30, p= 0.05, Cohens d effect size= 0.46), a nd no change in the neutral expectation group (mean difference +2.18, sd= 14.91, p= 0.53, Cohens d effect size= 0.15). A 2 x 3 ANOVA of change in expectation was not significant for the lower extremity (Wilks Lambda= 0.95, F(2,53)= 1.42, p= 0.25, partial 2 = 0.05), indicating a main effect of the instructional set for the lower extremity. Pairwise comparison in th e lower extremity indicated a mean increase in expected pain of 12.01 (sd= 12.14, p< 0.01, Cohens d effect size= 0.99). The results of the instructional set on expected pain perception in the low back are depicted in Figure 4-4. A three way interaction existed sugges ting change in pain percep tion differed by body area and group assignment (Wilks Lambda= 0.88, F(2,53)= 3.80, p= 0.03, partial 2= 0.13). No interaction between instructional set and pain perception wa s noted in the lower extremity (Wilks Lambda= 0.97, F (2,54)= 0.99, p= 0.38, partial 2= 0.04) suggesting the expect ation instructional set did not influence MT associated hypoalgesia in the lower extremity. A sign ificant main effect

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32 (Wilks Lambda= 0.85, F (1,54)= 9.22, p< 0.01, partial 2= 0.15) was found. Paired ttest determined a mean difference of 4.83 (sd= 12.05 ) between pre and post MT pain ratings with post MT rating being smaller in dicating hypoalgesia in the lowe r extremity after MT. This difference corresponded to a small Cohens d eff ect size of 0.21. A significant interaction was present between change in pain perception and group assignment in the low back (Wilks Lambda= 0.84, F(2,56)= 5.35, p= 0.01, partial 2= 0.16) suggesting a response dependent upon group assignment. Post hoc testing revealed no change in pain perception following MT in participants receiving the positive expectati on instructional set (mean difference +1.66, sd= 13.10, p= 0.57, Cohens d effect size= 0.13) and the neutral expectation in structional set (mean difference +4.17, sd= 13.10, p=0.16, Cohens d effect size= 0.32). Subj ects receiving the negative expectation inst ructional set exhibited a significan t increase in pain perception of moderate magnitude following the MT (mean difference -8.81, sd= 13.42, p< 0.01, Cohens d effect size= 0.66) (Figure 4-5). The model pathway for this study is shown in Figure 4-6 and clearly demonstrates the spinal effect accoun ted for by the monitoring of temporal summation and the supraspinal effect, accounte d for by expectation. Summary of Pilot Studies The m echanisms behind the clinical effectiven ess of MT are not established. Limitations of prior mechanistic studies are the study of individual mechanisms without regard for others and a failure to adequately account for nonspecifi c effects. We have proposed a comprehensive model to consolidate the current research and guide future resear ch into the mechanisms of MT and our pilot studies have investigated specific pathways of this model. We observed greater hypoalgesia following MT than other common phys ical therapy interventions in both healthy participants and those experienci ng low back pain. We attributed these findings to a mechanism of action of MT on cfiber mediated pain at the dorsal horn of the spinal cord due to the

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33 associated observation of decreas ed temporal summation. A shortc oming of the first two studies was the failure to consider potential supraspina l mechanisms as suggested by the model. We manipulated a potential supraspina l mechanism (expectation) in our third study. Consistent with our first two studies, we observe d lessening of temporal summa tion in the lower extremity of participants independent of group assignment. Conversely, we observed hyperalgesia in the trunk of participants in whom expectation was manipulated to expect greater thermal pain following the MT. This finding suggests a pote ntial role for a supraspinal mechanism and specifically, expectation in the ou tcomes associated with MT.

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34 Table 4-1. Descriptive statistics of sample (healthy participants) fo r Pilot Study 1 (George et al., 2006) Variable Stationary Bicycle (n = 20) Lumbar Extension (n = 20) Spinal Manipulation (n = 20) p-value Age (years) 23.90 (3.40) 24.10 (2.60) 24.10 (3.60) 0.98 Sex (# female, %) 12 (60%) 14 (70%) 14 (70%) 0.74 Worst pain experienced (NRS) 68.90 (18.50) 64.00 (21.80) 59.70 (25.90) 0.44 Fear of pain (FPQ) 82.60 (16.70) 75.10 (13.30) 77.50 (22.60) 0.41 Pain catastrophizing (CSQ-R) 7.60 ( 3.10) 7.20 (3.70) 7.50 (3.80) 0.96 Anxiety (STAI) 45.30 (10.40) 45.50 (11.60) 45.20 (10.70) 0.99 Anxiety sensitivity (ASI) 19.80 (7.60) 16.00 (7.10) 16.00 (7.20) 0.23 Pain threshold (degrees Celsius) 44.70 (2.40) 45.40 (2.20) 44.80 (2.50) 0.59 Pain threshold rating (NRS) 25.00 (21.00) 28.80 (19.00) 21.30 (15.10) 0.44 Key All data are reported as mean (standard de viation) ratings, unless otherwise indicated. NRS = Numerical rating scale FPQ = Fear of Pain Questionnaire CSQ-R = Coping Strategies Questionnaire-Revised STAI = State Trait Anxiety Inventory ASI = Anxiety Sensitivity Index Table 4-2. Change in A fiber mediated pain in P ilot Study 1 (George et al., 2006) Variable Stationary Bicycle (n = 20) Lumbar Extension (n = 20) Spinal Manipulation (n = 20) Partial 2# p-value# NRS change at 47 C 13.20 (17.20)$ 12.9 (17.9)$ 23.5 (17.3)$ 0.08 0.10 NRS change at 49 C 1.2 (20.20) 6.3 (22.4) 12.1 (19.7)$ 0.05 0.27 Key NRS = Numerical rating scale All data are reported as mean (standard deviation) ratings. Negative numbers indicate increased pain following treatment. # Significance and partial eta-square estimate are for the inte raction between type of treatment and first pain hypoalgesia Significant overall main effect for lower extremity hypoalgesia at 47C (F(1,57) = 53.8, p < 0.01) and at 49C (F(1,57) = 5.9, p = 0.02) $ Significant within group effect for hypoalgesia (p < 0.05)

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35 Figure 4-1. The cfiber mediat ed hypoalgesia for stationary bi cycle, lumbar extension, and spinal manipulation. Positive numbers indicate hypoalgesia. Error bars are 1 standard error. indica tes statistically significant (p < 0.05) difference in intervention for pain sensitivity in lower extremity area. (George et al., 2006) 0 2 4 6 8 10 12 14 16 18 20 Stationary Bike*Lumbar ExtensionSMT*change in pain perception (NRS)

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36 Table 4-3. Descriptive statistics of sample (participants with low back pain) for Pilot Study 2 Variable Stationary Bicycle (n = 11) Lumbar Extension (n = 12) Spinal Manipulation (n = 11) p-value Age (years) 35.55 (13.96) 33.25 (13.27) 30.45 (11.18) 0.65 Sex (# female, %) 6 (55%) 12 (100%) 8 (73%) 0.04 Worst pain experienced (NRS) 79.55 (15.08) 85.42 (8.65) 74.80 (29.65) 0.44 Fear of pain (FPQ) 73.11 (21.85) 93.91 (15.34) 85.55 (16.27) 0.05 Pain catastrophizing (CSQ-R) 11.45 (7.47) 12.08 (5.99) 7.4 (4.72) 0.19 Anxiety (STAI) 93.10 (4.15) 89.36 (8.52) 91.36 (7.94) 0.50 Anxiety sensitivity (ASI) 17.64 (10.43) 20.67 (7.75) 17.90 (8.49) 0.67 Pain threshold (degrees Celsius) 44.66 (4.11) 43.60 (1.61) 44.32 (2.69) 0.69 Pain threshold rating (NRS) 33.39 (24.77) 30.13 (22.28) 14.28 (8.38) 0.11 Duration current LBP (weeks) 197.90 (429.94) 256.60 (358.20) 250.82 (365.32) 0.93 Intensity current LBP (NRS) 41.25 (21.45) 48.09 (29.72) 31.60 (21.17) 0.32 Key All data are reported as mean (standard de viation) ratings, unless otherwise indicated. NRS = Numerical rating scale FPQ = Fear of Pain Questionnaire CSQ-R = Coping Strategies Questionnaire-Revised STAI = State Trait Anxiety Inventory ASI = Anxiety Sensitivity Index Table 4-4. Change in A fiber mediated pain in Pilot Study 2 Variable Stationary Bicycle (n = 11) Lumbar Extension (n = 12) Spinal Manipulation (n = 11) Partial 2# p-value# NRS change at 47 C -0.27 (21.21) 1.71 (34.21 ) 5.64(14.58 ) 0.03 0.59 NRS change at 49 C 0.27 (24.47) -0.54 (32.55) 12.51 (22.7) <0.01 0.96 Key NRS = Numerical rating scale All data are reported as mean (standard deviation) ratings. Negative numbers indicate increased pain following treatment. # Significance and partial eta-square estimate are for the inte raction between type of treatment and first pain hypoalgesia Insignificant overall main effect for lower extremity hypoalgesia at 47C (F(1,31) = 1.01, p= 0.32) and at 49C (F(1,31) = 0.02, p = 0.89)

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37 -10 -5 0 5 10 15 stationary bike lumbar extension MT*change in pain perception (NRS) Figure 4-2. The cfiber mediat ed hypoalgesia for stationary bi cycle, lumbar extension, and spinal manipulation. Positive numbers indicate hypoalgesia. Error bars are 1 standard error. indica tes statistically significant (p < 0.05) difference in intervention for pain sensitivity in lower extremity area.

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38 Figure 4-3. Model pathway depicting Pilot Studies 1 and 2. Note a spinal cord mediated effect is inferred by the measurement of an a ssociated response of lessening of temporal summation. Also note, that consideration is not given in the design of these two studies to potential peripheral effect and potential supraspinal effects. ACC = anterior cingular cortex; PAG = periaqueductal gray ; RVM = rostral ventromedial medulla

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39 Table 4-5. Descriptive statistics of sample (healthy participants) for Pilot Study 3 (Bialosky et al., 2008) Variable Positive (n = 20) Negative (n = 20) Neutral (n = 20) p-value Age (years) 22.95 (2.06) 23.20 (3.66) 23.08 (3.10) 0.97 Sex (# female, %) 15 (75%) 13 (65%) 16 (80%) 0.55 Worst pain experienced (NRS) 65.00 (21.09) 62.5 (22.62) 75.11 (16.27) 0.13 Fear of pain (FPQ) 72.25 (13.47) 76.65 (14.81) 81.10 (19.43) 0.23 Pain catastrophizing (PCS) 15.15 (9.15) 14.75 (8.43) 17.3 (9.53) 0.63 Anxiety (PASS) 29.25 (15.17) 30.05 (12.26) 36.85 (16.89) 0.22 Pain threshold (degrees Celsius) 42.42 (5.25) 41.97 (3.12) 42.99 (2.89) 0.72 Pain threshold rating (NRS) 13.89 (11.72) 17.40 (18.16) 19.63 (20.33) 0.57 Key All data are reported as mean (standard de viation) ratings, unless otherwise indicated. NRS = Numerical rating scale FPQ = Fear of Pain Questionnaire PCS = Pain Catastrophizing Scale PASS = Pain Anxiety Sensitivity Scale

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40 Figure 4-4. Group changes in expectation for pain in the trunk to quant itative sensory testing following MT. Positive numbers indicate an ex pected decrease in pain perception. Error bars indicate one standard error of the mean. i ndicates significant at p< 0.05. (Bialosky et al., 2008) -15 -10 -5 0 5 10 15 Positive Expectation*Neutral ExpectationNegative Expectation*Change in Expected Pain (NRS)

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41 Figure 4-5. The cfiber mediated hypoalgesia observed in Pilot Study 3. Positive numbers indicate hypoalgesia. Error bars are 1 standard error. in dicates statistically significant (p < 0.05) change in pain perception in low back. (Bialosky et al., 2008) -15 -10 -5 0 5 10 15 Positive Expectation Neutral Expectation Negative Expectation*Change in Pain Perception (NRS) Low Back Lower Extremity

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42 Figure 4-6. Model pathway depic ting Pilot Study 3. Note a spin al cord mediated effect is inferred by the measurement of an associat ed response of lessening of temporal summation. Also note, that a supraspina l mediated effect is inferred by the measurement of an associated response of expectation. Consideration is not given in the design of this study to potential peri pheral effects. ACC = anterior cingular cortex; PAG = periaqueductal gray; RVM = rostral ventromedial medulla

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43 CHAPTER 5 METHODS Specific Aims 1. Determ ine the believability of a novel placebo for MT in the treatment of carpal tunnel syndrome (CTS) in regards to a) participant s interpretation of which intervention they received and b) their expectation for the e ffectiveness of the individual interventions. 2. Determine the changes in pain perception to standardized thermal stimuli, self report of pain, and self report of function associated with a specific MT technique and a novel placebo. 3. Determine the relative strength of demographic variables, gr oup assignment, expectation, response to initial quantitative sensory testi ng, and physical exam variables in predicting three week measures of pain and disability. Research Hypothesis 1. It was hypothesized that particip ants receiving the indirect MT would not differ in their inte rpretation of which intervention they had re ceived or in their expectation of outcome in comparison to participants receiving the direct MT. 2. It was hypothesized that similar to our prio r studies, changes in pain perception to standardized thermal stimuli would not differ for protocols specific to A fiber mediated pain. We hypothesized that similar to our prio r studies, greater cfibe r mediated hypoalgesia would be observed in particip ants receiving the direct MT. Furthermore, we hypothesized changes in self report of CTS pain and function would not differ by group assignment. 3. It was hypothesized that expecta tion would be the strongest pred ictor of three week measures of pain and disability. Participants Participan ts between the ages of eighteen and seventy were recruited from the clinics of orthopedic surgeons at the Univ ersity of Florida and the gene ral public through posted flyers, electronic distribution of advertis ement, and word of mouth. Inclusion criteria: Participants were required to have a diagnosis of CTS as defined by: hand symptoms in the median nerve distribution and/or clinical examination findings consis tent with carpal tunnel syndrome CTS symptoms present for greater than twelve weeks CTS pain or symptoms rated as at leas t a 4/10 over the past twenty-four hours

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44 Exclusion criteria: Participants not appropriate for conservative intervention for CTS non English speaking previous surgery for CTS prior treatment involving the us e of median nerve mobilization systemic disease known to cause peripheral neuropathy current or history of chronic pa in conditions unrelated to CTS upper extremity fracture. Measures Demographics A de mographic questionnaire was used to gather information related to age, sex, ethnicity, racial group, em ployment status, marital status, education level, household income, hand dominance, CTS affect side, worse side if bilateral CTS, whether CTS was work related, whether litigation was involve d, and duration of CTS. Expectation Individual expectation for outcom e was a ssessed using the Patient Centered Outcome Questionnaire (PCOQ) (Robinson et al., 2005). Th e PCOQ is a five item questionnaire which uses individual 101 point numeric rating scales to quantify the usua l, desired, and expected levels of pain, fatigue, emotional distre ss, and interference with daily act ivities associated with a pain conditions. Additionally, the PCOQ uses the same numeric rating scale to quantify the rating for each category the subject would consider to be a successful treatment and the self-perceived importance of improvement in each category. We report descriptive results for measures of usual pain, expected pain, and expected interference with dail y activities. Additionally, we included the expected measures of pain in our re gression analysis of 3 week rating of pain and expected measure of interference with daily ac tivities in our regressi on analysis for 3 weeks rating of function.

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45 Psychological Questionnaires Fear of pain questionnaire-III (FPQ-III) We used a modified version of the The FPQ -III (McNeil & Rainwater, III, 1998) wh ich consists of 9 items, each scored on a 5-point adje ctival scale, which measures fear of normally painful situations. Higher scor es indicate greater pain related fear. The FPQ has demonstrated sound psychometric properties in both experi mental and clinical pa in studies (McNeil & Rainwater, III, 1998;Osman et al., 2002;Roelofs et al., 2005). Pain catastrophizing scale (PCS) The PCS consists of 13 item s specific to individual coping styles with pain which are each quantified with a five point ordinal scal e. Higher scores indicat e greater levels of catastrophizing. The score may be taken as a whole or as individual factors of rumination, helplessness, and magnification. Prior studies ha ve validated the factor structure and found good internal consistency reliability and validity of the PCS (Osman et al., 1997;Van Damme et al., 2002). Tampa scale of kinesiophobia (TSK) The Tam pa Scale for Kinesiophobia (TSK) is an 11-item questionnaire, with individual items scored from 1 to 4. The questionnaire was developed to quantify the fear of movement and injury/re-injury for individuals currently experi encing pain. Higher TSK sc ores indicate greater fear of movement and injury/r e-injury due to pain. The TSK has demonstrated acceptable psychometric properties in prior studies (Woby et al., 2005). Visual analog scale Separate 10 cm visual analog scales anchored with none at all and worst imaginable were used to quantify fear, anxiety, threat, and challenge in relation to the QST. These measures were obtained only to assure no group differe nces in the individual variables.

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46 Functional Questionnaires Disability of the arm, shoulder, and hand que stionnaire (DASH) The DASH is a self report measure of upper extremity disability and contains thirty items, ranging from 1 (no difficulty) to 5 (unable) The DASH contains three modules which are scored independently and includes an 11 question general module, a 4 item work module, and a 4 item sports/performing arts module. The DAS H is used in assessm ent of general upper extremity disorders and has sound psychometric prope rties (Beaton et al., 2005;Greenslade et al., 2004;Gummesson et al., 2003; Gummesson et al., 2006;Jester et al., 2005). We report only on the 11 question general module of the DASH for de scriptive statistics and in analysis. Boston questionnaire The Boston Questionnaire is a self report disabi lity m easure that is specific to patients with CTS. The Boston Questionnaire is widely used in the assessment of subjects with CTS and has sound psychometric prope rties (Greenslade et al., 2004; Leite et al., 2006;Sambandam et al., 2007). The Boston Questionnaire contains bo th an 11 item sympto m scale and a 9 item function scale. Each item consists of a 5 point adjectival scale scored from 1 to 5 with lower scores indicating greater functi on. We report only the 9 item function scale as a measure of function. Pain Measurement Mechanical visual analog scale (MVAS) An MVAS a nchored with No pain and The most intense pain sensation imaginable was used to assess pain. A dditionally, an MVAS anchored w ith Not at all unpleasant and The most unpleasant sensation imaginable was used to assess symptoms such as tingling and numbness. MVAS are commonly used in the as sessment of pain and have demonstrated sound psychometric properties including the characteristics of a rati o scale (Price et al., 1994).

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47 Numeric rating scale (NRS) An NRS anc hored with, No pain sensation at all and The most intense pain sensation imaginable was used to assess pain. NRS are commonly used in the assessment of pain. While lacking the ratio properties of MVAS (Price et al., 1994), the NR S has demonstrated adequate psychometric properties (Gagliese et al., 2005;Jensen et al., 1986) and is a common measure of both clinical and experimental pain. Nerve Conduction Study Participants underwent a nerve cond uction study (NCS) which assessed; bilateral m edian motor to abductor pollicis brevis median/ ulnar sensory comparison to digit #4 (at 14 cm) median/ ulnar sensory comparison transpalmer (8 cm across wrist) median/ radial sensory comparison to digit #1 (at 10 cm) Physical Examination The physical exam ination consisted of measures of wrist range of motion (ROM) using a standard goniometer. Strength was measured using a hand held dynamometer to measure grip strength with the forearm in neutral and the el bow flexed to 90 degrees. Lateral and 3chuck pinch were assessed using a dynamometer with th e elbow flexed to 90 degrees and the forearm pronated. Sensation was assessed using Symmes Weinstein monofilaments to the tip of each digit. Participants closed their eyes and were instructed to indicate when they felt the monofilament. Pressure was applied to just bend the monofilament and each individual stimulus was applied up to three times prior to moving to a thicker monofilament if the subject did not indicate sensation. Additionally, each participan t was evaluated for Phalens test, Tinnels test over the carpal tunnel, compression test to the median nerve, uppe r limb tension test with a median nerve bias, and upper limb tension test with an ulnar nerve bias. All special tests were documented as either positive or negative.

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48 Intervention Participants were random ly assigned to one of two intervention groups. Group 1 received a specific MT technique known as a neurodynamic intervention (NDI) (Figure 5-1A) which consisted of movements known to specifically and forcefully stress the median nerve (Coppieters & Butler, 2007;Coppieters & Alshami, 2007). The NDI consisted of 25 degrees of contralateral cervical sidebending, ipsilateral shoulder depression and abduction to 90 degrees, ER to 90 degrees, 45 degrees of elbow extension, forear m supination, and repeti tive wrist and finger flexion and extension through a 90 degree range of motion. Each repetition was controlled to allow for 6 seconds through the entire range and part icipants received 5 sets of 10 cycles for the first three sessions and 7 sets of 10 cycles for se ssions 4 through 6. Group 2 received the indirect NDI (Figure 5-1B) which consisted of movement s intended to mimic the direct NDI; however, minimize stress and movement of the median nerve. The indirect NDI consisted of the cervical spine maintained in neutral sidebending, no ipsi lateral shoulder depression and abduction to 45 degrees, ER to 45 degrees, 45 degrees of elbow extension, and forearm pronation with the same wrist and finger motion, timing, and repe titions as the direct technique. Procedures Refer to figure 5-2 for flow diagram of study procedures. Indi viduals agreeing to participate signed an informed consent form a pproved by the University of Florida Institutional Review Board and then completed intake forms consisting of a demographic form, psychological questionnaires, the PCOQ, and functional Questi onnaires. Next, participants underwent a nerve conduction study. The NCS was performed by a medical doctor using a TECASynergy N2 ultra-portable 2 channel NCS syst em (VIASYS Healthcare). Follo wing the NCS, a standardized physical examination was performed by a member of the research t eam after which the participant was provided with splints for their involved hand(s) along with instructions in use

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49 emphasizing night time wear. Participants then underwent quantitative sensory testing (QST) using thermal stimuli delivered through the Me doc Neurosensory Analyzer (TSA-2001, Ramat Yishai, Israel) with a hand-held, peltier-eleme nt-based stimulator. Our QSTprocedure used previously established protocols (Price et al., 2002;Staud et al., 2001) which were consistent with our previously reported pilot studies. A fiber mediated pain was assessed through heat impulses of 47 and 49 C for five seconds each and subjects rated their pain se nsation using a 100 mm MVAS. The thermode was applied to the volar forearm for this procedure and thermal stimuli were applied in a random order to avoid order bias This protocol was performed twice with the thermode repositioned and waiting sixty seconds between each session to avoid accommodation to the stimuli. The average pain rating of the two sessions was used to indicate pain perception associated with each temperature. Cfiber me diated pain was assessed through ten heat pulses at 51 C applied to the thenar surface of the palm of the hand with an inter-s timulus interval of .33 seconds. The average of the first five pulses wa s used to indicate cfiber mediated pain perception. Following the initial testing, subjects were ra ndomly assigned to receive either a direct NDI known to anatomically stress the median nerve (Coppieters & Butler, 2007;Coppieters & Alshami, 2007) or an indirect NDI that lessens the mechanical stress to the median nerve. Participants were positioned for their assigned intervention and received two cycles of wrist flexion and extension in this pos ition. Participants were then asked to again complete the expectation portion of the PCOQ an d this served as a measure of expectation following exposure to the intervention. Upon completion of the expectation portion of the PCOQ, participants underwent the first session of thei r assigned intervention and then immediately underwent follow up QST using the same protocol. Participants were followed over the next three weeks for

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50 application of the randomly assi gned intervention. Follow up sessi ons included measures of pain and symptoms using a MVAS and application of the assigned intervention. Immediately following the assigned interventi on, follow up measures of current pain and symptoms were obtained using a MVAS. The number of additional sessions was based on the availability of the participant and varied. Approxi mately three weeks following ra ndomization, participants were seen for a final visit consisting of follow up que stionnaires, NCS, physical examination, and pre and post intervention QST. Statistical Analysis We analyzed data from one extremity per par ticipant. The involved extremity was used in participants reporting unilateral CTS. The ex tremity indicated as more symptomatic was analyzed in participants with bilateral CTS. In cases of bilateral CTS where the participant reported no difference in pain or symptoms betw een the hands, the dominant extremity was then chosen for analysis. Individual t-tests and chi sq uare tests were used to assess the direct and indirect NDI groups for post-randomization differences in parametric and non-parametric variables, respectively. Alpha le vels were set at 0.05 and all analysis was performed using the SPSS statistical package (version 14.0) Believability of Placebo a. A Chisquare analysis was used to com p are assessment of group assignment (direct versus indirect treatment). Random assignment was compared to perceived assignment. b. Repeated measures ANOVA were used to test for an interaction betw een baseline measure of expectation (after signing the informed c onsent form) and measure of expectation (after brief exposure to the randomly assigned inte rvention) and group assi gnment (direct versus indirect). Treatment Effects a. Repeated measure ANOVA were used to test fo r a group (direct NDI ve rsus indirect NDI) x tim e (pre to post) interaction for measures of experimental pain sensitivity. Separate models were used to assess immediate differe nces at baseline, imme diate differences at

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51 discharge, and differences between the firs t measurement at evaluation and the final measurement at discharge. b. Repeated measure ANOVA were used to test fo r a group (direct NDI ve rsus indirect NDI) x time (baseline to 3 weeks) interaction for NC V measures of distal latency of the median motor to abductor pollicis brevis and the combined sensory index. c. Separate repeated measure ANOVA were used to test for a group (direct NDI versus. indirect NDI) x time (pre to post) interaction for measur es of pain, symptoms, and disability. We used the average of separate MVAS ratings of current, worst in the past 24 hours, and least in the past 24 hours to quantif y both pain and symptoms at baseline and at 3 weeks. We were also intere sted in immediate changes in se lf report of pain, so separate repeated measure ANOVA models were used with MVAS of current pain prior to and immediately following NDI. The DASH Qu estionnaire was used as a measure of disability. Predictors of Outcomes First, a corr elation matrix to investigate asso ciations of predictor variables and dependent variables, as well as to investigate the potenti al of multicollinearity was created. Separate regression models then assessed the variance ex plained by the independent variables of age, initial pain or disability, treatment group assignment, immediate hypoalgesic effect, and initial expectation on the dependent variables of 3-week pain and disability scores respectively. Hierarchical models were built us ing the following order of entry for variables. First, age was entered to account for demographic variables. Second, either baseline pain or function was entered depending upon the model. Third, treatmen t group was entered to account for direct or indirect neural mobilization rece ived as treatment. Fourth, th e immediate hypoalgesic effect was entered to account for neurophysiological modula tion occurring during the first session (as had been observed in our previous studies). Finall y, initial expectation was entered to account for this variable. R-square changes were tested for each step of th e hierarchical model. A final, parsimonious regression model was created by in cluding only those vari ables that uniquely contribute to the prediction of 3 week pain or disability. Multicollinearity was assessed through observation of the correlation betw een the independent variables. Frequency distribution was

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52 assessed for outliers. Histograms of the standardized residuals were used to assess for linearity and normal distribution. Homoscedasticity was assessed through analysis of partial residual plots and normal probability plots.

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53 A. B. Figure 5-1. Examples of randomly assigned interventions. Participant is positioned as noted and force is applied to the tissue through repeti tive wrist, finger, and thumb flexion and extension. A) Direct NDI. Note combin ation cervical, shoulder, elbow, and wrist positioning which imparts movement and stre ss to the median nerve (Coppieters & Butler, 2007;Coppieters & Alshami, 2007). B) Indirect NDI. Note positioning of cervical spine and upper extr emity in way to lessen movement and stress to the median nerve

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54 Figure 5-2. Study protocol. PCOQ= Patient Centered Outcome Questionnaire; QST= Quantitative Sensory Testing; MVAS= Mechanical Visual Analog Scale; NDI= Neurodynamic Intervention

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55 CHAPTER 6 RESULTS Eightythree individuals were screened for the study and 40 agreed to participate (Figure 6-1). Twenty seven participants repo rte d bilateral CTS. Baseline measures of demographic information, psychological factors, and physical factors did not differ between the groups (p> 0.05) (Table 6-1 and 6-2). Range of attended sessions was between 2 and 6 in individuals completing the study an d dependent upon individual par ticipants availability. Mean number of sessions attended was 4.74 (1.37). Believability of Placebo Perceived Group Assignment The frequencies of perceived group assignm ent did not significantly differ by actual group assignm ent 2 (1, N = 37) = 2.10, p = 0.15). Refer to table 6-3 for perceived compared to actual intervention. Expectation for Pain at Completion A group (direct NDI versus indirect NDI) by time (imm ediately post consent versus following brief exposure to assigned intervention) interaction was not observed for expected pain following the study (F(1,37)= 0.03, p= 0.87, partial 2< 0.01) suggesting the groups did not differ in their expectation for pain relief following brief exposure to the assigned intervention. Additionally, a main effect for time was not observed (F(1,37)= 2.38, p= 0.13, partial 2= 0.06) suggesting expectation for treatment did not differ at baseline and following brief exposure to the randomly assigned intervention.

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56 Treatment Effects Associated Experiment al Pain Perception Evaluation pre to post NDI (Table 6-4, Figure 6-2) Neither a group x tim e interaction (F(1,38)= 0.68, p= 0.41, partial 2= 0.02) nor a main treatment effect for time (F(1,38)= 0.21, p= 0.65, partial 2= 0.01) was observed for A fiber mediated pain at 47 C Neither a group x time interaction (F(1,37)= 0.53, p= 0.47, partial 2= 0.01) nor a main treatment effect for time (F(1,37)= 0.12, p= 0.73, partial 2< 0.01) was observed for A fiber mediated pain at 49 C Neither a group x time interaction (F(1,38)= 0.07, p= 0.79, partial 2< 0.01) nor a main treatment effect for time (F(1,38)= 0.04, p= 0.83, partial 2< 0.01) was observed for cfiber mediated pain. Discharge pre to post NDI (table 6-5, Figure 6-3) Neither a group x tim e interaction (F(1,35)= 0.29, p= 0.59, partial 2= 0.01) nor a main treatment effect for time(F(1,35)< 0.01, p= 0.96, partial 2< 0.01) was observed for A fiber mediated pain at 47 C. Neither a group x time interaction (F(1,36)= 0.20, p= 0.66, partial 2= 0.01) nor a main treatment effect for time (F(1,36)< 0.01, p= 0.99, partial 2 < 0.01) was observed for A fiber mediated pain at 49 C. A significant group x time interaction (F(1,37)= 6.86, p= 0.01, partial 2= 0.16) was observed for cfiber mediated pain.

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57 Baseline evaluation to discharge post NDI (lo ngitudinal) (ta ble 6-6, Figure 6-4) Neither a group x time interaction (F(1,35)= 3.15, p= 0.09, partial 2= 0.08) nor a main treatment effect for time (F(1,35)= 0.66, p= 0.42, partial 2= 0.02) was observed for A fiber mediated pain at 47 C. Neither a group x time interaction (F(1,35)= 0.69, p= 0.41, partial 2= 0.02) nor a main treatment effect for time (F(1,35)= 1.44, p= 0.24, partial 2= 0.04) was observed for A fiber mediated pain at 49 C. A significant group x time interaction (F(1,37)= 4.05, p= 0.05, partial 2= 0.10) was observed for cfiber mediated pain. Nerve Conduction Studies A subgroup of twelve participants received ba seline and discharge (3week) NCS. A group (direct NDI versus indirect NDI) by tim e (eva luation versus discharge) interaction was not observed for measures of distal latency from median motor to Abductor Pollicis Brevis (F(1,10)= 3.44, p= 0.09, partial 2= 0.26) or the combined sensory index (F(1,10)= 1.83, p= 0.21, partial 2= 0.15). A main treatment effect was not observed for measures of distal latency from median motor to Abductor Pollicis Brevis (F(1,10)= .02, p= 0.88, partial 2< 0.01) or the combined sensory index (F(1,10)= 1.06, p= 0.33, partial 2= 0.10). Associated Clinical Pain Symptoms, and Function Immediate change in clinical pa in and symptoms (Figure 6-5) A group (direct NDI versus indirect NDI) by time (pre NDI to imm ediately post NDI) interaction was not observed fo r self report of current pain at either evaluation (F(1,38)< .01, p= 0.96, partial 2< 0.01) or discharge (F(1,37)= .59, p= 0.45, partial 2= 0.02). However, a main treatment effect was observed at both evaluation (F(1,38)= 7.92, p= 0.01, partial 2= 0.17) and discharge (F(1,37)= 6.44, p= 0.02, partial 2= 0.15) suggesting an immedi ate improvement in pain

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58 which was not dependent upon group assignment. Mean current pain at evaluation baseline was 18.75 (16.31) and at evaluation im mediately following NDI was 11.93 (14.02). Mean current pain at discharge baseline was 14.33 (20.14) and immediately following NDI at discharge was 9.85 (16.22). Neither a group (direc t NDI versus indirect NDI) by time (pre NDI to immediately post NDI) interaction (F(1,38)= 0.04, p= 0.95, partial 2< 0.01) or main treatment effect (F(1,38)= 3.05, p= 0.09, partial 2= 0.07) was present for self report of current symptoms on evaluation. A group (direct NDI versus indirect NDI) by time (pre NDI to immediately post NDI) interaction (F(1,37)= 2.63, p= 0.11, partial 2= 0.07) was not present for change in self report of symptoms at discharge; however, a main treatment effect for self report of symptoms was observed at discharge (F(1,37)= 4.66, p= 0.04, partial 2= 0.11). Mean current symptoms at discharge were 13.21 (18.93) and immediately following NDI at discharge were 9.46 (15.09). Change in clinical pain and symptoms over 3 weeks Neither a group (direct NDI versus indirect NDI) by tim e (baseline versus discharge) interaction (F(1,37)= .16, p= 0.69, partial 2< 0.01) nor a main treatment effect (F(1,37)= 3.34, p= 0.08, partial 2= 0.08) existed for self report of pain. Neither a group (d irect NDI versus indirect NDI) by time (baseline versus discharge) interaction (F(1,37)= .04, p= 0.85, partial 2< 0.01) nor a main treatment effect (F(1,37)= 1.48, p= 0.23, partial 2= 0.04) existed for self report of symptoms. (Table 6-7) Three week change in function Neither a group (direct NDI versus indire ct NDI) by tim e (baseline to discharge) interaction (F(1,34)= 0.50, p= 0.48, partial 2= 0.01) nor a main treatment effect (F(1,34)= 2.95, p= 0.10, partial 2= 0.08) was present for the Boston Qu estionnaire functional scale. A group (direct NDI versus indirect NDI) by time (baseline to discharge) interaction was not present for

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59 the DASH Questionnaire (F(1,34)= 0.00, p= 1.00, partial 2< 0.01); however, a main treatment effect was observed (F(1,34)= 8.93, p= 0.01, partial 2= 0.21). (Table 6-7) Predictors of Outcomes Predictors of pain at 3 weeks We used hierarchical regression to determ ine the predictors of pain at 3 weeks. 1.) Age, 2.) baseline pain, 3.) group a ssignment, 4.) first session change in pain immediately following NDI, and 5.) expectation for pain taken at baseline served as predictor variables in the model. A correlation matrix was calculated to note the as sociation between variables and to assess for potential multicollinearity (Table 6-8). The a ssumption of no multicollinearity did not appear to be violated as all correlations were we ll below 0.90. Casewise diagnostics indicated 1 participant with standardized re siduals of 2.76. No actions were taken as the Cooks distance was < 1 (0.28) and Mahalanobis distance was 4.96. DurbinWatson for this model was 1.90 suggesting the assumption of independence of erro rs has been met. A 5 step model was used which provided the following results (Table 6-9 and 6-10). A parsimonious model was then constructed using the significant predictors from the initial model and cons isted of baseline pain, change in current clinical pain on evaluation, and expectation for pain (Table 6-11 and 6-12). Predictors of function at 3 weeks Next, we used hierarchical regression to determ ine the predictors of disability at 3 w eeks. The DASH score served as the de pendent variable. 1.) Age, 2.) baseline DASH, 3.) group assignment, 4.) first session change in clinical pain immediately immediately following NDI, and 5.) baseline expectation for 3 w eek function served as predicto r variables in the model. A correlation matrix was calculated to note the as sociation between variables and to assess for potential multicollinearity (Table 6-13). The assumption of no multicollinearity did not appear to be violated as all correlations were we ll below 0.90. Casewise diagnostics indicated 1

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60 participant with standardized re siduals of -3.06. No actions we re taken as the Cooks distance was < 1 (0.31) and Mahalanobis distance was 4.15. DurbinWatson for this model was 2.85 suggesting the assumption of independence of erro rs has been met. A 5 step model was used which provided the following results (6-14 and 6-15).

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61 Figure 6-1. Summary of recruitment, enro llment, randomization, allocation, follow up, and analysis for the study.

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62 Table 6-1. Baseline comparison of direct and indirect NDI groups in self report measures Direct Indirect Total Sample pvalue for difference Age (years) 44.30 (6.97) 49.50 (12.35) 46.90 (10.25) 0.11 Duration of CTS (weeks) 192.22 (273.21) 362.82 (256.85) 275.09 (275.41) 0.07 PCS 16.85 (11.17) 14.94 (8.79) 15.95 (10.03) 0.57 FPQ 23.05 (6.09) 23.42 (4.88) 23.24 (5.44) 0.84 TSK 23.35 (6.02) 23.35 (6.27) 23.35 (6.05) 0.99 VAS Fear 16.35 (19.33) 20.05 (20.27) 18.20 (19.64) 0.56 VAS Anxiety 14.70 (15.77) 20.15 (21.16) 17.43 (18.63) 0.36 VAS Challenge 17.75 (15.21) 21.10 (25.64) 19.43 (20.88) 0.62 VAS Threat 13.90 (19.62) 13.60 (20.50) 13.75 (19.81) 0.96 Baseline Expectation (Pain) 26.05 (19.51) 27.5 (20.49) 26.78 (19.76) 0.82 Baseline Expectation (Interference) 27.80 (29.58) 20.79 (22.56) 24.38 (26.29) 0.41 Expectation Assessment (Pain) #2 19.25 (20.98) 20.84 (16.72) 20.03 (18.79) 0.80 Usual Pain (PCOQ) 51.25 (28.00) 45.00 (28.52) 48.13 (28.07) 0.49 Boston Questionnaire 17.67 (5.82) 17.83 (6.98) 17.75 (6.34) 0.48 DASH Questionnaire 35.29 (15.35) 40.67 (18.69) 37.98 (17.09) 0.34 Baseline Pain (MVAS) 22.26 (13.70) 18.99 (17.24) 20.63 (15.46) 0.51 Baseline Symptoms (MVAS) 21.88 (1.34) 17.13 (18.01) 19.50 (15.84) 0.35 Key: All data are reported as mean (standard deviation) ratings, unless otherwise indicated. NDI= neurodynamic intervention, PCS = Pain Catastrophizing Scale, FPQ = Fear of Pain Questionnai re, TSK = Tampa Scale of Kinesiophobia, VAS= Visual Analog Scale, PCOQ= Patient Centered Ou tcome Questionnaire. VAS of fear, anxiety, threat, and challenge are in relation to quantitativ e sensory testing, Expectation= expectation for pain and interference from PCOQ. Baseline expectation for pain wa s obtained immediately following informed consent and #2 was obtained following brief exposure to randomly assigned intervention. Boston Questionnaire represents the functional status scale, DASH= Disability of Arm, Should er, and Hand Questionnaire, Baseline Pain represents

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63 average of three Mechanical Visual Analog Scale (MVAS) ratings of current pain, worst in past 24 hours, and best in past 24 hours. Baseline Symptoms represents averag e of three Mechanical Visual Analog Scale (MVAS) ratings of current symptoms, worst in past 24 hours, and best in past 24 hours. Expectation for pain ratings (PCOQ) are not directly comparable to pain ratings (MVAS) so baseline usual pain ratings (PCOQ) are provided to allow direct comparison.

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64 Table 6-2. Baseline comparison of the direct and indirect NDI groups on the physical examination Direct Indirect Total Sample pvalue for difference Wrist flexion ROM (in degrees) 67.22 (11.01) 72.16 (7.00) 69.76 (9.38) 0.11 Wrist extension ROM (in degrees) 70.56 (11.62) 66.05 (9.51) 68.24 (10.69) 0.20 Sensation Normal Thumb Min >Min 5 (28%) 10 (56%) 3 (17%) 5 (28%) 10 (56%) 3 (17%) 10 (28%) 20 (56%) 6 (17%) 1.00 Sensation Normal Index Min Finger >Min 6 (33%) 9 (50%) 3 (17%) 4 (22%) 11 (61%) 3 (17%) 9 (25%) 20 (56%) 6 (17%) 0.74 Sensation Normal Middle Min Finger >Min 4 (24%) 11 (65%) 2 (12%) 5 (28%) 12 (67%) 1 (6%) 9 (26%) 23 (66%) 3 (9%) 0.80 Sensation Normal Radial Min Ring >Min Finger 4 (22%) 13 (72%) 1 (6%) 6 (33%) 11 (61%) 1 (6%) 10 (28%) 24 (67%) 2 (6%) 0.75 Sensation Normal Ulnar Min Ring >Min Finger 7 (39%) 10 (56%) 1 (6%) 5 (28%) 12 (67%) 1 (6%) 12 (33%) 22 (61%) 2 (6%) 0.77 Sensation Normal Little Min Finger >Min 8 (44%) 9 (50%) 1 (6%) 6 (33%) 12 (67%) 0 (0%) 14 (39%) 21 (58%) 1 (3%) 0.42 Phalens Test + 17 (94%) 1 (6%) 15 (79%) 4 (21%) 32 (86%) 5 (14%) 0.17 Tinnels Test + 14 (78%) 4 (22%) 13 (68%) 6 (32%) 27 (73%) 10 (27%) 0.52 Compression + Test 14 (78%) 4 (22%) 17 (89%) 2 (11%) 31 (84%) 6 (16%) 0.34 ULTT + Median bias 9 (50%) 9 (50%) 8 (44%) 10 (56%) 17 (47%) 19 (53%) 0.74 Grip (3 trial average on dynamometer) 21.76 (10.88) 22.25 (7.84) 22.00 (9.35) 0.88 NCS distal latency 4.64 (1.95) 4.61 (1.38) 4.63 (1.64) 0.97

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65 Table 6-2. Continued Direct Indirect Total Sample pvalue for difference NCS CSI 1.89 (1.81) 1.92 (1.38) 1.90 (1.53) 0.98 Pain Threshold (C) 43.26 (2.40) 44.12 (2.99) 43.69 (2.71) 0.32 Rating for pain threshold (MVAS) 18.53 (16.86) 17.00 (13.58) 17.76 (15.13) 0.75 Pain Tolerance (C) 48.57 (1.34) 47.70 (2.70) 48.13 (2.15) 0.20 Rating for pain tolerance (MVAS) 46.85 (24.41) 39.23 (23.11) 43.04 (23.78) 0.32 Key All data are reported as mean (standard devi ation) ratings, unless otherwise indicated. NDI= neurodynamic intervention, ROM = Range of Motio n, Sensation as measured by Symmes Weinstein monofilament: Normal <=2.83, Min= minimal loss of sensation (3.61 to 4.31), > Min= moderate to severe loss of sensation (>=4.56), ULTT = Upper limb tension test. Performed in this study with a median nerve bias (Coppieters & Butler, 2007;Coppieters & Alshami, 2007). NCS= Nerve conduction study, CSI= Combined Sensory Index, MVAS= Mechan ical Visual Analog Scale. Pain threshold and tolerance ratings obtained through quantitative sensory testing. Table 6-3. Comparison of perceived to actual group assignment. Indirect NDI Direct NDI Total Perceived Indirect NDI 7 (39%) 12 (63%) 19 (51%) Perceived Direct NDI 11 (61%) 7 (37%) 18 (49%) Participants were asked at 3 week follow up session of study to indicate whether they believed they had received direct or indirect neurodynamic intervention (NDI).

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66 Table 6-4. Immediate effects of NDI on pain perception to QST on evaluation Pre direct NDI QST rating Post direct NDI QST rating Mean difference in pain rating for direct NDI (Pre-Post) Pre indirect NDI QST rating Post indirect NDI QST rating Mean difference in pain rating for indirect NDI (PrePost) A (47 C) 24.05 (21.01) 21.21 (25.44) 2.85 16.65 (16.48) 17.48 (18.04) -0.83 A (49 C) 38.16 (25.65) 34.40 (26.23) 3.76 33.48 (22.09) 34.80 (27.46) -1.32 cfiber 36.92 (22.56) 38.24 (27.95) -1.32 33.26 (29.88) 33.11 (28.75) 0.15 Pain ratings to quantitative sensory testing on the initial visit comparing b aseline ratings with those immediately following neurodynamic intervention. A ssociated pain quantified with mechanical visual analog scale for A fiber mediated pain and numerical rating scale for cfiber mediated pain. All data are reported as mean (standard deviation) ratings, unless otherwise indicated. NDI= neurodynamic intervention 0 5 10 15 20 25 30 35 40 45 pre NDI post NDISelf Report of Pain Direct NDI 47 C Indirect NDI 47 C Direct NDI 49 C Indirect NDI 49 C Direct NDI c-fiber Indirect NDI cfiber Figure 6-2. Immediate effect of ND I on self report of pain to st andardized painfu l stimuli during evaluation. Pain perception measured with mechanical visual analog scale for 47 and 49 C ratings and using numeric rating scale for cfiber mediated pain ratings. NDI= neurodynamic intervention.

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67 Table 6-5. Immediate effects of NDI on pain perception to QST at discharge Pre direct NDI QST rating Post direct NDI QST rating Mean difference in pain rating for direct NDI (Pre-Post) Pre indirect NDI QST rating Post indirect NDI QST rating Mean difference in pain rating for indirect NDI (PrePost) A (47 C) 16.86 (13.56) 15.61 (14.78) 1.25 16.24 (21.42) 19.68 (27.39) -3.44 A (49 C) 32.66 (22.41) 31.53 (28.68) 1.13 30.15 (29.58) 31.62 (32.49) -1.47 cfiber* 43.61 (25.78) 34.86 (24.91) 8.75 43.01 (28.67) 47.16 (32.09) -4.15 Pain ratings to quantitative sensory testing on the 3 week visit comparing 3 week baseline ratings with those immediately following neurodynamic intervention. Associated pain quantified with mechanical visual analog scale for A fiber mediated pain and numeric rating scale for cfiber mediated pain. All data are reported as mean (standard deviation) ra tings, unless otherwise indicated. NDI= neurodynamic intervention. 0 5 10 15 20 25 30 35 40 45 50 pre NDI post NDISelf Report of Pain Direct NDI 47 C Indirect NDI 47 C Direct NDI 49 C Indirect NDI 49 C Direct NDI c-fiber* Indirect NDI cfiber Figure 6-3. Immediate effect of ND I on self report of pain to st andardized painfu l stimuli during discharge. Pain perception measured with mechanical visual analog scale for 47 and 49 C ratings and using numeric rating scale for cfiber mediated pain ratings. NDI= neurodynamic intervention.

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68 Table 6-6. Longitudinal effect of NDI on pain perception to QST Pre direct NDI QST rating Post direct NDI QST rating Mean difference in pain rating for direct NDI (Pre-Post) Pre indirect NDI QST rating Post indirect NDI QST rating Mean difference in pain rating for indirect NDI (PrePost) A (47 C) 23.83 (21.12) 15.61 (14.78) 8.22 16.66 (16.93) 19.71 (25.88) -3.05 A (49 C) 39.53 (25.67) 33.14 (28.61) 6.39 32.92 (22.55) 31.76 (30.70) 1.16 cfiber 37.18 (23.14) 34.86 (24.91) 2.32 33.26 (29.88) 47.16 (32.09) -13.90* Pain ratings to quantitative sensory testing compari ng baseline ratings on the initial visit with those immediately following neurodynamic intervention on the 3 week visit. Associated pain quantified with mechanical visual analog scale for A fiber mediated pain and numerical rating scale for cfiber mediated pain. All data are reported as mean (standard de viation) ratings, unless otherwise indicated. NDI= neurodynamic intervention. *= significant at p 0.05. 0 5 10 15 20 25 30 35 40 45 50 baseline at first session post NDI at 3 weeksSelf Report of Pain Direct NDI 47 C Indirect NDI 47 C Direct NDI 49 C Indirect NDI 49 C Direct NDI c-fiber Indirect NDI cfiber* Figure 6-4. Pain perception to st andardized thermal stimuli measured longitudinally i.e. baseline at first session to following NDI at 3 w eeks. Pain perception measured with mechanical visual analog scale for 47 and 49 C ratings and using numeric rating scale for cfiber mediated pain ratings. NDI= neurodynamic intervention. = significant at p 0.05.

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69 0 2 4 6 8 10 12 14 16 18 20Pre NDI Eval Post NDI Eval Pre NDI Discharge Post NDI DischargeSelf Report of Pain Pain Symptoms Figure 6-5. Immediate effect of NDI on self report of curren t carpal tunnel related pain and symptoms. A significant treat ment effect (p<0.05) independent of group assignment (p>0.05) was observed in self reports of pain at evaluation and discharge. A significant treatment effect (p<0.05) inde pendent of group assignment (p>0.05) was observed for self report of symptoms at discharge; however, significant changes were not observed in symptoms on evaluation (p> 0.05) Pain and symptom perception were measured with a mechanical visual an alog scale. NDI= neurodynamic intervention. Table 6-7. Baseline to 3 week measures of pain, symptoms, and function for entire sample Baseline 3 weeks pvalue for change Pain 20.46 (15.63) 15.67 (17.00) 0.08 Symptoms 19.31 (16.00) 15.85 (20.51) 0.23 Boston Questionnaire 17.75 (6.34) 16.81(5.8) 0.10 DASH Questionnaire 38.64 (17.31) 33.21 (18.55) 0.01 Key All data are reported as mean (standard de viation) ratings, unless otherwise indicated. Pain and symptoms each obtained through mechanical visual analog scale. Ratings of least in past 24 hours, worst in past 24 hours for both pain and symt ptoms were obtained and number represents average rating of these 3 values. Boston questionnaire represents the functional scale DASH= Disability of arm, shoulder, and hand questionnaire

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70 Table 6-8. Correlation matrix for pred iction of rating of pain at 3 weeks Pain at discharge Age Baseline pain Change in pain Baseline expectation Pain at discharge 1.00 Age 0.08 1.00 Baseline pain 0.52* -0.20 1.00 Change in pain -0.20 0.05 0.06 1.00 Baseline expectation for pain at 3 weeks 0.22 0.21 -0.03 0.19 1.00 Baseline expectation obtained from expectation portion of the PCOQ. *= significant at p<0.05 Table 6-9. Regression model for pain at 3 weeks (Full Model) Model R R2 Adj R2 F change p for change 1 Age 0.08 0.01 -0.02 0.24 0.63 2 Age, baseline pain 0.52 0.28 0.24 13.33 <0.01* 3 Model 2 + group assignment 0.54 0.29 0.23 0.83 0.37 4 Model 3 + immediate change in self report of carpal tunnel pain following NDI 0.59 0.35 0.27 3.00 0.09 5 Model 4+ baseline expectation for pain at 3 weeks 0.65 0.42 0.33 4.09 0.05* Baseline expectation obtained from expectation por tion of the PCOQ. *= significant at p<0.05

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71 Table 6-10. Regression model for pain at 3 weeks (Individual Variables) Model B Standard error of B p 1 Age 0.01 0.03 0.08 0.63 2 Age Baseline pain 0.02 0.56 0.02 0.15 0.09 0.52 0.53 <0.01* 3 Age Baseline pain Group assignment 0.02 0.55 0.45 0.02 0.16 0.50 0.12 0.51 0.13 0.41 <0.01* 0.37 4 Age Baseline pain Group assignment Immediate change in se lf report of carpal tunnel pain following NDI 0.02 0.57 0.46 -0.27 0.02 0.15 0.48 0.15 0.14 0.52 0.14 -0.24 0.34 < 0.01* 0.35 0.09 5 Age Baseline pain Group assignment Immediate change in se lf report of carpal tunnel pain following NDI Baseline expectation for pain at 3 weeks 0.01 0.57 0.48 -0.32 0.02 0.02 0.15 0.46 0.15 0.01 0.08 0.54 0.14 -0.29 0.28 0.56 <0.01* 0.31 0.04* 0.05* Baseline expectation obtained from expectation portion of the PCOQ. *= significant at p<0.05 Table 6-11. Parsimonious regression mode l for pain at 3 weeks (Full Model) Model R R2 Adj R2 F change p for change 1 Baseline pain 0.52 0.27 0.25 13.46 < 0.01* 2 Baseline pain + immediate change in self report of CTS pain following NDI 0.57 0.32 0.28 2.88 0.10 3 Model 2 + baseline expectation for pain at 3 weeks 0.63 0.40 0.35 4.60 0.04* Baseline expectation obtained from expectation portion of the PCOQ. *= significant at p<0.05

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72 Table 6-12. Parsimonious regr ession model for pain at 3 weeks (Individual Variables) Model B Standard error of B p 1 Baseline pain 0.56 0.15 0.52 <0.01* 2 Baseline pain Immediate change in self report of CTS pain following NDI 0.58 -0.26 0.15 0.15 0.53 10.23 <0.01* 0.10 3 Baseline pain Immediate change in self report of CTS pain following NDI Baseline expectation for pain at 3 weeks 0.59 -0.32 0.03 0.14 0.15 0.01 0.54 -0.29 0.29 <0.01* 0.04* 0.04* Table 6-13. Correlation matrix for predicti on of rating of disability at 3 weeks Pain at discharge Age Baseline DASH Change in pain Baseline expectation DASH at 3 weeks 1.00 Age 0.41* 1.00 Baseline DASH 0.82* 0.35* 1.00 Immediate change in clinical pain following NDI -0.15 0.06 -0.15 1.00 Baseline expectation for function at 3 weeks 0.31* 0.03 0.56* 0.18 1.00 = significant at p<0.05 DASH= Disability of Arm, Shoulder, Hand Questionnaire Immediate change in self report of clinical pain following NDI obtained from mechanical visual analog score of current pain prior to neurodynamic intervention (NDI) and immediately following NDI

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73 Table 6-14. Regression model for disa bility at 3 weeks (Full Model) Model R R2 Adj R2 F change p for change 1 Age 0.41 0.17 0.15 7.02 0.01* 2 Age, baseline DASH 0.83 0.69 0.68 56.43 <0.01* 3 Model 2 + group assignment 0.83 0.69 0.67 0.00 0.98 4 Model 3 + immediate change in self report of clinical pain following NDI 0.84 0.70 0.66 0.26 0.62 5 Model 4+ baseline expectation for function at 3 weeks 0.85 0.72 0.67 2.36 0.14 DASH= Disability of Arm, Shoulder, and Hand Questionnaire Immediate change in self report of clinical pain following NDI obtained from mechanical visual analog score of current pain prior to neurodynamic intervention (NDI) and immediately following NDI Baseline expectation obtained from expectation portion of the PCOQ *= significant at p<0.05

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74 Table 6-15. Regression mode l for disability at 3 weeks (Individual Variables) Model B Standard error of B p 1 Age 0.74 0.28 0.41 0.01* 2 Age Baseline DASH 0.25 0.83 0.18 0.11 0.14 0.77 0.18 <0.01* 3 Age Baseline pain Group assignment 0.25 0.83 0.10 0.19 0.11 3.66 0.14 0.77 0.00 0.18 <0.01* 0.98 4 Age Baseline pain Group assignment Immediate change in self report of clinical pain following NDI 0.27 0.82 0.08 -0.60 0.19 0.12 3.71 1.19 0.15 0.76 0.00 -0.05 0.18 <0.01* 0.98 0.62 5 Age Baseline pain Group assignment Immediate change in self report of clinical pain following NDI Baseline expectation for function at 3 weeks 0.19 0.96 0.92 0.09 -0.17 0.19 0.15 3.67 1.25 0.11 0.11 0.90 0.03 0.10 -0.20 0.33 <0.01* 0.80 0.94 0.14 DASH= Disability of Arm, Shoulder, and Hand Questionnaire Immediate change in self report of clinical pain following NDI obtained from mechanical visual analog score of current pain prior to neurodynamic intervention (NDI) and immediately following NDI Baseline expectation obtained from expectation portion of the PCOQ *= significant at p<0.05

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75 CHAPTER 7 DISCUSSION Believability of Placebo We have proposed a m odel for the mechan istic study of MT. The model allows visualization of the potential m echanisms behind MT (as supporte d by the current literature) and provides a framework for the design of future studi es. The model pathway of the current study is visualized in Figure 7-1. As previously discussed, a weakne ss of the current mechanistic literature of MT is the failure to adequately account for nonspecific effects such at placebo and expectation. A validated placebo does not curren tly exist for MT. In fact, many prior placebo controlled studies of MT have made use of placebos of unknown validity. For example, prior efficacy studies have compared MT to potentiall y nonsimilar placebo interventions such as sham laser (Preyde, 2000) or sham ultrasound (Deyle et al., 2000). The use of a noncomparable placebo may be invalid as participants may not be as likely to believe the placebo is an actual treatment or may have lower exp ectations for the placebo th an for the studied MT technique. While not studied ex tensively in MT, the believability and individual expectation of a placebo are important considerations in studies of interventions dire cted at pain. Similar to MT, acupuncture is an alterna tive therapy for pain which appears to provide an easier model for a placebo and, in fact, a placebo ac upuncture technique has been de veloped and validated (Pariente et al., 2005). Placebo has been studied more extensively in the acupuncture literature and this body of work may have applicabil ity to MT. Functional imaging studies of acupuncture have noted significant overlap in brain activity between actual acupuncture and placebo acupuncture in which subjects believe they are receiving real acupuncture (Pariente et al., 2005). In contrast, both are dissimilar from placebo ac upuncture in which subjects do not believe they are receiving actual treatment. Furthermore, clinical outcomes in acupuncture studies are associated with the

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76 participants expectations (Kalauokalani et al., 2001;Linde et al., 2007). One study noted no difference between actual and placebo acupuncture in analgesic effect; however, subjects who believed they had received the actual acupuncture treatment expe rienced significan tly less pain than those believing they had received the pl acebo (Linde et al., 2007). Collectively, these studies suggest the importance of expectation and believability of a given intervention in a placebo controlled study for complim entary and alternative medicine which is likely applicable to MT. The indirect NDI used in our study a ppears to be a valid placebo in the sense that participants receiving either te chnique had similar beliefs rega rding their random assignment of intervention. Subsequently, participants in our study accepted the indirect NDI as an active treatment at the same rate as the direct NDI. Interestingly, though not si gnificantly different, a greater percentage of particip ants receiving the direct NDI reported believing they were receiving the indirect NDI. We did not assess perceived group assignment until the 3 week time point of the study. Future studies may wi sh to assess perception of group assignment immediately following a brief demonstration of th e assigned technique at the initial visit. Quantification of perception at ba seline would allow the use of this variable in a regression model as a predictor of future pain or func tional outcomes. The design of our study did not allow such an analysis. In addition to the appare nt believability of the indirect technique, the expectations for the effectiveness of each interv ention were similar. Specifically, individual baseline expectation for pain following participat ion in the study was similar at baseline and after the participant received a brief demonstration of their assigned interven tion. To our knowledge, longitudinal studies of change in expectation have not been pe rformed. While expectation is associated with clinical outcomes, the most in formative time point to quantify expectation has not been established. Not only did we observe no between group differences in expectation at

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77 baseline (with presumed lack of specific know ledge of the intervention) and following brief exposure to the intervention, but we also observed a lack of significant main effect between the two time points. Subsequently, a significant change was not observed at baseline or following exposure to the intervention and this suggests that the particul ar NDI technique used in the current study may not change preconceived expectation. The resu lts of our study indicate that our indirect NDI technique had si milar believability and created similar expectations for pain outcomes as the direct NDI in part icipants presenting with CTS. Treatment Effects A second goal of our study was to compare the outcom es in pain and function associated with the direct NDI and the indi rect NDI. Prior studies attempti ng to validate a placebo for MT have emphasized the identification of an in ert placebo (Hawk et al., 2002;Hawk et al., 2005;Vernon et al., 2005); however, such criteria may be inappropriate as the placebo literature suggests a robust effect of placebo on pain (Price et al., 2007;Vase et al., 2002;Vase et al., 2003). Clinical studies suggest the same may occur in MT. For example, placebo controlled trials of MT have demonstrated a str onger effect of MT over the placebo group; however, both the intervention and the placebo group have show n significant improvement over nontreatment group (Hawk et al., 2005;Licciardone et al., 2003). The prior st udies suggest an appropriate placebo for MT will likely have a significant in fluence on outcomes and we wished to observe how our indirect NDI compared to the direct NDI. Response to Experimental Pain First we observed the perception of experim e ntal pain (QST) and how this differed by intervention. The QST protocols we used in th is study includes standard noxious thermal stimuli which have been associated with activity in the dorsal horn of the spinal cord (Craig & Andrew, 2002;Duggan et al., 1990;Jeftinija & Urban, 1994). Subsequently, a benefit of this assessment

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78 over clinical pain assessment is a controlled painful stimulus to which altered pain perception is suggestive of a specific spinal cord mediated effect of MT. In a prior study, we observed hypoalgesia to A fiber mediated pain perception at both 47 and 49 C associated with MT; however, the resultant hypoa lgesia did not differ from particip ants riding a stationary bike or performing lumbar range of motion exercises (Geo rge et al., 2006). In the present study, we observed no group dependent or main treatment effects of NDI on pain perception at these temperatures. Similar to our prior studies (George et al., 2006;Bial osky et al., 2008), we observed a cfiber mediated hypoalgesia in resp onse to MT. Interestingly, the effect was not observed until the three week assessment a nd was dependent upon group assignment. These findings differ from our prior fi ndings in that our previous studies have included only one session and noted immediate altera tions in cfiber mediated pa in perception (Bialosky et al., 2008;George et al., 2006). A poten tial explanation for the delaye d c-fiber mediated hypoalgesia is the difference in biomechanical features of the techniques between our studies. Our pilot studies used a high velocity, low amplitude form of MT. The current study used a slower velocity MT. Several studies have observed greater neurophysiological responses associated with higher velocity and/or more forceful MT (Pickar et al., 2007;McLe an et al., 2002;Sung et al., 2005). A plausible explanation is that the biomechanical parame ters of the technique used in our first 3 studies produces more immediate neur ophysiological responses than the technique in the current study. Additionally, two of our three prior studies incl uded only healthy participants while the current study included individuals with a minimum 12 week history of CTS. Changes in cfiber mediated pain perception in response to experimental pain ar e plausibly more difficult to affect in individuals experiencing chronic clinical pain in comparison to the healthy participants in our earlier studies.

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79 In the current study, individuals receiving th e direct NDI demonstr ated a significant decrease in cfiber mediated pain perception immediately following the intervention at the 3 week follow up, while those receiving the indire ct technique demonstr ated a trend toward increased pain perception. A reduction of cfiber mediated pain associated with MT has been a consistent finding across our studi es and represents a potential mechanism for the effectiveness of MT in the treatment of musculoskeletal pai n. The cfibers have been implicated in the progression of acute pain to chronic pain and in the maintenance of chronic pain (Rygh et al., 2005). Subsequently, interventions effective in al tering cfiber mediated pain have potential benefits in halting the progression of acute pain to chronic pain or in the treatment of chronic pain. The collective results of our studies suggest that greater cfiber mediated hypoalgesia to QST may be observed with MT in comparison to other interventions and these findings are generalized across different types of MT. Specific to the present study, greater cfiber mediated hypoalgesia was observed in partic ipants with CTS receiving the direct NDI in comparison to those receiving the indirect NDI. Implications to the Model of the Mechanistic Study of MT Using the fram ework of the model, these finding s suggest a potential spinal cord mediated effect of MT. Specifically, the associated res ponse of diminished temporal summation suggests a dorsal horn mediated hypoalgesic effect through the cfibers which differs significantly between the direct and indirect NDI. This finding adds further validity to the proposed placebo in that the direct techniqu e provided greater hypoalgesia th an the indirect technique. Subsequently, the indirect technique appears to meet the criteria fo r an appropriate placebo as it is not distinguishable from the direct technique does not alter expectatio n differently than the direct technique, and has a signifi cantly different effect on cfiber mediated hypoalgesia. These

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80 findings suggest that the indirect NDI used in this study may be an appropriate placebo for further studies of potential supraspinal effects of MT. Clinical Pain and Symptoms Response We also studied the effects of NDI on self report of clinical pain and sym ptoms. We assessed an immediate effect at base line, an immediate effect at disc harge, and the change in self report which occurred over 3 weeks. We found an immediate effect of NDI on self report of CTS pain at both evaluation and 3 week follow up which was not dependent upon group assignment. Additionally, an immediate effect of NDI on self report of symptoms (tingling/numbness) was observed at 3 weeks and this too was independent of group assignment. Interestingly, the participants in our study did not experience a si gnificant reduction in their self report of CTS pain or symptoms over the three week period of the study. Subsequently, both the direct and indirect NDI appear to be effective in producing a tr ansient decrease in pain over multiple sessions and in symptoms over a follo w up session which did not correspond to a lasting change in pain or symptoms. These findings suggest that NDI is accompanied by immediate, transient decreases in clinical pain and sympto ms which occur regardless of the biomechanical properties of the given intervention; however, are in contrast to re sponses to experimental pain in which responses were dependent upon the specif ic technique. Despite the hypoalgesic response to both experimental and clinical pain, longitudi nal complaints of pain and symptoms were not altered by participation in this study. These findings are in contrast to others who observed significant decreases in pain and symptoms asso ciated with NDI (Akalin et al., 2002;Rozmaryn et al., 1998;Pinar et al., 2005). One possible explanation for the lack of a lasting change in pain or symptoms in the participants in our study ma y be the length of our follow up period. Prior studies have observed QST to be predictive of future pain response (Schiff & Eisenberg, 2003;Hartrick et al., 2004;Sterling et al., 2005;Rudin et al., 2008). For example, (Rudin et al.,

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81 2008) observed preoperative pain sensitivity to QST to be predictive of post operative pain intensity. Group dependent treatment effects were not observed in pain perception to QST in our study until the discharge visit. NDI may require multiple sessions in order to initiate the neuroplastic changes associated with lessening of temporal summation. Longer follow up than the 3 weeks in the current study may be necessary to observe significant changes in self report of CTS pain in individuals receiving NDI. Additiona lly, our study differed from other studies of the effectiveness of NDI in th e treatment of CTS in that ot her studies were conducted in a clinical setting using participants seeking or referred for treatme nt (Akalin et al., 2002;Rozmaryn et al., 1998). In contrast, our study occurred in a research setting with participants responding to requests for research participants. Although specula tive, the expectations of our participants may have been significantly different than individuals partic ipating in a study as part of their normal clinical care. Furthermore, the participants in our study were informed that they would receive either the direct or indirect intervention while prior studies offered usual care (Akalin et al., 2002;Rozmaryn et al., 1998;Pinar et al., 2005) Prior placebo controlled studies have observed a greater treatment effect when placebo is tested specifically rather than included as a control (Vase et al., 2002). Subsequentl y, the participants awareness of the potential to receive an indirect technique may have lessened the magnitude of pain relie f in comparison to other studies without the known possibili ty of receiving a placebo. An inte resting observation is that 53% of the participants in our study (i ncluding 63% of the participants who received the direct NDI) reported believing they had received the indir ect technique. We only assessed perceived group assignment at the end of our study and are therefor e, unable to determine if perception of group assignment was causative of clinical pain response or vice versa. Indivi duals receiving NDI in a clinical setting would lik ely perceive a direct intervention at a higher rate than we observed. In

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82 summary, we observed transient de creases in pain and symptoms associated with NDI which were not dependent upon group placement. The tr ansient changes combined with the lack of lasting changes in CTS pain and symptoms s uggests that future studies may require longer follow up period and perhaps alter the instructional set provided to participants to maximize the magnitude of potential n onspecific effects. Finally, in contrast to what was observed for pain, we observed a main treatment effect for function which was not dependent upon group assignment. Specifically, we observed a significant improvement in self report of function as quantified by the DASH functional questionnaire over three week wh ich did not differ by direct or indirect NDI. Our results are similar to other studies which have observed a significant improvement in function associated with NDI (Pinar et al., 2005;Akalin et al., 2002;Rozmaryn et al., 1998). Interestingly, the biomechanical features of the NDI did not influen ce the outcome. A general improvement in self report of function was observed whether the particip ant received the direct or the indirect NDI. These findings are similar to what was observed in immediate effect of NDI on self report of CTS pain in that the use of NDI appeared to be more important than the specific biomechanical mechanism. Furthermore, these findings suggest something other than a biomechanical effect is behind the mechanisms of NDI in the treatment of CTS. Implications to the Model of the Mechanistic Study of MT Similar to prior studies (George et al., 2006;Mohammadian et al., 2004;Vernon, 2000;Vicenzino et al., 2001), we observed immediate hypoalgesia of clinical pain associated with MT. The current study adds to this body of literature in that hypoalgesia has been associated with MT (George et al., 2006;M ohammadian et al., 2004;Vernon, 2000;Vicenzino et al., 2001); however, to our knowledge, prior stud ies have not documented hypoalgesia associated with the particular MT used in the current study (NDI). The model stresses that a biomechanical

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83 force from MT initiates a cascade of neurophysiol ogical effects. The cu rrent study suggests that the specific parameters of the bi omechanical force are irrelevant in the transient improvements in pain and symptoms associated with NDI in indivi duals with CTS. Specifically, the participants in our study experienced transient hypoalgesia whethe r they received a direct or an indirect NDI. The long term (3week) outcomes in our study were significant only for improvements in function as no significant changes o ccurred in self reports of pai n. Changes in function were not dependent upon group assignment and further sugge st a nonspecific biomechanical effect of NDI in the mechanism behind th e clinical outcomes. Predictors of Outcomes Predictors of Pain and Disability The third goal of our study was to assess indi vidual com ponents of the model as to their ability to predict 3 week outcomes of pain and disability. We observed baseline pain, immediate hypoalgesic response, and baseline expectation for pain at 3 week s all significantly predictive of clinical pain at 3 weeks. In fact, the final parsimonious model accounted for 40% of the variance in self report of clinical pain at 3 weeks. Ou r observation of expectation as predictive of 3 week clinical pain ratings is consistent with other st udies of musculoskeletal pa in in which expectation was predictive of post surgical pain (Pollo et al., 2001), functional outcom es following total joint replacement (Mahomed et al., 2002) and rotator cuff repair (Henn, III et al., 2007), and low back pain treatment outcomes (Goldstein et al., 2002 ;Heymans et al., 2006;Kapoor et al., 2006;Myers et al., 2008). Specific to MT, a smaller number of studies have observed an association between expectation and outcomes (Kala uokalani et al., 2001;Bialosky et al., 2008). The current study was consistent with prior findings and suggests that expectation predicts a significant amount of the variance in 3 week pain outcomes when controlling for baseline pain and immediate hypoalgesic effect of treatment. Interestingly, expectation was a significa nt predictor of pain

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84 while group assignment was not. Subsequently, expect ation is suggested to pl ay a greater role in the outcomes associated with MT than the actual mechanical properties of the MT. Additionally, we were particularly interested in the predictive value of the imme diate clinical pain response to MT. Prior studies of placebo have observed an increased magnitude of the placebo hypoalgesia if the intensity of the stimulus is surreptitiously lessened immediately following the application of the placebo (Price et al., 1999;Colloca & Benedetti, 2006). Th e participants in our study experienced a main treatment effect of reduced clinical pain immediat ely following the initial NDI session independent of group assignment. The prognostic value of the immediate clinical pain hypoalgesic response may indicate a dire ct influence of MT on neuroplastic changes associated with pain (Boal & Gillette, 2004) or a conditioning res ponse related to placebo (Colloca & Benedetti, 2006;Pric e et al., 1999). The design of our study does not allow more than speculation on the specific mechanism of the prognostic value of immediate clinical pain hypoalgesic effect. Implications to the Model of the Mechanistic Study of MT Nonspecific effects such as expectation ha ve been im plicated in the outcomes of musculoskeletal pain conditions (Myers et al., 2008;Goldstein et al., 2002;Mahomed et al., 2002) and studies have begun to associate expectation with the outcomes follo wing MT (Kalauokalani et al., 2001;Bialosky et al., 2008) The current study provides st ronger evidence of a causal relationship between expectation and the outcomes associated with MT in that we observed a longitudinal relationship in indivi duals experiencing CTS. Clinical Implications The current study offers several im plications for the clinical use of NDI in the treatment of CTS. First, perception of experimental pain was significantly lessened at the three week follow up session in participants receiving the direct NDI technique. MT has been suggested to exert an

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85 effect upon the neuroplastic changes associated with pain in the central nervous system (Boal & Gillette, 2004). The lessening of temporal su mmation as observed in the present study is consistent with our prior studies (Bialosky et al., 2008;George et al., 2006) and suggests a potentially similar mechanism. Specifically, cent ral sensitization is ch aracterized by allodynia and hyperalgesia and hypothesized as instrumental in the maintenance of pain conditions (Rygh et al., 2005). Temporal summation serves as a proxy measure of central sensitization and our finding of lessened temporal summation associat ed with the direct NDI suggests a potential action upon the neuroplastic changes associated w ith pain. The results of our study suggest the clinical use of NDI may require techniques which provide maximal force and movement to the median nerve in order to affect the neuroplastic changes associat ed with pain in individuals presenting with CTS. Additiona lly, neuroplastic changes associat ed with NDI to the median nerve may not become apparent until several week s and contrasts to our prior studies of MT to the low back in which reductions in temporal summation were observed immediately following 1 session (George et al., 2006;Bialos ky et al., 2008). Subsequently, clinicians using NDI in the treatment of CTS could possibly expect a longer time period to achieve treatment goals than what might be expected with the use of higher force and velocity MT to treat low back pain. A second clinical implication of the current study is the transient reduction observed in CTS pain and symptoms immediately following the NDI independent of group assignment. Prior studies have observed similar outcomes a ssociated with MT of varying biomechanical features (Hessell et al., 1990;Ke nt et al., 2005;Ngan et al., 2005) We observed similar findings in that pain and symptoms imme diately decreased regardless of whether the NDI was applied in a means to maximally stress and move the median nerve or in a way to re duce the stresses to the nerve. This finding adds to the growing body of literature suggesting outcomes in MT are

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86 dependent upon identifying indivi duals likely to respond rather than the identification of a specific dysfunction and specific techniques. Concern has been expressed concerning the potential for adverse effects of NDI due to biomechanical stress to the nerves (Shacklock, 2005). Our findings suggest similar transient decreases in clinical pain and symptoms related to CTS may be observed regardless of the biomechanical parameters of the intervention. Subsequently, clinicians concerned for the forces applied with traditional median nerve biased NDI in the treatment of CTS may achieve si milar within treatment session results through the use of a technique designed to lessen the mechanical strain. A third clinical implication of the current study is the 3 week effect on measure of CTS pain and disability. Clinical pain reports did not change significantly from the initial visit to the 3 week follow up. These findings suggest a treatmen t protocol of splints and NDI for 3 weeks is inadequate to observe a significan t lasting change in clinical pa in in individuals with chronic CTS. Subsequently, in individuals with a grea ter than 12 week history of CTS, health care providers may expect no significan t changes in clinical pain over the first three weeks with the use of NDI and splints or should consider the add itional treatment options if a lasting decrease in pain is a treatment priority for the first three weeks. The nonCTS specific functional questionnaire (DASH Questionnaire) demonstrated a significant improvement over three weeks which was not observed in the CTS specific func tional questionnaire (Boston Questionnaire). Despite the significant changes observed in DASH scores, the mean change was 5.43. A clinically meaningful change in DASH score has been suggested as 10 (Gummesson et al., 2003) so our findings are of questionable clinical value. Similar to pain, our findings suggest that 3 weeks is an inadequate time to observe meani ngful changes in functi on in individuals with greater than 12 week history of CTS receiving MT and splints. Clinicians intending to use these

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87 techniques should be aware of this when develo ping a plan of care for individuals with CTS and should consider alternative treatments if meaningf ul reductions in disability are desired within a 3 week period. A final clinical implication is the value of expectation and immediat e hypoalgesic effect of clinical pain for predicting pain at 3 weeks. Expectation has been suggested as pertinent in the mechanisms behind the outcomes of MT (Bialosky et al., 2008;Kalauokalani et al., 2001) and the current study re-enforces this notion. Clinic ians seeking prognostic indicators may wish to quantify expectation for MT on the initial visit. A patient with higher expectations may strengthen the clinical decision to include MT in the treatment pl an. Conversely, in patients with lower expectations for MT, the clinician may wish to consider an alternative form of treatment. Furthermore, our study suggests an immediate hypoalg esic response to NDI in individuals with CTS may serve as a good prognostic indicator. C linicians may wish to quantify clinical pain immediately prior to and following NDI in indi viduals with CTS. Based on our observations, NDI may be more effective in individuals e xperiencing an immediate hypoalgesic effect. Subsequently, future researchers seeking to iden tify individuals likely to respond favorably to MT may wish to include expectation and an immediate hypoalgesic e ffect of clinical pain in the tested variables. Limitations There are several lim itations to the current study. While not intentional, our sample consists only of women. CTS is more common in females (Bongers et al., 2007;Tanaka et al., 1994;McDiarmid et al., 2000), so a higher freque ncy of women to men was expected; however, with no males represented, the results may not be applicable in men experiencing CTS. A second limitation is the lack of a control group. We are able to co mpare the findings of the direct to the indirect NDI; however, we are unable to compare either to natural history. Subsequently,

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88 we can not say that our results differ significan tly from what would have occurred with no intervention. The lack of a cont rol group also prevents us from commenting on the effect size of the indirect intervention in situations where th e groups differ. For example, we observed the direct NDI group to experience si gnificantly less pain perception to cfiber mediated pain at 3 week follow up than the indirect NDI group; howev er, we can not ascertain the magnitude of the effect of the indirect NDI in comparison to natu ral history. A further lim itation of this study is our use of the indirect NDI as a placebo. The magnitude of placebo has been observed to be dependent upon a number of factors (Price et al., 1999). In particular, the instructional set given with placebo may influence the magnitude. Spec ifically, the instruction that a placebo is a powerful pain killer has been shown to signifi cantly enhance the effect and particularly in studies where participants are not aware they ma y be receiving a placebo (Vase et al., 2002;Vase et al., 2003). The participants in our study were aware they ha d the potential to receive an indirect technique and received no instructional set specific to the pain relieving ability of the NDI. Subsequently, the magnitude of the effect may not have been as high as possible if instructional set was altered. Finally, our i ndirect technique was based on biomechanical principals to minimize the force and movement through the median nerve in comparison to the direct technique (Coppieters & Butler, 2007;C oppieters & Alshami, 2007). We did not specifically measure the movement or forces asso ciated with either technique and subsequently, are unable to quantify the extent to which they differed. Future Directions The present study sets important groundwork for future studies. W e have developed a placebo model for NDI which is believable and produ ces similar expectations as the direct NDI. Future studies are now necessary to clarify the treatment effe ct. The placebo (indirect NDI) differentiated from the direct NDI in this study in the associated experimental pain perception

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89 observed at 3 weeks. Future st udies should provide longer follow up in order to determine if the group differences in experimental pain percep tion correspond to changes in clinical pain perception. Future studies should also include a control group to allow comparison to natural history for outcomes in which the direct and indirect NDI do not differ and to allow for determination of the magnitude of placebo effect in outcomes for which they do differ. Once an adequate placebo model is developed for MT, future studies may also wish to test the placebo alone and include in structional sets sugge sting strong analgesic properties as these have been shown to increase the magnitude of the placebo effect (Vase et al., 2002;Vase et al., 2003). Such studies will provide a truer estimate of the effect size of placebo and are likely more representative of the effect obs erved during clinical care. Finally, future studies should consider the potential multiple mechanisms of MT. The described model provides a framework for c onsideration when desi gning studies of the mechanisms of MT. The mechanisms behind MT are likely multifactorial. Continued attempts should be made to verify individual aspects of the model while continuing to account for others. We believe a priority is to determine the influe nce and magnitude of nonspecific effects on the outcomes associated with MT. Nonspecific e ffects have a potential role in many of the neurophysiological effects associat ed with MT (Figure 7-2) a nd have not been adequately accounted for in prior literature. Once the influence of nonspecific effects is determined, other pertinent factors may be established.

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90 Figure 7-1. Model pathway of disse rtation study. Spinal cord medi ated effect is inferred by the measurement of an associated response of lessening of temporal summation. Also note, that a supraspinal mediated effect is inferred by the measurement of an associated response of expectation. Note, that consideration is not given in the design of this study to pot ential peripheral effect ACC = anterior cingular cortex; PAG = periaqueductal gray; RVM = rostral ventromedial medulla

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91 Figure 7-2. Model depicting neur ophysiological effects also associated with placebo. Figure emphasizes that many potential mechanisms behind the clinical effectiveness of manual therapy may also be attributed to placebo. An emphasis of future studies should be to determine the magnitude of th e placebo effect in the outcomes of manual therapy. ACC = anterior cingular cortex; PAG = periaqueductal gray; RVM = rostral ventromedial medulla

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103 BIOGRAPHICAL SKETCH Joel Bialosk y graduated from Ithaca college with a bachelors degree in physical therapy in 1990. He received a masters degree in musculoskeletal physical therapy from the University of Pittsburgh in 1998. He received his PhD in Re habilitation Science from the University of Florida in 2008.